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INSPIRE: Raltegravir ( Isentress ) Pilot Study in Relapsing MS

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Page 1: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

INSPIRE Raltegravir (Isentress) Pilot Study in Relapsing MS

Dr Jean-Martin Charcot

Viruses and MSRabies virus Dick GW et al Br Med J 1958

Measles virus Reed D et al Arch Neurol 1964

Varicella-Zoster Virus (VZV) Ross CA et al BMJ1965

Mumps virus Millar JH et al Br Med J 1971

Rubella Horikawa Y et al Lancet 1973

Flaviviridae (Tick borne encephalitis) Salmi AA Ann Clin Res 1973

Herpes Simplex Virus Ito M et al Proc Soc Exp Biol Med 1975

Epstein-Barr Virus (EBV) Sumaya CV Arch Neurol 1980

Coronavirus Gerdes JC et al Adv Exp Med Biol 1981

HTLV-1 Newton M et al Lancet 1987

Human Herpes Virus 6 (HHV-6) Sola PJ et al Neurol Neurosurg Psychiatry 1993

JC polyomavirus Boerman R H Acta Neurol Scand 1993

Human Endogenous Retrovirus Perron H et al Res Virol 1992 Garson J A et al Lancet 1998 Christensen T et al Acta Neurologica Scandinavica 2000

First mention on pubmedCourtesy of Ute-C Meier

Are human endogenous retroviruses pathogenic An approach to testing the hypothesis

BioEssaysVolume 35 Issue 9 pages 794-803 17 JUL 2013 DOI 101002bies201300049httponlinelibrarywileycomdoi101002bies201300049fullbies201300049-fig-0001

Preacutesentateur
Commentaires de preacutesentation
131313Typified retroviral life cycle Retroviral infection begins with virion attachment usually to a cellular receptor followed by fusion of virion and plasma membranes In the cytosol the two copies of genomic RNA are reverse‐transcribed and following capsid disassembly they form the pre‐integration complex which then enters the nucleus The reverse‐transcribed cDNA copy is then integrated into the host cell DNA and from that point this provirus behaves analogously to a cellular gene in that cellular division of an infected cell will create two infected daughter cells Expression of mRNA from the provirus provides both new genomic RNAs as well as synthesis of viral proteins which are all then assembled into new virions These are then released from the plasma membrane and undergo maturation before they infect the next cell1313copy This slide is made available for non-commercial use only Please note that permission may be required for re-use of images in which the copyright is owned by a third party

How HERVs may induce autoimmune response

People living with MS (Total)

People living with

HIV(Total)

MS PrevalencePer 100000

HIV Prevalence

Per 100000

USA 400000 1200000 135 508

Canada 65000 60000 240 222

France 80000 130000 80 263

Germany 122000 49000 149 69

Netherlands 16000 18000 100 127

UK 85000 75000 110 137

Denmark 7500 6000 122 125

How many cases of HIV and MS have been reported

bull 1989 Berger reported 7 cases of an MS-like complex in HIV patients but none were followed up or apparently treated with ARVs

bull 2004 Corral reported a case of focal monophasic leukoencephalopathy in an HIV patients No details were provided on Follow-up or treatment

bull In all about 10 cases have been referred to in the medical literature in 30 years Six of these are questionable

What do cohort studies show

bull A single study in Danish National Registry of Patients (Nexo Pederson Sorensen and Koch-Henriksen Epidem 2013242 332-333) Cohort from 1994-2011

bull 5018 first time HIV diagnosis followed for 31875 person yearsbull 50194 controls matched for age and sex followed for 393871

person yearsbull One person with HIV developed MS which was a non-

significant relative risk of around 03 (95CI 004-22)

bull Interesting but not convincing

What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral

therapybull They affect similar demographic populations in western

countriesbull Literature consists of 950000 peer reviewed publications on

HIVAIDS and gt270000 peer reviewed papers on MS They are two of the most studied and documented conditions in medical science

bull Only one case of a patient with both MS and HIV documented as treated with anti-retroviral therapy (Eur J Neurol 201118110-111)

bull Unable to find HIV patients who have MS in major HIV clinics in Europe US and Australia

bull Unusual to find no documentation or company advice for treating HIV patients who have MS with DMT especially interferon

Methodsbull Hospital Episode Statistics of all 55 million people in

the UK from 1999 to 2011bull Any contact with healthcare system including

admissions day cases and deaths Multiple contacts are linked to individual record

bull Database analyzed at Unit of Health-care Epidemiology Oxford University

bull Exposed (HIV) and unexposed matched on week of first contact age area of residence and socio-economic status

bull Relative risk calculated using MS as outcome (OHIVEHIV)(OCCECC)

Age distribution of people entering the HIV cohort the percentage female and the number of people entering the reference cohort1

Age (yrs) N entering HIV cohort

( of total) female N entering the

reference cohort 0-4

139 (07) 446 137461

5-9

168 (08) 452 172624 10-14

138 (07) 572 138003

15-19

173 (08) 590 216875 20-24

653 (31) 444 267177

25-29

2136 (101) 439 340834 30-34

4066 (192) 369 459410

35-39

4792 (226) 296 541994 40-44

3701 (175) 249 496704

45-49

2228 (105) 206 433194 50-54

1293 (61) 186 446510

55-59

776 (37) 174 482105 60-64

480 (23) 163 506958

65-69

274 (13) 212 503916 70-74

98 (05) 214 508750

75-79

37 (02) 270 485042 80-84

22 (01) 227 353716

85+

33 (02) 455 252837

All ages 21207 (100) 302 6744110

Following 21207 patients with HIV for 152618 person years and 6744301 controls for 42148179person years to see who would develop MS On average the follow-up was 7 years

exposure outcome MS in HIVMS in

Controls

rate ratio(Relative

Risk)Protective

Effect low CI upr CI chi-sq p-value

HIVmultiple sclerosis 7 183 038 gt62 015 079 639 0011

NHS Data on UK Healthcare events 1999-2011

Sheet1

NHS Cohort gt One year after Exposure (HIV) Contact

Exposure OutcomeMS in

exposedMS in

Controls

Rate ratio (Relative

Risk)Protective

Effect Low CIHigh

CI Chi-sqP

value

HIVMultiple Sclerosis 4 158 022 80 007 065 81 0004

Assuming that HIV diagnosis was made on first contact assessmentof cohort after one year would probably account for effect of HIVtherapy on all exposed If no effect of HIV treatment then expect noreduction in Relative Risk

Cohort of HIV and Autoimmune Diseases-all casesexposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-valueHIV Addisons disease 1868 35 35 1008 7 1408 27231 0HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0HIV Coeliac disease 8127 7 156 045 018 092 423 00396HIV Crohns disease 12300 31 349 089 06 126 034 05606HIV ITP 4694 43 78 552 399 745 15331 0HIV Myxoedema 181453 85 1577 054 043 067 331 0HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492HIV Polymyositis 631 10 15 691 33 1279 4409 0HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381HIV Psoriasis 18690 65 473 137 106 175 624 00125

HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113HIV Scleroderma 1930 1 25 04 001 221 042 05189HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929

all

aged 0-14

15-34

35-54

55-64

65+

interval lt1yr

1-4

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 830 15 15 998 556 1655 11032 0
HIV Ankylosing spondylitis 1995 2 56 035 004 128 174 01866
HIV Autoimmune haemolytic anaemia 796 4 09 423 115 1088 687 00088
HIV Chronic active hepatitis 340 3 06 537 11 1582 668 00098
HIV Coeliac disease 3639 6 79 076 028 165 025 0616
HIV Crohns disease 5695 13 167 078 041 133 061 04355
HIV ITP 2142 15 32 473 265 783 4024 0
HIV Myxoedema 77911 43 698 062 045 083 992 00016
HIV Pernicious anaemia 7615 3 37 082 017 239 001 09271
HIV Polymyositis 302 8 08 1018 435 2031 5584 0
HIV Primary biliary cirrhosis 919 0 12 0 0 317 038 05375
HIV Psoriasis 8090 27 217 125 082 182 108 02985
HIV Rheumatoid arthritis 23991 17 266 064 037 102 314 00763
HIV Scleroderma 911 1 12 085 002 475 009 07639
HIV Sjogrens syndrome 1836 0 21 0 0 176 121 02704
HIV Systematic lupus erythematosus 1703 6 5 121 044 263 006 0813
HIV Thyrotoxicosis 11529 14 155 09 049 151 007 0797
HIV Ulcerative colitis 9323 30 282 106 072 152 006 08069
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 352 17 09 1992 1147 3236 27362 0
HIV Ankylosing spondylitis 767 1 11 088 002 493 012 07296
HIV Autoimmune haemolytic anaemia 306 7 04 1792 714 3736 9338 0
HIV Chronic active hepatitis 118 6 02 3067 1103 6878 13684 0
HIV Coeliac disease 1206 0 16 0 0 226 079 03752
HIV Crohns disease 1896 15 5 3 167 496 1787 0
HIV ITP 728 22 21 1068 665 1629 17803 0
HIV Myxoedema 28047 13 163 08 042 136 048 04889
HIV Pernicious anaemia 2773 1 09 106 003 593 021 06495
HIV Polymyositis 113 1 01 785 02 4461 108 02995
HIV Primary biliary cirrhosis 308 1 02 646 016 3624 077 03817
HIV Psoriasis 3072 22 61 361 226 548 3875 0
HIV Rheumatoid arthritis 9101 11 69 16 08 286 189 01697
HIV Scleroderma 294 0 03 0 0 1121 009 07682
HIV Sjogrens syndrome 565 2 05 436 053 1581 235 01253
HIV Systematic lupus erythematosus 608 1 12 082 002 461 007 07944
HIV Thyrotoxicosis 4243 5 43 118 038 275 001 09048
HIV Ulcerative colitis 3123 17 75 229 133 367 1101 00009
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 821 1 01 78 02 4358 108 02995
HIV Ankylosing spondylitis 1672 0 04 0 0 887 002 08966
HIV Autoimmune haemolytic anaemia 1142 1 02 418 011 2333 028 05943
HIV Chronic active hepatitis 300 1 01 1674 042 9401 323 00721
HIV Coeliac disease 3003 0 04 0 0 836 001 09297
HIV Crohns disease 4249 1 07 14 004 779 006 07988
HIV ITP 2750 4 05 823 224 2109 1866 0
HIV Myxoedema 111802 12 124 097 05 169 0 09748
HIV Pernicious anaemia 13040 0 15 0 0 253 063 04283
HIV Polymyositis 333 2 0 4371 527 15913 4594 0
HIV Primary biliary cirrhosis 1120 0 01 0 0 3586 153 02162
HIV Psoriasis 6100 2 15 131 016 472 0 09797
HIV Rheumatoid arthritis 30228 7 41 172 069 355 146 02269
HIV Scleroderma 909 0 01 0 0 3312 135 02449
HIV Sjogrens syndrome 1883 0 02 0 0 1969 052 04704
HIV Systematic lupus erythematosus 1056 0 02 0 0 1993 053 04648
HIV Thyrotoxicosis 15247 4 19 21 057 538 134 0247
HIV Ulcerative colitis 7697 5 16 317 103 74 541 002
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 326 3 03 893 183 2632 138 00002
HIV Ankylosing spondylitis 971 0 14 0 0 272 054 04621
HIV Autoimmune haemolytic anaemia 261 0 03 0 0 1419 022 06407
HIV Chronic active hepatitis 143 1 01 733 018 415 096 03272
HIV Coeliac disease 1492 0 11 0 0 331 034 05598
HIV Crohns disease 1923 1 24 042 001 234 032 05686
HIV ITP 712 3 09 329 068 964 274 00976
HIV Myxoedema 30859 11 201 055 027 098 368 00552
HIV Pernicious anaemia 1970 1 13 078 002 437 004 0844
HIV Polymyositis 135 2 01 1436 172 5288 1309 00003
HIV Primary biliary cirrhosis 377 1 02 575 015 3225 061 0435
HIV Psoriasis 3545 5 48 104 034 244 002 08955
HIV Rheumatoid arthritis 10250 4 88 045 012 116 214 01439
HIV Scleroderma 463 0 03 0 0 1449 023 06285
HIV Sjogrens syndrome 1053 1 05 2 005 1119 0 09991
HIV Systematic lupus erythematosus 715 0 06 0 0 606 002 0888
HIV Thyrotoxicosis 4076 4 35 115 031 295 0 0988
HIV Ulcerative colitis 3588 8 49 164 071 324 141 02348
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 458 20 2 1017 615 1589 14969 0
HIV Ankylosing spondylitis 1430 1 74 013 0 075 476 00291
HIV Autoimmune haemolytic anaemia 195 9 11 854 385 1655 5027 0
HIV Chronic active hepatitis 126 6 06 1068 385 2391 4141 0
HIV Coeliac disease 2230 5 96 052 017 122 173 01884
HIV Crohns disease 3262 22 203 108 068 164 007 07958
HIV ITP 694 23 44 533 335 806 7409 0
HIV Myxoedema 30770 47 922 051 037 068 2172 0
HIV Pernicious anaemia 1664 3 43 07 014 204 015 07013
HIV Polymyositis 127 3 1 316 064 945 246 01165
HIV Primary biliary cirrhosis 359 1 14 07 002 393 0 09501
HIV Psoriasis 6137 35 30 117 081 162 067 04141
HIV Rheumatoid arthritis 10968 21 365 057 036 088 617 0013
HIV Scleroderma 455 1 17 059 001 331 002 08849
HIV Sjogrens syndrome 995 1 29 034 001 192 068 04097
HIV Systematic lupus erythematosus 1279 7 63 112 045 231 001 09219
HIV Thyrotoxicosis 4589 18 191 094 056 149 002 08979
HIV Ulcerative colitis 5315 34 346 098 068 138 0 09893
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 213 11 1 1186 583 2166 9395 0
HIV Ankylosing spondylitis 486 2 27 074 009 269 002 09025
HIV Autoimmune haemolytic anaemia 66 2 03 627 074 2356 422 00398
HIV Chronic active hepatitis 39 2 02 1257 147 4856 1072 00011
HIV Coeliac disease 909 2 42 047 006 171 071 03994
HIV Crohns disease 2215 7 111 063 025 13 118 02778
HIV ITP 331 11 19 606 3 1098 4019 0
HIV Myxoedema 7241 15 325 046 026 076 896 00028
HIV Pernicious anaemia 472 0 17 0 0 212 089 03468
HIV Polymyositis 32 3 03 1034 203 3306 1533 00001
HIV Primary biliary cirrhosis 59 0 03 0 0 1176 01 07528
HIV Psoriasis 2551 23 109 213 135 32 1253 00004
HIV Rheumatoid arthritis 2238 7 95 073 03 152 043 05128
HIV Scleroderma 89 0 05 0 0 805 0 09596
HIV Sjogrens syndrome 160 0 07 0 0 564 004 08448
HIV Systematic lupus erythematosus 554 3 27 111 023 326 002 0899
HIV Thyrotoxicosis 1784 6 88 068 025 148 062 04293
HIV Ulcerative colitis 2667 15 151 1 056 165 001 09074
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 50 0 0 0 0 8184 44 00359
HIV Ankylosing spondylitis 10 0 0 0 0 71245 3898 0
HIV Autoimmune haemolytic anaemia 24 0 0 0 0 24127 1416 00002
HIV Chronic active hepatitis 17 0 0 0 0 12064 638 00115
HIV Coeliac disease 493 0 03 0 0 1306 017 06837
HIV Crohns disease 651 0 04 0 0 933 003 08691
HIV ITP 207 2 01 139 167 5086 1266 00004
HIV Myxoedema 781 0 05 0 0 704 0 09722
HIV Pernicious anaemia 14 0 0 0 0 84591 4915 0
HIV Polymyositis 4 0 0 0 0 6051 24878 0
HIV Primary biliary cirrhosis 2 0 0 0 0 0 0 0
HIV Psoriasis 357 0 01 0 0 2873 107 03016
HIV Rheumatoid arthritis 109 0 0 0 0 7558 409 00431
HIV Scleroderma 14 0 0 0 0 107299 626 0
HIV Sjogrens syndrome 10 0 0 0 0 396158 22105 0
HIV Systematic lupus erythematosus 64 0 0 0 0 7928 427 00387
HIV Thyrotoxicosis 173 0 01 0 0 3713 159 0207
HIV Ulcerative colitis 504 0 03 0 0 1346 018 06677
Cohort of HIV and Autoimmune Diseases-all cases
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1868 35 35 1008 7 1408 27231 0
HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147
HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0
HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0
HIV Coeliac disease 8127 7 156 045 018 092 423 00396
HIV Crohns disease 12300 31 349 089 06 126 034 05606
HIV ITP 4694 43 78 552 399 745 15331 0
HIV Myxoedema 181453 85 1577 054 043 067 331 0
HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492
HIV Polymyositis 631 10 15 691 33 1279 4409 0
HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381
HIV Psoriasis 18690 65 473 137 106 175 624 00125
HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113
HIV Scleroderma 1930 1 25 04 001 221 042 05189
HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396
HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218
HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879
HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929
Page 2: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Dr Jean-Martin Charcot

Viruses and MSRabies virus Dick GW et al Br Med J 1958

Measles virus Reed D et al Arch Neurol 1964

Varicella-Zoster Virus (VZV) Ross CA et al BMJ1965

Mumps virus Millar JH et al Br Med J 1971

Rubella Horikawa Y et al Lancet 1973

Flaviviridae (Tick borne encephalitis) Salmi AA Ann Clin Res 1973

Herpes Simplex Virus Ito M et al Proc Soc Exp Biol Med 1975

Epstein-Barr Virus (EBV) Sumaya CV Arch Neurol 1980

Coronavirus Gerdes JC et al Adv Exp Med Biol 1981

HTLV-1 Newton M et al Lancet 1987

Human Herpes Virus 6 (HHV-6) Sola PJ et al Neurol Neurosurg Psychiatry 1993

JC polyomavirus Boerman R H Acta Neurol Scand 1993

Human Endogenous Retrovirus Perron H et al Res Virol 1992 Garson J A et al Lancet 1998 Christensen T et al Acta Neurologica Scandinavica 2000

First mention on pubmedCourtesy of Ute-C Meier

Are human endogenous retroviruses pathogenic An approach to testing the hypothesis

BioEssaysVolume 35 Issue 9 pages 794-803 17 JUL 2013 DOI 101002bies201300049httponlinelibrarywileycomdoi101002bies201300049fullbies201300049-fig-0001

Preacutesentateur
Commentaires de preacutesentation
131313Typified retroviral life cycle Retroviral infection begins with virion attachment usually to a cellular receptor followed by fusion of virion and plasma membranes In the cytosol the two copies of genomic RNA are reverse‐transcribed and following capsid disassembly they form the pre‐integration complex which then enters the nucleus The reverse‐transcribed cDNA copy is then integrated into the host cell DNA and from that point this provirus behaves analogously to a cellular gene in that cellular division of an infected cell will create two infected daughter cells Expression of mRNA from the provirus provides both new genomic RNAs as well as synthesis of viral proteins which are all then assembled into new virions These are then released from the plasma membrane and undergo maturation before they infect the next cell1313copy This slide is made available for non-commercial use only Please note that permission may be required for re-use of images in which the copyright is owned by a third party

How HERVs may induce autoimmune response

People living with MS (Total)

People living with

HIV(Total)

MS PrevalencePer 100000

HIV Prevalence

Per 100000

USA 400000 1200000 135 508

Canada 65000 60000 240 222

France 80000 130000 80 263

Germany 122000 49000 149 69

Netherlands 16000 18000 100 127

UK 85000 75000 110 137

Denmark 7500 6000 122 125

How many cases of HIV and MS have been reported

bull 1989 Berger reported 7 cases of an MS-like complex in HIV patients but none were followed up or apparently treated with ARVs

bull 2004 Corral reported a case of focal monophasic leukoencephalopathy in an HIV patients No details were provided on Follow-up or treatment

bull In all about 10 cases have been referred to in the medical literature in 30 years Six of these are questionable

What do cohort studies show

bull A single study in Danish National Registry of Patients (Nexo Pederson Sorensen and Koch-Henriksen Epidem 2013242 332-333) Cohort from 1994-2011

bull 5018 first time HIV diagnosis followed for 31875 person yearsbull 50194 controls matched for age and sex followed for 393871

person yearsbull One person with HIV developed MS which was a non-

significant relative risk of around 03 (95CI 004-22)

bull Interesting but not convincing

What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral

therapybull They affect similar demographic populations in western

countriesbull Literature consists of 950000 peer reviewed publications on

HIVAIDS and gt270000 peer reviewed papers on MS They are two of the most studied and documented conditions in medical science

bull Only one case of a patient with both MS and HIV documented as treated with anti-retroviral therapy (Eur J Neurol 201118110-111)

bull Unable to find HIV patients who have MS in major HIV clinics in Europe US and Australia

bull Unusual to find no documentation or company advice for treating HIV patients who have MS with DMT especially interferon

Methodsbull Hospital Episode Statistics of all 55 million people in

the UK from 1999 to 2011bull Any contact with healthcare system including

admissions day cases and deaths Multiple contacts are linked to individual record

bull Database analyzed at Unit of Health-care Epidemiology Oxford University

bull Exposed (HIV) and unexposed matched on week of first contact age area of residence and socio-economic status

bull Relative risk calculated using MS as outcome (OHIVEHIV)(OCCECC)

Age distribution of people entering the HIV cohort the percentage female and the number of people entering the reference cohort1

Age (yrs) N entering HIV cohort

( of total) female N entering the

reference cohort 0-4

139 (07) 446 137461

5-9

168 (08) 452 172624 10-14

138 (07) 572 138003

15-19

173 (08) 590 216875 20-24

653 (31) 444 267177

25-29

2136 (101) 439 340834 30-34

4066 (192) 369 459410

35-39

4792 (226) 296 541994 40-44

3701 (175) 249 496704

45-49

2228 (105) 206 433194 50-54

1293 (61) 186 446510

55-59

776 (37) 174 482105 60-64

480 (23) 163 506958

65-69

274 (13) 212 503916 70-74

98 (05) 214 508750

75-79

37 (02) 270 485042 80-84

22 (01) 227 353716

85+

33 (02) 455 252837

All ages 21207 (100) 302 6744110

Following 21207 patients with HIV for 152618 person years and 6744301 controls for 42148179person years to see who would develop MS On average the follow-up was 7 years

exposure outcome MS in HIVMS in

Controls

rate ratio(Relative

Risk)Protective

Effect low CI upr CI chi-sq p-value

HIVmultiple sclerosis 7 183 038 gt62 015 079 639 0011

NHS Data on UK Healthcare events 1999-2011

Sheet1

NHS Cohort gt One year after Exposure (HIV) Contact

Exposure OutcomeMS in

exposedMS in

Controls

Rate ratio (Relative

Risk)Protective

Effect Low CIHigh

CI Chi-sqP

value

HIVMultiple Sclerosis 4 158 022 80 007 065 81 0004

Assuming that HIV diagnosis was made on first contact assessmentof cohort after one year would probably account for effect of HIVtherapy on all exposed If no effect of HIV treatment then expect noreduction in Relative Risk

Cohort of HIV and Autoimmune Diseases-all casesexposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-valueHIV Addisons disease 1868 35 35 1008 7 1408 27231 0HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0HIV Coeliac disease 8127 7 156 045 018 092 423 00396HIV Crohns disease 12300 31 349 089 06 126 034 05606HIV ITP 4694 43 78 552 399 745 15331 0HIV Myxoedema 181453 85 1577 054 043 067 331 0HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492HIV Polymyositis 631 10 15 691 33 1279 4409 0HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381HIV Psoriasis 18690 65 473 137 106 175 624 00125

HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113HIV Scleroderma 1930 1 25 04 001 221 042 05189HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929

all

aged 0-14

15-34

35-54

55-64

65+

interval lt1yr

1-4

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 830 15 15 998 556 1655 11032 0
HIV Ankylosing spondylitis 1995 2 56 035 004 128 174 01866
HIV Autoimmune haemolytic anaemia 796 4 09 423 115 1088 687 00088
HIV Chronic active hepatitis 340 3 06 537 11 1582 668 00098
HIV Coeliac disease 3639 6 79 076 028 165 025 0616
HIV Crohns disease 5695 13 167 078 041 133 061 04355
HIV ITP 2142 15 32 473 265 783 4024 0
HIV Myxoedema 77911 43 698 062 045 083 992 00016
HIV Pernicious anaemia 7615 3 37 082 017 239 001 09271
HIV Polymyositis 302 8 08 1018 435 2031 5584 0
HIV Primary biliary cirrhosis 919 0 12 0 0 317 038 05375
HIV Psoriasis 8090 27 217 125 082 182 108 02985
HIV Rheumatoid arthritis 23991 17 266 064 037 102 314 00763
HIV Scleroderma 911 1 12 085 002 475 009 07639
HIV Sjogrens syndrome 1836 0 21 0 0 176 121 02704
HIV Systematic lupus erythematosus 1703 6 5 121 044 263 006 0813
HIV Thyrotoxicosis 11529 14 155 09 049 151 007 0797
HIV Ulcerative colitis 9323 30 282 106 072 152 006 08069
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 352 17 09 1992 1147 3236 27362 0
HIV Ankylosing spondylitis 767 1 11 088 002 493 012 07296
HIV Autoimmune haemolytic anaemia 306 7 04 1792 714 3736 9338 0
HIV Chronic active hepatitis 118 6 02 3067 1103 6878 13684 0
HIV Coeliac disease 1206 0 16 0 0 226 079 03752
HIV Crohns disease 1896 15 5 3 167 496 1787 0
HIV ITP 728 22 21 1068 665 1629 17803 0
HIV Myxoedema 28047 13 163 08 042 136 048 04889
HIV Pernicious anaemia 2773 1 09 106 003 593 021 06495
HIV Polymyositis 113 1 01 785 02 4461 108 02995
HIV Primary biliary cirrhosis 308 1 02 646 016 3624 077 03817
HIV Psoriasis 3072 22 61 361 226 548 3875 0
HIV Rheumatoid arthritis 9101 11 69 16 08 286 189 01697
HIV Scleroderma 294 0 03 0 0 1121 009 07682
HIV Sjogrens syndrome 565 2 05 436 053 1581 235 01253
HIV Systematic lupus erythematosus 608 1 12 082 002 461 007 07944
HIV Thyrotoxicosis 4243 5 43 118 038 275 001 09048
HIV Ulcerative colitis 3123 17 75 229 133 367 1101 00009
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 821 1 01 78 02 4358 108 02995
HIV Ankylosing spondylitis 1672 0 04 0 0 887 002 08966
HIV Autoimmune haemolytic anaemia 1142 1 02 418 011 2333 028 05943
HIV Chronic active hepatitis 300 1 01 1674 042 9401 323 00721
HIV Coeliac disease 3003 0 04 0 0 836 001 09297
HIV Crohns disease 4249 1 07 14 004 779 006 07988
HIV ITP 2750 4 05 823 224 2109 1866 0
HIV Myxoedema 111802 12 124 097 05 169 0 09748
HIV Pernicious anaemia 13040 0 15 0 0 253 063 04283
HIV Polymyositis 333 2 0 4371 527 15913 4594 0
HIV Primary biliary cirrhosis 1120 0 01 0 0 3586 153 02162
HIV Psoriasis 6100 2 15 131 016 472 0 09797
HIV Rheumatoid arthritis 30228 7 41 172 069 355 146 02269
HIV Scleroderma 909 0 01 0 0 3312 135 02449
HIV Sjogrens syndrome 1883 0 02 0 0 1969 052 04704
HIV Systematic lupus erythematosus 1056 0 02 0 0 1993 053 04648
HIV Thyrotoxicosis 15247 4 19 21 057 538 134 0247
HIV Ulcerative colitis 7697 5 16 317 103 74 541 002
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 326 3 03 893 183 2632 138 00002
HIV Ankylosing spondylitis 971 0 14 0 0 272 054 04621
HIV Autoimmune haemolytic anaemia 261 0 03 0 0 1419 022 06407
HIV Chronic active hepatitis 143 1 01 733 018 415 096 03272
HIV Coeliac disease 1492 0 11 0 0 331 034 05598
HIV Crohns disease 1923 1 24 042 001 234 032 05686
HIV ITP 712 3 09 329 068 964 274 00976
HIV Myxoedema 30859 11 201 055 027 098 368 00552
HIV Pernicious anaemia 1970 1 13 078 002 437 004 0844
HIV Polymyositis 135 2 01 1436 172 5288 1309 00003
HIV Primary biliary cirrhosis 377 1 02 575 015 3225 061 0435
HIV Psoriasis 3545 5 48 104 034 244 002 08955
HIV Rheumatoid arthritis 10250 4 88 045 012 116 214 01439
HIV Scleroderma 463 0 03 0 0 1449 023 06285
HIV Sjogrens syndrome 1053 1 05 2 005 1119 0 09991
HIV Systematic lupus erythematosus 715 0 06 0 0 606 002 0888
HIV Thyrotoxicosis 4076 4 35 115 031 295 0 0988
HIV Ulcerative colitis 3588 8 49 164 071 324 141 02348
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 458 20 2 1017 615 1589 14969 0
HIV Ankylosing spondylitis 1430 1 74 013 0 075 476 00291
HIV Autoimmune haemolytic anaemia 195 9 11 854 385 1655 5027 0
HIV Chronic active hepatitis 126 6 06 1068 385 2391 4141 0
HIV Coeliac disease 2230 5 96 052 017 122 173 01884
HIV Crohns disease 3262 22 203 108 068 164 007 07958
HIV ITP 694 23 44 533 335 806 7409 0
HIV Myxoedema 30770 47 922 051 037 068 2172 0
HIV Pernicious anaemia 1664 3 43 07 014 204 015 07013
HIV Polymyositis 127 3 1 316 064 945 246 01165
HIV Primary biliary cirrhosis 359 1 14 07 002 393 0 09501
HIV Psoriasis 6137 35 30 117 081 162 067 04141
HIV Rheumatoid arthritis 10968 21 365 057 036 088 617 0013
HIV Scleroderma 455 1 17 059 001 331 002 08849
HIV Sjogrens syndrome 995 1 29 034 001 192 068 04097
HIV Systematic lupus erythematosus 1279 7 63 112 045 231 001 09219
HIV Thyrotoxicosis 4589 18 191 094 056 149 002 08979
HIV Ulcerative colitis 5315 34 346 098 068 138 0 09893
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 213 11 1 1186 583 2166 9395 0
HIV Ankylosing spondylitis 486 2 27 074 009 269 002 09025
HIV Autoimmune haemolytic anaemia 66 2 03 627 074 2356 422 00398
HIV Chronic active hepatitis 39 2 02 1257 147 4856 1072 00011
HIV Coeliac disease 909 2 42 047 006 171 071 03994
HIV Crohns disease 2215 7 111 063 025 13 118 02778
HIV ITP 331 11 19 606 3 1098 4019 0
HIV Myxoedema 7241 15 325 046 026 076 896 00028
HIV Pernicious anaemia 472 0 17 0 0 212 089 03468
HIV Polymyositis 32 3 03 1034 203 3306 1533 00001
HIV Primary biliary cirrhosis 59 0 03 0 0 1176 01 07528
HIV Psoriasis 2551 23 109 213 135 32 1253 00004
HIV Rheumatoid arthritis 2238 7 95 073 03 152 043 05128
HIV Scleroderma 89 0 05 0 0 805 0 09596
HIV Sjogrens syndrome 160 0 07 0 0 564 004 08448
HIV Systematic lupus erythematosus 554 3 27 111 023 326 002 0899
HIV Thyrotoxicosis 1784 6 88 068 025 148 062 04293
HIV Ulcerative colitis 2667 15 151 1 056 165 001 09074
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 50 0 0 0 0 8184 44 00359
HIV Ankylosing spondylitis 10 0 0 0 0 71245 3898 0
HIV Autoimmune haemolytic anaemia 24 0 0 0 0 24127 1416 00002
HIV Chronic active hepatitis 17 0 0 0 0 12064 638 00115
HIV Coeliac disease 493 0 03 0 0 1306 017 06837
HIV Crohns disease 651 0 04 0 0 933 003 08691
HIV ITP 207 2 01 139 167 5086 1266 00004
HIV Myxoedema 781 0 05 0 0 704 0 09722
HIV Pernicious anaemia 14 0 0 0 0 84591 4915 0
HIV Polymyositis 4 0 0 0 0 6051 24878 0
HIV Primary biliary cirrhosis 2 0 0 0 0 0 0 0
HIV Psoriasis 357 0 01 0 0 2873 107 03016
HIV Rheumatoid arthritis 109 0 0 0 0 7558 409 00431
HIV Scleroderma 14 0 0 0 0 107299 626 0
HIV Sjogrens syndrome 10 0 0 0 0 396158 22105 0
HIV Systematic lupus erythematosus 64 0 0 0 0 7928 427 00387
HIV Thyrotoxicosis 173 0 01 0 0 3713 159 0207
HIV Ulcerative colitis 504 0 03 0 0 1346 018 06677
Cohort of HIV and Autoimmune Diseases-all cases
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1868 35 35 1008 7 1408 27231 0
HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147
HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0
HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0
HIV Coeliac disease 8127 7 156 045 018 092 423 00396
HIV Crohns disease 12300 31 349 089 06 126 034 05606
HIV ITP 4694 43 78 552 399 745 15331 0
HIV Myxoedema 181453 85 1577 054 043 067 331 0
HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492
HIV Polymyositis 631 10 15 691 33 1279 4409 0
HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381
HIV Psoriasis 18690 65 473 137 106 175 624 00125
HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113
HIV Scleroderma 1930 1 25 04 001 221 042 05189
HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396
HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218
HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879
HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929
Page 3: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Viruses and MSRabies virus Dick GW et al Br Med J 1958

Measles virus Reed D et al Arch Neurol 1964

Varicella-Zoster Virus (VZV) Ross CA et al BMJ1965

Mumps virus Millar JH et al Br Med J 1971

Rubella Horikawa Y et al Lancet 1973

Flaviviridae (Tick borne encephalitis) Salmi AA Ann Clin Res 1973

Herpes Simplex Virus Ito M et al Proc Soc Exp Biol Med 1975

Epstein-Barr Virus (EBV) Sumaya CV Arch Neurol 1980

Coronavirus Gerdes JC et al Adv Exp Med Biol 1981

HTLV-1 Newton M et al Lancet 1987

Human Herpes Virus 6 (HHV-6) Sola PJ et al Neurol Neurosurg Psychiatry 1993

JC polyomavirus Boerman R H Acta Neurol Scand 1993

Human Endogenous Retrovirus Perron H et al Res Virol 1992 Garson J A et al Lancet 1998 Christensen T et al Acta Neurologica Scandinavica 2000

First mention on pubmedCourtesy of Ute-C Meier

Are human endogenous retroviruses pathogenic An approach to testing the hypothesis

BioEssaysVolume 35 Issue 9 pages 794-803 17 JUL 2013 DOI 101002bies201300049httponlinelibrarywileycomdoi101002bies201300049fullbies201300049-fig-0001

Preacutesentateur
Commentaires de preacutesentation
131313Typified retroviral life cycle Retroviral infection begins with virion attachment usually to a cellular receptor followed by fusion of virion and plasma membranes In the cytosol the two copies of genomic RNA are reverse‐transcribed and following capsid disassembly they form the pre‐integration complex which then enters the nucleus The reverse‐transcribed cDNA copy is then integrated into the host cell DNA and from that point this provirus behaves analogously to a cellular gene in that cellular division of an infected cell will create two infected daughter cells Expression of mRNA from the provirus provides both new genomic RNAs as well as synthesis of viral proteins which are all then assembled into new virions These are then released from the plasma membrane and undergo maturation before they infect the next cell1313copy This slide is made available for non-commercial use only Please note that permission may be required for re-use of images in which the copyright is owned by a third party

How HERVs may induce autoimmune response

People living with MS (Total)

People living with

HIV(Total)

MS PrevalencePer 100000

HIV Prevalence

Per 100000

USA 400000 1200000 135 508

Canada 65000 60000 240 222

France 80000 130000 80 263

Germany 122000 49000 149 69

Netherlands 16000 18000 100 127

UK 85000 75000 110 137

Denmark 7500 6000 122 125

How many cases of HIV and MS have been reported

bull 1989 Berger reported 7 cases of an MS-like complex in HIV patients but none were followed up or apparently treated with ARVs

bull 2004 Corral reported a case of focal monophasic leukoencephalopathy in an HIV patients No details were provided on Follow-up or treatment

bull In all about 10 cases have been referred to in the medical literature in 30 years Six of these are questionable

What do cohort studies show

bull A single study in Danish National Registry of Patients (Nexo Pederson Sorensen and Koch-Henriksen Epidem 2013242 332-333) Cohort from 1994-2011

bull 5018 first time HIV diagnosis followed for 31875 person yearsbull 50194 controls matched for age and sex followed for 393871

person yearsbull One person with HIV developed MS which was a non-

significant relative risk of around 03 (95CI 004-22)

bull Interesting but not convincing

What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral

therapybull They affect similar demographic populations in western

countriesbull Literature consists of 950000 peer reviewed publications on

HIVAIDS and gt270000 peer reviewed papers on MS They are two of the most studied and documented conditions in medical science

bull Only one case of a patient with both MS and HIV documented as treated with anti-retroviral therapy (Eur J Neurol 201118110-111)

bull Unable to find HIV patients who have MS in major HIV clinics in Europe US and Australia

bull Unusual to find no documentation or company advice for treating HIV patients who have MS with DMT especially interferon

Methodsbull Hospital Episode Statistics of all 55 million people in

the UK from 1999 to 2011bull Any contact with healthcare system including

admissions day cases and deaths Multiple contacts are linked to individual record

bull Database analyzed at Unit of Health-care Epidemiology Oxford University

bull Exposed (HIV) and unexposed matched on week of first contact age area of residence and socio-economic status

bull Relative risk calculated using MS as outcome (OHIVEHIV)(OCCECC)

Age distribution of people entering the HIV cohort the percentage female and the number of people entering the reference cohort1

Age (yrs) N entering HIV cohort

( of total) female N entering the

reference cohort 0-4

139 (07) 446 137461

5-9

168 (08) 452 172624 10-14

138 (07) 572 138003

15-19

173 (08) 590 216875 20-24

653 (31) 444 267177

25-29

2136 (101) 439 340834 30-34

4066 (192) 369 459410

35-39

4792 (226) 296 541994 40-44

3701 (175) 249 496704

45-49

2228 (105) 206 433194 50-54

1293 (61) 186 446510

55-59

776 (37) 174 482105 60-64

480 (23) 163 506958

65-69

274 (13) 212 503916 70-74

98 (05) 214 508750

75-79

37 (02) 270 485042 80-84

22 (01) 227 353716

85+

33 (02) 455 252837

All ages 21207 (100) 302 6744110

Following 21207 patients with HIV for 152618 person years and 6744301 controls for 42148179person years to see who would develop MS On average the follow-up was 7 years

exposure outcome MS in HIVMS in

Controls

rate ratio(Relative

Risk)Protective

Effect low CI upr CI chi-sq p-value

HIVmultiple sclerosis 7 183 038 gt62 015 079 639 0011

NHS Data on UK Healthcare events 1999-2011

Sheet1

NHS Cohort gt One year after Exposure (HIV) Contact

Exposure OutcomeMS in

exposedMS in

Controls

Rate ratio (Relative

Risk)Protective

Effect Low CIHigh

CI Chi-sqP

value

HIVMultiple Sclerosis 4 158 022 80 007 065 81 0004

Assuming that HIV diagnosis was made on first contact assessmentof cohort after one year would probably account for effect of HIVtherapy on all exposed If no effect of HIV treatment then expect noreduction in Relative Risk

Cohort of HIV and Autoimmune Diseases-all casesexposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-valueHIV Addisons disease 1868 35 35 1008 7 1408 27231 0HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0HIV Coeliac disease 8127 7 156 045 018 092 423 00396HIV Crohns disease 12300 31 349 089 06 126 034 05606HIV ITP 4694 43 78 552 399 745 15331 0HIV Myxoedema 181453 85 1577 054 043 067 331 0HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492HIV Polymyositis 631 10 15 691 33 1279 4409 0HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381HIV Psoriasis 18690 65 473 137 106 175 624 00125

HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113HIV Scleroderma 1930 1 25 04 001 221 042 05189HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929

all

aged 0-14

15-34

35-54

55-64

65+

interval lt1yr

1-4

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 830 15 15 998 556 1655 11032 0
HIV Ankylosing spondylitis 1995 2 56 035 004 128 174 01866
HIV Autoimmune haemolytic anaemia 796 4 09 423 115 1088 687 00088
HIV Chronic active hepatitis 340 3 06 537 11 1582 668 00098
HIV Coeliac disease 3639 6 79 076 028 165 025 0616
HIV Crohns disease 5695 13 167 078 041 133 061 04355
HIV ITP 2142 15 32 473 265 783 4024 0
HIV Myxoedema 77911 43 698 062 045 083 992 00016
HIV Pernicious anaemia 7615 3 37 082 017 239 001 09271
HIV Polymyositis 302 8 08 1018 435 2031 5584 0
HIV Primary biliary cirrhosis 919 0 12 0 0 317 038 05375
HIV Psoriasis 8090 27 217 125 082 182 108 02985
HIV Rheumatoid arthritis 23991 17 266 064 037 102 314 00763
HIV Scleroderma 911 1 12 085 002 475 009 07639
HIV Sjogrens syndrome 1836 0 21 0 0 176 121 02704
HIV Systematic lupus erythematosus 1703 6 5 121 044 263 006 0813
HIV Thyrotoxicosis 11529 14 155 09 049 151 007 0797
HIV Ulcerative colitis 9323 30 282 106 072 152 006 08069
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 352 17 09 1992 1147 3236 27362 0
HIV Ankylosing spondylitis 767 1 11 088 002 493 012 07296
HIV Autoimmune haemolytic anaemia 306 7 04 1792 714 3736 9338 0
HIV Chronic active hepatitis 118 6 02 3067 1103 6878 13684 0
HIV Coeliac disease 1206 0 16 0 0 226 079 03752
HIV Crohns disease 1896 15 5 3 167 496 1787 0
HIV ITP 728 22 21 1068 665 1629 17803 0
HIV Myxoedema 28047 13 163 08 042 136 048 04889
HIV Pernicious anaemia 2773 1 09 106 003 593 021 06495
HIV Polymyositis 113 1 01 785 02 4461 108 02995
HIV Primary biliary cirrhosis 308 1 02 646 016 3624 077 03817
HIV Psoriasis 3072 22 61 361 226 548 3875 0
HIV Rheumatoid arthritis 9101 11 69 16 08 286 189 01697
HIV Scleroderma 294 0 03 0 0 1121 009 07682
HIV Sjogrens syndrome 565 2 05 436 053 1581 235 01253
HIV Systematic lupus erythematosus 608 1 12 082 002 461 007 07944
HIV Thyrotoxicosis 4243 5 43 118 038 275 001 09048
HIV Ulcerative colitis 3123 17 75 229 133 367 1101 00009
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 821 1 01 78 02 4358 108 02995
HIV Ankylosing spondylitis 1672 0 04 0 0 887 002 08966
HIV Autoimmune haemolytic anaemia 1142 1 02 418 011 2333 028 05943
HIV Chronic active hepatitis 300 1 01 1674 042 9401 323 00721
HIV Coeliac disease 3003 0 04 0 0 836 001 09297
HIV Crohns disease 4249 1 07 14 004 779 006 07988
HIV ITP 2750 4 05 823 224 2109 1866 0
HIV Myxoedema 111802 12 124 097 05 169 0 09748
HIV Pernicious anaemia 13040 0 15 0 0 253 063 04283
HIV Polymyositis 333 2 0 4371 527 15913 4594 0
HIV Primary biliary cirrhosis 1120 0 01 0 0 3586 153 02162
HIV Psoriasis 6100 2 15 131 016 472 0 09797
HIV Rheumatoid arthritis 30228 7 41 172 069 355 146 02269
HIV Scleroderma 909 0 01 0 0 3312 135 02449
HIV Sjogrens syndrome 1883 0 02 0 0 1969 052 04704
HIV Systematic lupus erythematosus 1056 0 02 0 0 1993 053 04648
HIV Thyrotoxicosis 15247 4 19 21 057 538 134 0247
HIV Ulcerative colitis 7697 5 16 317 103 74 541 002
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 326 3 03 893 183 2632 138 00002
HIV Ankylosing spondylitis 971 0 14 0 0 272 054 04621
HIV Autoimmune haemolytic anaemia 261 0 03 0 0 1419 022 06407
HIV Chronic active hepatitis 143 1 01 733 018 415 096 03272
HIV Coeliac disease 1492 0 11 0 0 331 034 05598
HIV Crohns disease 1923 1 24 042 001 234 032 05686
HIV ITP 712 3 09 329 068 964 274 00976
HIV Myxoedema 30859 11 201 055 027 098 368 00552
HIV Pernicious anaemia 1970 1 13 078 002 437 004 0844
HIV Polymyositis 135 2 01 1436 172 5288 1309 00003
HIV Primary biliary cirrhosis 377 1 02 575 015 3225 061 0435
HIV Psoriasis 3545 5 48 104 034 244 002 08955
HIV Rheumatoid arthritis 10250 4 88 045 012 116 214 01439
HIV Scleroderma 463 0 03 0 0 1449 023 06285
HIV Sjogrens syndrome 1053 1 05 2 005 1119 0 09991
HIV Systematic lupus erythematosus 715 0 06 0 0 606 002 0888
HIV Thyrotoxicosis 4076 4 35 115 031 295 0 0988
HIV Ulcerative colitis 3588 8 49 164 071 324 141 02348
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 458 20 2 1017 615 1589 14969 0
HIV Ankylosing spondylitis 1430 1 74 013 0 075 476 00291
HIV Autoimmune haemolytic anaemia 195 9 11 854 385 1655 5027 0
HIV Chronic active hepatitis 126 6 06 1068 385 2391 4141 0
HIV Coeliac disease 2230 5 96 052 017 122 173 01884
HIV Crohns disease 3262 22 203 108 068 164 007 07958
HIV ITP 694 23 44 533 335 806 7409 0
HIV Myxoedema 30770 47 922 051 037 068 2172 0
HIV Pernicious anaemia 1664 3 43 07 014 204 015 07013
HIV Polymyositis 127 3 1 316 064 945 246 01165
HIV Primary biliary cirrhosis 359 1 14 07 002 393 0 09501
HIV Psoriasis 6137 35 30 117 081 162 067 04141
HIV Rheumatoid arthritis 10968 21 365 057 036 088 617 0013
HIV Scleroderma 455 1 17 059 001 331 002 08849
HIV Sjogrens syndrome 995 1 29 034 001 192 068 04097
HIV Systematic lupus erythematosus 1279 7 63 112 045 231 001 09219
HIV Thyrotoxicosis 4589 18 191 094 056 149 002 08979
HIV Ulcerative colitis 5315 34 346 098 068 138 0 09893
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 213 11 1 1186 583 2166 9395 0
HIV Ankylosing spondylitis 486 2 27 074 009 269 002 09025
HIV Autoimmune haemolytic anaemia 66 2 03 627 074 2356 422 00398
HIV Chronic active hepatitis 39 2 02 1257 147 4856 1072 00011
HIV Coeliac disease 909 2 42 047 006 171 071 03994
HIV Crohns disease 2215 7 111 063 025 13 118 02778
HIV ITP 331 11 19 606 3 1098 4019 0
HIV Myxoedema 7241 15 325 046 026 076 896 00028
HIV Pernicious anaemia 472 0 17 0 0 212 089 03468
HIV Polymyositis 32 3 03 1034 203 3306 1533 00001
HIV Primary biliary cirrhosis 59 0 03 0 0 1176 01 07528
HIV Psoriasis 2551 23 109 213 135 32 1253 00004
HIV Rheumatoid arthritis 2238 7 95 073 03 152 043 05128
HIV Scleroderma 89 0 05 0 0 805 0 09596
HIV Sjogrens syndrome 160 0 07 0 0 564 004 08448
HIV Systematic lupus erythematosus 554 3 27 111 023 326 002 0899
HIV Thyrotoxicosis 1784 6 88 068 025 148 062 04293
HIV Ulcerative colitis 2667 15 151 1 056 165 001 09074
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 50 0 0 0 0 8184 44 00359
HIV Ankylosing spondylitis 10 0 0 0 0 71245 3898 0
HIV Autoimmune haemolytic anaemia 24 0 0 0 0 24127 1416 00002
HIV Chronic active hepatitis 17 0 0 0 0 12064 638 00115
HIV Coeliac disease 493 0 03 0 0 1306 017 06837
HIV Crohns disease 651 0 04 0 0 933 003 08691
HIV ITP 207 2 01 139 167 5086 1266 00004
HIV Myxoedema 781 0 05 0 0 704 0 09722
HIV Pernicious anaemia 14 0 0 0 0 84591 4915 0
HIV Polymyositis 4 0 0 0 0 6051 24878 0
HIV Primary biliary cirrhosis 2 0 0 0 0 0 0 0
HIV Psoriasis 357 0 01 0 0 2873 107 03016
HIV Rheumatoid arthritis 109 0 0 0 0 7558 409 00431
HIV Scleroderma 14 0 0 0 0 107299 626 0
HIV Sjogrens syndrome 10 0 0 0 0 396158 22105 0
HIV Systematic lupus erythematosus 64 0 0 0 0 7928 427 00387
HIV Thyrotoxicosis 173 0 01 0 0 3713 159 0207
HIV Ulcerative colitis 504 0 03 0 0 1346 018 06677
Cohort of HIV and Autoimmune Diseases-all cases
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1868 35 35 1008 7 1408 27231 0
HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147
HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0
HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0
HIV Coeliac disease 8127 7 156 045 018 092 423 00396
HIV Crohns disease 12300 31 349 089 06 126 034 05606
HIV ITP 4694 43 78 552 399 745 15331 0
HIV Myxoedema 181453 85 1577 054 043 067 331 0
HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492
HIV Polymyositis 631 10 15 691 33 1279 4409 0
HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381
HIV Psoriasis 18690 65 473 137 106 175 624 00125
HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113
HIV Scleroderma 1930 1 25 04 001 221 042 05189
HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396
HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218
HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879
HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929
Page 4: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Are human endogenous retroviruses pathogenic An approach to testing the hypothesis

BioEssaysVolume 35 Issue 9 pages 794-803 17 JUL 2013 DOI 101002bies201300049httponlinelibrarywileycomdoi101002bies201300049fullbies201300049-fig-0001

Preacutesentateur
Commentaires de preacutesentation
131313Typified retroviral life cycle Retroviral infection begins with virion attachment usually to a cellular receptor followed by fusion of virion and plasma membranes In the cytosol the two copies of genomic RNA are reverse‐transcribed and following capsid disassembly they form the pre‐integration complex which then enters the nucleus The reverse‐transcribed cDNA copy is then integrated into the host cell DNA and from that point this provirus behaves analogously to a cellular gene in that cellular division of an infected cell will create two infected daughter cells Expression of mRNA from the provirus provides both new genomic RNAs as well as synthesis of viral proteins which are all then assembled into new virions These are then released from the plasma membrane and undergo maturation before they infect the next cell1313copy This slide is made available for non-commercial use only Please note that permission may be required for re-use of images in which the copyright is owned by a third party

How HERVs may induce autoimmune response

People living with MS (Total)

People living with

HIV(Total)

MS PrevalencePer 100000

HIV Prevalence

Per 100000

USA 400000 1200000 135 508

Canada 65000 60000 240 222

France 80000 130000 80 263

Germany 122000 49000 149 69

Netherlands 16000 18000 100 127

UK 85000 75000 110 137

Denmark 7500 6000 122 125

How many cases of HIV and MS have been reported

bull 1989 Berger reported 7 cases of an MS-like complex in HIV patients but none were followed up or apparently treated with ARVs

bull 2004 Corral reported a case of focal monophasic leukoencephalopathy in an HIV patients No details were provided on Follow-up or treatment

bull In all about 10 cases have been referred to in the medical literature in 30 years Six of these are questionable

What do cohort studies show

bull A single study in Danish National Registry of Patients (Nexo Pederson Sorensen and Koch-Henriksen Epidem 2013242 332-333) Cohort from 1994-2011

bull 5018 first time HIV diagnosis followed for 31875 person yearsbull 50194 controls matched for age and sex followed for 393871

person yearsbull One person with HIV developed MS which was a non-

significant relative risk of around 03 (95CI 004-22)

bull Interesting but not convincing

What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral

therapybull They affect similar demographic populations in western

countriesbull Literature consists of 950000 peer reviewed publications on

HIVAIDS and gt270000 peer reviewed papers on MS They are two of the most studied and documented conditions in medical science

bull Only one case of a patient with both MS and HIV documented as treated with anti-retroviral therapy (Eur J Neurol 201118110-111)

bull Unable to find HIV patients who have MS in major HIV clinics in Europe US and Australia

bull Unusual to find no documentation or company advice for treating HIV patients who have MS with DMT especially interferon

Methodsbull Hospital Episode Statistics of all 55 million people in

the UK from 1999 to 2011bull Any contact with healthcare system including

admissions day cases and deaths Multiple contacts are linked to individual record

bull Database analyzed at Unit of Health-care Epidemiology Oxford University

bull Exposed (HIV) and unexposed matched on week of first contact age area of residence and socio-economic status

bull Relative risk calculated using MS as outcome (OHIVEHIV)(OCCECC)

Age distribution of people entering the HIV cohort the percentage female and the number of people entering the reference cohort1

Age (yrs) N entering HIV cohort

( of total) female N entering the

reference cohort 0-4

139 (07) 446 137461

5-9

168 (08) 452 172624 10-14

138 (07) 572 138003

15-19

173 (08) 590 216875 20-24

653 (31) 444 267177

25-29

2136 (101) 439 340834 30-34

4066 (192) 369 459410

35-39

4792 (226) 296 541994 40-44

3701 (175) 249 496704

45-49

2228 (105) 206 433194 50-54

1293 (61) 186 446510

55-59

776 (37) 174 482105 60-64

480 (23) 163 506958

65-69

274 (13) 212 503916 70-74

98 (05) 214 508750

75-79

37 (02) 270 485042 80-84

22 (01) 227 353716

85+

33 (02) 455 252837

All ages 21207 (100) 302 6744110

Following 21207 patients with HIV for 152618 person years and 6744301 controls for 42148179person years to see who would develop MS On average the follow-up was 7 years

exposure outcome MS in HIVMS in

Controls

rate ratio(Relative

Risk)Protective

Effect low CI upr CI chi-sq p-value

HIVmultiple sclerosis 7 183 038 gt62 015 079 639 0011

NHS Data on UK Healthcare events 1999-2011

Sheet1

NHS Cohort gt One year after Exposure (HIV) Contact

Exposure OutcomeMS in

exposedMS in

Controls

Rate ratio (Relative

Risk)Protective

Effect Low CIHigh

CI Chi-sqP

value

HIVMultiple Sclerosis 4 158 022 80 007 065 81 0004

Assuming that HIV diagnosis was made on first contact assessmentof cohort after one year would probably account for effect of HIVtherapy on all exposed If no effect of HIV treatment then expect noreduction in Relative Risk

Cohort of HIV and Autoimmune Diseases-all casesexposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-valueHIV Addisons disease 1868 35 35 1008 7 1408 27231 0HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0HIV Coeliac disease 8127 7 156 045 018 092 423 00396HIV Crohns disease 12300 31 349 089 06 126 034 05606HIV ITP 4694 43 78 552 399 745 15331 0HIV Myxoedema 181453 85 1577 054 043 067 331 0HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492HIV Polymyositis 631 10 15 691 33 1279 4409 0HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381HIV Psoriasis 18690 65 473 137 106 175 624 00125

HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113HIV Scleroderma 1930 1 25 04 001 221 042 05189HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929

all

aged 0-14

15-34

35-54

55-64

65+

interval lt1yr

1-4

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
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  • Acknowledgements
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HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 830 15 15 998 556 1655 11032 0
HIV Ankylosing spondylitis 1995 2 56 035 004 128 174 01866
HIV Autoimmune haemolytic anaemia 796 4 09 423 115 1088 687 00088
HIV Chronic active hepatitis 340 3 06 537 11 1582 668 00098
HIV Coeliac disease 3639 6 79 076 028 165 025 0616
HIV Crohns disease 5695 13 167 078 041 133 061 04355
HIV ITP 2142 15 32 473 265 783 4024 0
HIV Myxoedema 77911 43 698 062 045 083 992 00016
HIV Pernicious anaemia 7615 3 37 082 017 239 001 09271
HIV Polymyositis 302 8 08 1018 435 2031 5584 0
HIV Primary biliary cirrhosis 919 0 12 0 0 317 038 05375
HIV Psoriasis 8090 27 217 125 082 182 108 02985
HIV Rheumatoid arthritis 23991 17 266 064 037 102 314 00763
HIV Scleroderma 911 1 12 085 002 475 009 07639
HIV Sjogrens syndrome 1836 0 21 0 0 176 121 02704
HIV Systematic lupus erythematosus 1703 6 5 121 044 263 006 0813
HIV Thyrotoxicosis 11529 14 155 09 049 151 007 0797
HIV Ulcerative colitis 9323 30 282 106 072 152 006 08069
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 352 17 09 1992 1147 3236 27362 0
HIV Ankylosing spondylitis 767 1 11 088 002 493 012 07296
HIV Autoimmune haemolytic anaemia 306 7 04 1792 714 3736 9338 0
HIV Chronic active hepatitis 118 6 02 3067 1103 6878 13684 0
HIV Coeliac disease 1206 0 16 0 0 226 079 03752
HIV Crohns disease 1896 15 5 3 167 496 1787 0
HIV ITP 728 22 21 1068 665 1629 17803 0
HIV Myxoedema 28047 13 163 08 042 136 048 04889
HIV Pernicious anaemia 2773 1 09 106 003 593 021 06495
HIV Polymyositis 113 1 01 785 02 4461 108 02995
HIV Primary biliary cirrhosis 308 1 02 646 016 3624 077 03817
HIV Psoriasis 3072 22 61 361 226 548 3875 0
HIV Rheumatoid arthritis 9101 11 69 16 08 286 189 01697
HIV Scleroderma 294 0 03 0 0 1121 009 07682
HIV Sjogrens syndrome 565 2 05 436 053 1581 235 01253
HIV Systematic lupus erythematosus 608 1 12 082 002 461 007 07944
HIV Thyrotoxicosis 4243 5 43 118 038 275 001 09048
HIV Ulcerative colitis 3123 17 75 229 133 367 1101 00009
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 821 1 01 78 02 4358 108 02995
HIV Ankylosing spondylitis 1672 0 04 0 0 887 002 08966
HIV Autoimmune haemolytic anaemia 1142 1 02 418 011 2333 028 05943
HIV Chronic active hepatitis 300 1 01 1674 042 9401 323 00721
HIV Coeliac disease 3003 0 04 0 0 836 001 09297
HIV Crohns disease 4249 1 07 14 004 779 006 07988
HIV ITP 2750 4 05 823 224 2109 1866 0
HIV Myxoedema 111802 12 124 097 05 169 0 09748
HIV Pernicious anaemia 13040 0 15 0 0 253 063 04283
HIV Polymyositis 333 2 0 4371 527 15913 4594 0
HIV Primary biliary cirrhosis 1120 0 01 0 0 3586 153 02162
HIV Psoriasis 6100 2 15 131 016 472 0 09797
HIV Rheumatoid arthritis 30228 7 41 172 069 355 146 02269
HIV Scleroderma 909 0 01 0 0 3312 135 02449
HIV Sjogrens syndrome 1883 0 02 0 0 1969 052 04704
HIV Systematic lupus erythematosus 1056 0 02 0 0 1993 053 04648
HIV Thyrotoxicosis 15247 4 19 21 057 538 134 0247
HIV Ulcerative colitis 7697 5 16 317 103 74 541 002
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 326 3 03 893 183 2632 138 00002
HIV Ankylosing spondylitis 971 0 14 0 0 272 054 04621
HIV Autoimmune haemolytic anaemia 261 0 03 0 0 1419 022 06407
HIV Chronic active hepatitis 143 1 01 733 018 415 096 03272
HIV Coeliac disease 1492 0 11 0 0 331 034 05598
HIV Crohns disease 1923 1 24 042 001 234 032 05686
HIV ITP 712 3 09 329 068 964 274 00976
HIV Myxoedema 30859 11 201 055 027 098 368 00552
HIV Pernicious anaemia 1970 1 13 078 002 437 004 0844
HIV Polymyositis 135 2 01 1436 172 5288 1309 00003
HIV Primary biliary cirrhosis 377 1 02 575 015 3225 061 0435
HIV Psoriasis 3545 5 48 104 034 244 002 08955
HIV Rheumatoid arthritis 10250 4 88 045 012 116 214 01439
HIV Scleroderma 463 0 03 0 0 1449 023 06285
HIV Sjogrens syndrome 1053 1 05 2 005 1119 0 09991
HIV Systematic lupus erythematosus 715 0 06 0 0 606 002 0888
HIV Thyrotoxicosis 4076 4 35 115 031 295 0 0988
HIV Ulcerative colitis 3588 8 49 164 071 324 141 02348
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 458 20 2 1017 615 1589 14969 0
HIV Ankylosing spondylitis 1430 1 74 013 0 075 476 00291
HIV Autoimmune haemolytic anaemia 195 9 11 854 385 1655 5027 0
HIV Chronic active hepatitis 126 6 06 1068 385 2391 4141 0
HIV Coeliac disease 2230 5 96 052 017 122 173 01884
HIV Crohns disease 3262 22 203 108 068 164 007 07958
HIV ITP 694 23 44 533 335 806 7409 0
HIV Myxoedema 30770 47 922 051 037 068 2172 0
HIV Pernicious anaemia 1664 3 43 07 014 204 015 07013
HIV Polymyositis 127 3 1 316 064 945 246 01165
HIV Primary biliary cirrhosis 359 1 14 07 002 393 0 09501
HIV Psoriasis 6137 35 30 117 081 162 067 04141
HIV Rheumatoid arthritis 10968 21 365 057 036 088 617 0013
HIV Scleroderma 455 1 17 059 001 331 002 08849
HIV Sjogrens syndrome 995 1 29 034 001 192 068 04097
HIV Systematic lupus erythematosus 1279 7 63 112 045 231 001 09219
HIV Thyrotoxicosis 4589 18 191 094 056 149 002 08979
HIV Ulcerative colitis 5315 34 346 098 068 138 0 09893
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 213 11 1 1186 583 2166 9395 0
HIV Ankylosing spondylitis 486 2 27 074 009 269 002 09025
HIV Autoimmune haemolytic anaemia 66 2 03 627 074 2356 422 00398
HIV Chronic active hepatitis 39 2 02 1257 147 4856 1072 00011
HIV Coeliac disease 909 2 42 047 006 171 071 03994
HIV Crohns disease 2215 7 111 063 025 13 118 02778
HIV ITP 331 11 19 606 3 1098 4019 0
HIV Myxoedema 7241 15 325 046 026 076 896 00028
HIV Pernicious anaemia 472 0 17 0 0 212 089 03468
HIV Polymyositis 32 3 03 1034 203 3306 1533 00001
HIV Primary biliary cirrhosis 59 0 03 0 0 1176 01 07528
HIV Psoriasis 2551 23 109 213 135 32 1253 00004
HIV Rheumatoid arthritis 2238 7 95 073 03 152 043 05128
HIV Scleroderma 89 0 05 0 0 805 0 09596
HIV Sjogrens syndrome 160 0 07 0 0 564 004 08448
HIV Systematic lupus erythematosus 554 3 27 111 023 326 002 0899
HIV Thyrotoxicosis 1784 6 88 068 025 148 062 04293
HIV Ulcerative colitis 2667 15 151 1 056 165 001 09074
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 50 0 0 0 0 8184 44 00359
HIV Ankylosing spondylitis 10 0 0 0 0 71245 3898 0
HIV Autoimmune haemolytic anaemia 24 0 0 0 0 24127 1416 00002
HIV Chronic active hepatitis 17 0 0 0 0 12064 638 00115
HIV Coeliac disease 493 0 03 0 0 1306 017 06837
HIV Crohns disease 651 0 04 0 0 933 003 08691
HIV ITP 207 2 01 139 167 5086 1266 00004
HIV Myxoedema 781 0 05 0 0 704 0 09722
HIV Pernicious anaemia 14 0 0 0 0 84591 4915 0
HIV Polymyositis 4 0 0 0 0 6051 24878 0
HIV Primary biliary cirrhosis 2 0 0 0 0 0 0 0
HIV Psoriasis 357 0 01 0 0 2873 107 03016
HIV Rheumatoid arthritis 109 0 0 0 0 7558 409 00431
HIV Scleroderma 14 0 0 0 0 107299 626 0
HIV Sjogrens syndrome 10 0 0 0 0 396158 22105 0
HIV Systematic lupus erythematosus 64 0 0 0 0 7928 427 00387
HIV Thyrotoxicosis 173 0 01 0 0 3713 159 0207
HIV Ulcerative colitis 504 0 03 0 0 1346 018 06677
Cohort of HIV and Autoimmune Diseases-all cases
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1868 35 35 1008 7 1408 27231 0
HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147
HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0
HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0
HIV Coeliac disease 8127 7 156 045 018 092 423 00396
HIV Crohns disease 12300 31 349 089 06 126 034 05606
HIV ITP 4694 43 78 552 399 745 15331 0
HIV Myxoedema 181453 85 1577 054 043 067 331 0
HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492
HIV Polymyositis 631 10 15 691 33 1279 4409 0
HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381
HIV Psoriasis 18690 65 473 137 106 175 624 00125
HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113
HIV Scleroderma 1930 1 25 04 001 221 042 05189
HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396
HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218
HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879
HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929
Page 5: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

How HERVs may induce autoimmune response

People living with MS (Total)

People living with

HIV(Total)

MS PrevalencePer 100000

HIV Prevalence

Per 100000

USA 400000 1200000 135 508

Canada 65000 60000 240 222

France 80000 130000 80 263

Germany 122000 49000 149 69

Netherlands 16000 18000 100 127

UK 85000 75000 110 137

Denmark 7500 6000 122 125

How many cases of HIV and MS have been reported

bull 1989 Berger reported 7 cases of an MS-like complex in HIV patients but none were followed up or apparently treated with ARVs

bull 2004 Corral reported a case of focal monophasic leukoencephalopathy in an HIV patients No details were provided on Follow-up or treatment

bull In all about 10 cases have been referred to in the medical literature in 30 years Six of these are questionable

What do cohort studies show

bull A single study in Danish National Registry of Patients (Nexo Pederson Sorensen and Koch-Henriksen Epidem 2013242 332-333) Cohort from 1994-2011

bull 5018 first time HIV diagnosis followed for 31875 person yearsbull 50194 controls matched for age and sex followed for 393871

person yearsbull One person with HIV developed MS which was a non-

significant relative risk of around 03 (95CI 004-22)

bull Interesting but not convincing

What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral

therapybull They affect similar demographic populations in western

countriesbull Literature consists of 950000 peer reviewed publications on

HIVAIDS and gt270000 peer reviewed papers on MS They are two of the most studied and documented conditions in medical science

bull Only one case of a patient with both MS and HIV documented as treated with anti-retroviral therapy (Eur J Neurol 201118110-111)

bull Unable to find HIV patients who have MS in major HIV clinics in Europe US and Australia

bull Unusual to find no documentation or company advice for treating HIV patients who have MS with DMT especially interferon

Methodsbull Hospital Episode Statistics of all 55 million people in

the UK from 1999 to 2011bull Any contact with healthcare system including

admissions day cases and deaths Multiple contacts are linked to individual record

bull Database analyzed at Unit of Health-care Epidemiology Oxford University

bull Exposed (HIV) and unexposed matched on week of first contact age area of residence and socio-economic status

bull Relative risk calculated using MS as outcome (OHIVEHIV)(OCCECC)

Age distribution of people entering the HIV cohort the percentage female and the number of people entering the reference cohort1

Age (yrs) N entering HIV cohort

( of total) female N entering the

reference cohort 0-4

139 (07) 446 137461

5-9

168 (08) 452 172624 10-14

138 (07) 572 138003

15-19

173 (08) 590 216875 20-24

653 (31) 444 267177

25-29

2136 (101) 439 340834 30-34

4066 (192) 369 459410

35-39

4792 (226) 296 541994 40-44

3701 (175) 249 496704

45-49

2228 (105) 206 433194 50-54

1293 (61) 186 446510

55-59

776 (37) 174 482105 60-64

480 (23) 163 506958

65-69

274 (13) 212 503916 70-74

98 (05) 214 508750

75-79

37 (02) 270 485042 80-84

22 (01) 227 353716

85+

33 (02) 455 252837

All ages 21207 (100) 302 6744110

Following 21207 patients with HIV for 152618 person years and 6744301 controls for 42148179person years to see who would develop MS On average the follow-up was 7 years

exposure outcome MS in HIVMS in

Controls

rate ratio(Relative

Risk)Protective

Effect low CI upr CI chi-sq p-value

HIVmultiple sclerosis 7 183 038 gt62 015 079 639 0011

NHS Data on UK Healthcare events 1999-2011

Sheet1

NHS Cohort gt One year after Exposure (HIV) Contact

Exposure OutcomeMS in

exposedMS in

Controls

Rate ratio (Relative

Risk)Protective

Effect Low CIHigh

CI Chi-sqP

value

HIVMultiple Sclerosis 4 158 022 80 007 065 81 0004

Assuming that HIV diagnosis was made on first contact assessmentof cohort after one year would probably account for effect of HIVtherapy on all exposed If no effect of HIV treatment then expect noreduction in Relative Risk

Cohort of HIV and Autoimmune Diseases-all casesexposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-valueHIV Addisons disease 1868 35 35 1008 7 1408 27231 0HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0HIV Coeliac disease 8127 7 156 045 018 092 423 00396HIV Crohns disease 12300 31 349 089 06 126 034 05606HIV ITP 4694 43 78 552 399 745 15331 0HIV Myxoedema 181453 85 1577 054 043 067 331 0HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492HIV Polymyositis 631 10 15 691 33 1279 4409 0HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381HIV Psoriasis 18690 65 473 137 106 175 624 00125

HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113HIV Scleroderma 1930 1 25 04 001 221 042 05189HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929

all

aged 0-14

15-34

35-54

55-64

65+

interval lt1yr

1-4

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 830 15 15 998 556 1655 11032 0
HIV Ankylosing spondylitis 1995 2 56 035 004 128 174 01866
HIV Autoimmune haemolytic anaemia 796 4 09 423 115 1088 687 00088
HIV Chronic active hepatitis 340 3 06 537 11 1582 668 00098
HIV Coeliac disease 3639 6 79 076 028 165 025 0616
HIV Crohns disease 5695 13 167 078 041 133 061 04355
HIV ITP 2142 15 32 473 265 783 4024 0
HIV Myxoedema 77911 43 698 062 045 083 992 00016
HIV Pernicious anaemia 7615 3 37 082 017 239 001 09271
HIV Polymyositis 302 8 08 1018 435 2031 5584 0
HIV Primary biliary cirrhosis 919 0 12 0 0 317 038 05375
HIV Psoriasis 8090 27 217 125 082 182 108 02985
HIV Rheumatoid arthritis 23991 17 266 064 037 102 314 00763
HIV Scleroderma 911 1 12 085 002 475 009 07639
HIV Sjogrens syndrome 1836 0 21 0 0 176 121 02704
HIV Systematic lupus erythematosus 1703 6 5 121 044 263 006 0813
HIV Thyrotoxicosis 11529 14 155 09 049 151 007 0797
HIV Ulcerative colitis 9323 30 282 106 072 152 006 08069
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 352 17 09 1992 1147 3236 27362 0
HIV Ankylosing spondylitis 767 1 11 088 002 493 012 07296
HIV Autoimmune haemolytic anaemia 306 7 04 1792 714 3736 9338 0
HIV Chronic active hepatitis 118 6 02 3067 1103 6878 13684 0
HIV Coeliac disease 1206 0 16 0 0 226 079 03752
HIV Crohns disease 1896 15 5 3 167 496 1787 0
HIV ITP 728 22 21 1068 665 1629 17803 0
HIV Myxoedema 28047 13 163 08 042 136 048 04889
HIV Pernicious anaemia 2773 1 09 106 003 593 021 06495
HIV Polymyositis 113 1 01 785 02 4461 108 02995
HIV Primary biliary cirrhosis 308 1 02 646 016 3624 077 03817
HIV Psoriasis 3072 22 61 361 226 548 3875 0
HIV Rheumatoid arthritis 9101 11 69 16 08 286 189 01697
HIV Scleroderma 294 0 03 0 0 1121 009 07682
HIV Sjogrens syndrome 565 2 05 436 053 1581 235 01253
HIV Systematic lupus erythematosus 608 1 12 082 002 461 007 07944
HIV Thyrotoxicosis 4243 5 43 118 038 275 001 09048
HIV Ulcerative colitis 3123 17 75 229 133 367 1101 00009
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 821 1 01 78 02 4358 108 02995
HIV Ankylosing spondylitis 1672 0 04 0 0 887 002 08966
HIV Autoimmune haemolytic anaemia 1142 1 02 418 011 2333 028 05943
HIV Chronic active hepatitis 300 1 01 1674 042 9401 323 00721
HIV Coeliac disease 3003 0 04 0 0 836 001 09297
HIV Crohns disease 4249 1 07 14 004 779 006 07988
HIV ITP 2750 4 05 823 224 2109 1866 0
HIV Myxoedema 111802 12 124 097 05 169 0 09748
HIV Pernicious anaemia 13040 0 15 0 0 253 063 04283
HIV Polymyositis 333 2 0 4371 527 15913 4594 0
HIV Primary biliary cirrhosis 1120 0 01 0 0 3586 153 02162
HIV Psoriasis 6100 2 15 131 016 472 0 09797
HIV Rheumatoid arthritis 30228 7 41 172 069 355 146 02269
HIV Scleroderma 909 0 01 0 0 3312 135 02449
HIV Sjogrens syndrome 1883 0 02 0 0 1969 052 04704
HIV Systematic lupus erythematosus 1056 0 02 0 0 1993 053 04648
HIV Thyrotoxicosis 15247 4 19 21 057 538 134 0247
HIV Ulcerative colitis 7697 5 16 317 103 74 541 002
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 326 3 03 893 183 2632 138 00002
HIV Ankylosing spondylitis 971 0 14 0 0 272 054 04621
HIV Autoimmune haemolytic anaemia 261 0 03 0 0 1419 022 06407
HIV Chronic active hepatitis 143 1 01 733 018 415 096 03272
HIV Coeliac disease 1492 0 11 0 0 331 034 05598
HIV Crohns disease 1923 1 24 042 001 234 032 05686
HIV ITP 712 3 09 329 068 964 274 00976
HIV Myxoedema 30859 11 201 055 027 098 368 00552
HIV Pernicious anaemia 1970 1 13 078 002 437 004 0844
HIV Polymyositis 135 2 01 1436 172 5288 1309 00003
HIV Primary biliary cirrhosis 377 1 02 575 015 3225 061 0435
HIV Psoriasis 3545 5 48 104 034 244 002 08955
HIV Rheumatoid arthritis 10250 4 88 045 012 116 214 01439
HIV Scleroderma 463 0 03 0 0 1449 023 06285
HIV Sjogrens syndrome 1053 1 05 2 005 1119 0 09991
HIV Systematic lupus erythematosus 715 0 06 0 0 606 002 0888
HIV Thyrotoxicosis 4076 4 35 115 031 295 0 0988
HIV Ulcerative colitis 3588 8 49 164 071 324 141 02348
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 458 20 2 1017 615 1589 14969 0
HIV Ankylosing spondylitis 1430 1 74 013 0 075 476 00291
HIV Autoimmune haemolytic anaemia 195 9 11 854 385 1655 5027 0
HIV Chronic active hepatitis 126 6 06 1068 385 2391 4141 0
HIV Coeliac disease 2230 5 96 052 017 122 173 01884
HIV Crohns disease 3262 22 203 108 068 164 007 07958
HIV ITP 694 23 44 533 335 806 7409 0
HIV Myxoedema 30770 47 922 051 037 068 2172 0
HIV Pernicious anaemia 1664 3 43 07 014 204 015 07013
HIV Polymyositis 127 3 1 316 064 945 246 01165
HIV Primary biliary cirrhosis 359 1 14 07 002 393 0 09501
HIV Psoriasis 6137 35 30 117 081 162 067 04141
HIV Rheumatoid arthritis 10968 21 365 057 036 088 617 0013
HIV Scleroderma 455 1 17 059 001 331 002 08849
HIV Sjogrens syndrome 995 1 29 034 001 192 068 04097
HIV Systematic lupus erythematosus 1279 7 63 112 045 231 001 09219
HIV Thyrotoxicosis 4589 18 191 094 056 149 002 08979
HIV Ulcerative colitis 5315 34 346 098 068 138 0 09893
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 213 11 1 1186 583 2166 9395 0
HIV Ankylosing spondylitis 486 2 27 074 009 269 002 09025
HIV Autoimmune haemolytic anaemia 66 2 03 627 074 2356 422 00398
HIV Chronic active hepatitis 39 2 02 1257 147 4856 1072 00011
HIV Coeliac disease 909 2 42 047 006 171 071 03994
HIV Crohns disease 2215 7 111 063 025 13 118 02778
HIV ITP 331 11 19 606 3 1098 4019 0
HIV Myxoedema 7241 15 325 046 026 076 896 00028
HIV Pernicious anaemia 472 0 17 0 0 212 089 03468
HIV Polymyositis 32 3 03 1034 203 3306 1533 00001
HIV Primary biliary cirrhosis 59 0 03 0 0 1176 01 07528
HIV Psoriasis 2551 23 109 213 135 32 1253 00004
HIV Rheumatoid arthritis 2238 7 95 073 03 152 043 05128
HIV Scleroderma 89 0 05 0 0 805 0 09596
HIV Sjogrens syndrome 160 0 07 0 0 564 004 08448
HIV Systematic lupus erythematosus 554 3 27 111 023 326 002 0899
HIV Thyrotoxicosis 1784 6 88 068 025 148 062 04293
HIV Ulcerative colitis 2667 15 151 1 056 165 001 09074
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 50 0 0 0 0 8184 44 00359
HIV Ankylosing spondylitis 10 0 0 0 0 71245 3898 0
HIV Autoimmune haemolytic anaemia 24 0 0 0 0 24127 1416 00002
HIV Chronic active hepatitis 17 0 0 0 0 12064 638 00115
HIV Coeliac disease 493 0 03 0 0 1306 017 06837
HIV Crohns disease 651 0 04 0 0 933 003 08691
HIV ITP 207 2 01 139 167 5086 1266 00004
HIV Myxoedema 781 0 05 0 0 704 0 09722
HIV Pernicious anaemia 14 0 0 0 0 84591 4915 0
HIV Polymyositis 4 0 0 0 0 6051 24878 0
HIV Primary biliary cirrhosis 2 0 0 0 0 0 0 0
HIV Psoriasis 357 0 01 0 0 2873 107 03016
HIV Rheumatoid arthritis 109 0 0 0 0 7558 409 00431
HIV Scleroderma 14 0 0 0 0 107299 626 0
HIV Sjogrens syndrome 10 0 0 0 0 396158 22105 0
HIV Systematic lupus erythematosus 64 0 0 0 0 7928 427 00387
HIV Thyrotoxicosis 173 0 01 0 0 3713 159 0207
HIV Ulcerative colitis 504 0 03 0 0 1346 018 06677
Cohort of HIV and Autoimmune Diseases-all cases
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1868 35 35 1008 7 1408 27231 0
HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147
HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0
HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0
HIV Coeliac disease 8127 7 156 045 018 092 423 00396
HIV Crohns disease 12300 31 349 089 06 126 034 05606
HIV ITP 4694 43 78 552 399 745 15331 0
HIV Myxoedema 181453 85 1577 054 043 067 331 0
HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492
HIV Polymyositis 631 10 15 691 33 1279 4409 0
HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381
HIV Psoriasis 18690 65 473 137 106 175 624 00125
HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113
HIV Scleroderma 1930 1 25 04 001 221 042 05189
HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396
HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218
HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879
HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929
Page 6: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

People living with MS (Total)

People living with

HIV(Total)

MS PrevalencePer 100000

HIV Prevalence

Per 100000

USA 400000 1200000 135 508

Canada 65000 60000 240 222

France 80000 130000 80 263

Germany 122000 49000 149 69

Netherlands 16000 18000 100 127

UK 85000 75000 110 137

Denmark 7500 6000 122 125

How many cases of HIV and MS have been reported

bull 1989 Berger reported 7 cases of an MS-like complex in HIV patients but none were followed up or apparently treated with ARVs

bull 2004 Corral reported a case of focal monophasic leukoencephalopathy in an HIV patients No details were provided on Follow-up or treatment

bull In all about 10 cases have been referred to in the medical literature in 30 years Six of these are questionable

What do cohort studies show

bull A single study in Danish National Registry of Patients (Nexo Pederson Sorensen and Koch-Henriksen Epidem 2013242 332-333) Cohort from 1994-2011

bull 5018 first time HIV diagnosis followed for 31875 person yearsbull 50194 controls matched for age and sex followed for 393871

person yearsbull One person with HIV developed MS which was a non-

significant relative risk of around 03 (95CI 004-22)

bull Interesting but not convincing

What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral

therapybull They affect similar demographic populations in western

countriesbull Literature consists of 950000 peer reviewed publications on

HIVAIDS and gt270000 peer reviewed papers on MS They are two of the most studied and documented conditions in medical science

bull Only one case of a patient with both MS and HIV documented as treated with anti-retroviral therapy (Eur J Neurol 201118110-111)

bull Unable to find HIV patients who have MS in major HIV clinics in Europe US and Australia

bull Unusual to find no documentation or company advice for treating HIV patients who have MS with DMT especially interferon

Methodsbull Hospital Episode Statistics of all 55 million people in

the UK from 1999 to 2011bull Any contact with healthcare system including

admissions day cases and deaths Multiple contacts are linked to individual record

bull Database analyzed at Unit of Health-care Epidemiology Oxford University

bull Exposed (HIV) and unexposed matched on week of first contact age area of residence and socio-economic status

bull Relative risk calculated using MS as outcome (OHIVEHIV)(OCCECC)

Age distribution of people entering the HIV cohort the percentage female and the number of people entering the reference cohort1

Age (yrs) N entering HIV cohort

( of total) female N entering the

reference cohort 0-4

139 (07) 446 137461

5-9

168 (08) 452 172624 10-14

138 (07) 572 138003

15-19

173 (08) 590 216875 20-24

653 (31) 444 267177

25-29

2136 (101) 439 340834 30-34

4066 (192) 369 459410

35-39

4792 (226) 296 541994 40-44

3701 (175) 249 496704

45-49

2228 (105) 206 433194 50-54

1293 (61) 186 446510

55-59

776 (37) 174 482105 60-64

480 (23) 163 506958

65-69

274 (13) 212 503916 70-74

98 (05) 214 508750

75-79

37 (02) 270 485042 80-84

22 (01) 227 353716

85+

33 (02) 455 252837

All ages 21207 (100) 302 6744110

Following 21207 patients with HIV for 152618 person years and 6744301 controls for 42148179person years to see who would develop MS On average the follow-up was 7 years

exposure outcome MS in HIVMS in

Controls

rate ratio(Relative

Risk)Protective

Effect low CI upr CI chi-sq p-value

HIVmultiple sclerosis 7 183 038 gt62 015 079 639 0011

NHS Data on UK Healthcare events 1999-2011

Sheet1

NHS Cohort gt One year after Exposure (HIV) Contact

Exposure OutcomeMS in

exposedMS in

Controls

Rate ratio (Relative

Risk)Protective

Effect Low CIHigh

CI Chi-sqP

value

HIVMultiple Sclerosis 4 158 022 80 007 065 81 0004

Assuming that HIV diagnosis was made on first contact assessmentof cohort after one year would probably account for effect of HIVtherapy on all exposed If no effect of HIV treatment then expect noreduction in Relative Risk

Cohort of HIV and Autoimmune Diseases-all casesexposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-valueHIV Addisons disease 1868 35 35 1008 7 1408 27231 0HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0HIV Coeliac disease 8127 7 156 045 018 092 423 00396HIV Crohns disease 12300 31 349 089 06 126 034 05606HIV ITP 4694 43 78 552 399 745 15331 0HIV Myxoedema 181453 85 1577 054 043 067 331 0HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492HIV Polymyositis 631 10 15 691 33 1279 4409 0HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381HIV Psoriasis 18690 65 473 137 106 175 624 00125

HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113HIV Scleroderma 1930 1 25 04 001 221 042 05189HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929

all

aged 0-14

15-34

35-54

55-64

65+

interval lt1yr

1-4

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 830 15 15 998 556 1655 11032 0
HIV Ankylosing spondylitis 1995 2 56 035 004 128 174 01866
HIV Autoimmune haemolytic anaemia 796 4 09 423 115 1088 687 00088
HIV Chronic active hepatitis 340 3 06 537 11 1582 668 00098
HIV Coeliac disease 3639 6 79 076 028 165 025 0616
HIV Crohns disease 5695 13 167 078 041 133 061 04355
HIV ITP 2142 15 32 473 265 783 4024 0
HIV Myxoedema 77911 43 698 062 045 083 992 00016
HIV Pernicious anaemia 7615 3 37 082 017 239 001 09271
HIV Polymyositis 302 8 08 1018 435 2031 5584 0
HIV Primary biliary cirrhosis 919 0 12 0 0 317 038 05375
HIV Psoriasis 8090 27 217 125 082 182 108 02985
HIV Rheumatoid arthritis 23991 17 266 064 037 102 314 00763
HIV Scleroderma 911 1 12 085 002 475 009 07639
HIV Sjogrens syndrome 1836 0 21 0 0 176 121 02704
HIV Systematic lupus erythematosus 1703 6 5 121 044 263 006 0813
HIV Thyrotoxicosis 11529 14 155 09 049 151 007 0797
HIV Ulcerative colitis 9323 30 282 106 072 152 006 08069
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 352 17 09 1992 1147 3236 27362 0
HIV Ankylosing spondylitis 767 1 11 088 002 493 012 07296
HIV Autoimmune haemolytic anaemia 306 7 04 1792 714 3736 9338 0
HIV Chronic active hepatitis 118 6 02 3067 1103 6878 13684 0
HIV Coeliac disease 1206 0 16 0 0 226 079 03752
HIV Crohns disease 1896 15 5 3 167 496 1787 0
HIV ITP 728 22 21 1068 665 1629 17803 0
HIV Myxoedema 28047 13 163 08 042 136 048 04889
HIV Pernicious anaemia 2773 1 09 106 003 593 021 06495
HIV Polymyositis 113 1 01 785 02 4461 108 02995
HIV Primary biliary cirrhosis 308 1 02 646 016 3624 077 03817
HIV Psoriasis 3072 22 61 361 226 548 3875 0
HIV Rheumatoid arthritis 9101 11 69 16 08 286 189 01697
HIV Scleroderma 294 0 03 0 0 1121 009 07682
HIV Sjogrens syndrome 565 2 05 436 053 1581 235 01253
HIV Systematic lupus erythematosus 608 1 12 082 002 461 007 07944
HIV Thyrotoxicosis 4243 5 43 118 038 275 001 09048
HIV Ulcerative colitis 3123 17 75 229 133 367 1101 00009
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 821 1 01 78 02 4358 108 02995
HIV Ankylosing spondylitis 1672 0 04 0 0 887 002 08966
HIV Autoimmune haemolytic anaemia 1142 1 02 418 011 2333 028 05943
HIV Chronic active hepatitis 300 1 01 1674 042 9401 323 00721
HIV Coeliac disease 3003 0 04 0 0 836 001 09297
HIV Crohns disease 4249 1 07 14 004 779 006 07988
HIV ITP 2750 4 05 823 224 2109 1866 0
HIV Myxoedema 111802 12 124 097 05 169 0 09748
HIV Pernicious anaemia 13040 0 15 0 0 253 063 04283
HIV Polymyositis 333 2 0 4371 527 15913 4594 0
HIV Primary biliary cirrhosis 1120 0 01 0 0 3586 153 02162
HIV Psoriasis 6100 2 15 131 016 472 0 09797
HIV Rheumatoid arthritis 30228 7 41 172 069 355 146 02269
HIV Scleroderma 909 0 01 0 0 3312 135 02449
HIV Sjogrens syndrome 1883 0 02 0 0 1969 052 04704
HIV Systematic lupus erythematosus 1056 0 02 0 0 1993 053 04648
HIV Thyrotoxicosis 15247 4 19 21 057 538 134 0247
HIV Ulcerative colitis 7697 5 16 317 103 74 541 002
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 326 3 03 893 183 2632 138 00002
HIV Ankylosing spondylitis 971 0 14 0 0 272 054 04621
HIV Autoimmune haemolytic anaemia 261 0 03 0 0 1419 022 06407
HIV Chronic active hepatitis 143 1 01 733 018 415 096 03272
HIV Coeliac disease 1492 0 11 0 0 331 034 05598
HIV Crohns disease 1923 1 24 042 001 234 032 05686
HIV ITP 712 3 09 329 068 964 274 00976
HIV Myxoedema 30859 11 201 055 027 098 368 00552
HIV Pernicious anaemia 1970 1 13 078 002 437 004 0844
HIV Polymyositis 135 2 01 1436 172 5288 1309 00003
HIV Primary biliary cirrhosis 377 1 02 575 015 3225 061 0435
HIV Psoriasis 3545 5 48 104 034 244 002 08955
HIV Rheumatoid arthritis 10250 4 88 045 012 116 214 01439
HIV Scleroderma 463 0 03 0 0 1449 023 06285
HIV Sjogrens syndrome 1053 1 05 2 005 1119 0 09991
HIV Systematic lupus erythematosus 715 0 06 0 0 606 002 0888
HIV Thyrotoxicosis 4076 4 35 115 031 295 0 0988
HIV Ulcerative colitis 3588 8 49 164 071 324 141 02348
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 458 20 2 1017 615 1589 14969 0
HIV Ankylosing spondylitis 1430 1 74 013 0 075 476 00291
HIV Autoimmune haemolytic anaemia 195 9 11 854 385 1655 5027 0
HIV Chronic active hepatitis 126 6 06 1068 385 2391 4141 0
HIV Coeliac disease 2230 5 96 052 017 122 173 01884
HIV Crohns disease 3262 22 203 108 068 164 007 07958
HIV ITP 694 23 44 533 335 806 7409 0
HIV Myxoedema 30770 47 922 051 037 068 2172 0
HIV Pernicious anaemia 1664 3 43 07 014 204 015 07013
HIV Polymyositis 127 3 1 316 064 945 246 01165
HIV Primary biliary cirrhosis 359 1 14 07 002 393 0 09501
HIV Psoriasis 6137 35 30 117 081 162 067 04141
HIV Rheumatoid arthritis 10968 21 365 057 036 088 617 0013
HIV Scleroderma 455 1 17 059 001 331 002 08849
HIV Sjogrens syndrome 995 1 29 034 001 192 068 04097
HIV Systematic lupus erythematosus 1279 7 63 112 045 231 001 09219
HIV Thyrotoxicosis 4589 18 191 094 056 149 002 08979
HIV Ulcerative colitis 5315 34 346 098 068 138 0 09893
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 213 11 1 1186 583 2166 9395 0
HIV Ankylosing spondylitis 486 2 27 074 009 269 002 09025
HIV Autoimmune haemolytic anaemia 66 2 03 627 074 2356 422 00398
HIV Chronic active hepatitis 39 2 02 1257 147 4856 1072 00011
HIV Coeliac disease 909 2 42 047 006 171 071 03994
HIV Crohns disease 2215 7 111 063 025 13 118 02778
HIV ITP 331 11 19 606 3 1098 4019 0
HIV Myxoedema 7241 15 325 046 026 076 896 00028
HIV Pernicious anaemia 472 0 17 0 0 212 089 03468
HIV Polymyositis 32 3 03 1034 203 3306 1533 00001
HIV Primary biliary cirrhosis 59 0 03 0 0 1176 01 07528
HIV Psoriasis 2551 23 109 213 135 32 1253 00004
HIV Rheumatoid arthritis 2238 7 95 073 03 152 043 05128
HIV Scleroderma 89 0 05 0 0 805 0 09596
HIV Sjogrens syndrome 160 0 07 0 0 564 004 08448
HIV Systematic lupus erythematosus 554 3 27 111 023 326 002 0899
HIV Thyrotoxicosis 1784 6 88 068 025 148 062 04293
HIV Ulcerative colitis 2667 15 151 1 056 165 001 09074
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 50 0 0 0 0 8184 44 00359
HIV Ankylosing spondylitis 10 0 0 0 0 71245 3898 0
HIV Autoimmune haemolytic anaemia 24 0 0 0 0 24127 1416 00002
HIV Chronic active hepatitis 17 0 0 0 0 12064 638 00115
HIV Coeliac disease 493 0 03 0 0 1306 017 06837
HIV Crohns disease 651 0 04 0 0 933 003 08691
HIV ITP 207 2 01 139 167 5086 1266 00004
HIV Myxoedema 781 0 05 0 0 704 0 09722
HIV Pernicious anaemia 14 0 0 0 0 84591 4915 0
HIV Polymyositis 4 0 0 0 0 6051 24878 0
HIV Primary biliary cirrhosis 2 0 0 0 0 0 0 0
HIV Psoriasis 357 0 01 0 0 2873 107 03016
HIV Rheumatoid arthritis 109 0 0 0 0 7558 409 00431
HIV Scleroderma 14 0 0 0 0 107299 626 0
HIV Sjogrens syndrome 10 0 0 0 0 396158 22105 0
HIV Systematic lupus erythematosus 64 0 0 0 0 7928 427 00387
HIV Thyrotoxicosis 173 0 01 0 0 3713 159 0207
HIV Ulcerative colitis 504 0 03 0 0 1346 018 06677
Cohort of HIV and Autoimmune Diseases-all cases
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1868 35 35 1008 7 1408 27231 0
HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147
HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0
HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0
HIV Coeliac disease 8127 7 156 045 018 092 423 00396
HIV Crohns disease 12300 31 349 089 06 126 034 05606
HIV ITP 4694 43 78 552 399 745 15331 0
HIV Myxoedema 181453 85 1577 054 043 067 331 0
HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492
HIV Polymyositis 631 10 15 691 33 1279 4409 0
HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381
HIV Psoriasis 18690 65 473 137 106 175 624 00125
HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113
HIV Scleroderma 1930 1 25 04 001 221 042 05189
HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396
HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218
HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879
HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929
Page 7: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

How many cases of HIV and MS have been reported

bull 1989 Berger reported 7 cases of an MS-like complex in HIV patients but none were followed up or apparently treated with ARVs

bull 2004 Corral reported a case of focal monophasic leukoencephalopathy in an HIV patients No details were provided on Follow-up or treatment

bull In all about 10 cases have been referred to in the medical literature in 30 years Six of these are questionable

What do cohort studies show

bull A single study in Danish National Registry of Patients (Nexo Pederson Sorensen and Koch-Henriksen Epidem 2013242 332-333) Cohort from 1994-2011

bull 5018 first time HIV diagnosis followed for 31875 person yearsbull 50194 controls matched for age and sex followed for 393871

person yearsbull One person with HIV developed MS which was a non-

significant relative risk of around 03 (95CI 004-22)

bull Interesting but not convincing

What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral

therapybull They affect similar demographic populations in western

countriesbull Literature consists of 950000 peer reviewed publications on

HIVAIDS and gt270000 peer reviewed papers on MS They are two of the most studied and documented conditions in medical science

bull Only one case of a patient with both MS and HIV documented as treated with anti-retroviral therapy (Eur J Neurol 201118110-111)

bull Unable to find HIV patients who have MS in major HIV clinics in Europe US and Australia

bull Unusual to find no documentation or company advice for treating HIV patients who have MS with DMT especially interferon

Methodsbull Hospital Episode Statistics of all 55 million people in

the UK from 1999 to 2011bull Any contact with healthcare system including

admissions day cases and deaths Multiple contacts are linked to individual record

bull Database analyzed at Unit of Health-care Epidemiology Oxford University

bull Exposed (HIV) and unexposed matched on week of first contact age area of residence and socio-economic status

bull Relative risk calculated using MS as outcome (OHIVEHIV)(OCCECC)

Age distribution of people entering the HIV cohort the percentage female and the number of people entering the reference cohort1

Age (yrs) N entering HIV cohort

( of total) female N entering the

reference cohort 0-4

139 (07) 446 137461

5-9

168 (08) 452 172624 10-14

138 (07) 572 138003

15-19

173 (08) 590 216875 20-24

653 (31) 444 267177

25-29

2136 (101) 439 340834 30-34

4066 (192) 369 459410

35-39

4792 (226) 296 541994 40-44

3701 (175) 249 496704

45-49

2228 (105) 206 433194 50-54

1293 (61) 186 446510

55-59

776 (37) 174 482105 60-64

480 (23) 163 506958

65-69

274 (13) 212 503916 70-74

98 (05) 214 508750

75-79

37 (02) 270 485042 80-84

22 (01) 227 353716

85+

33 (02) 455 252837

All ages 21207 (100) 302 6744110

Following 21207 patients with HIV for 152618 person years and 6744301 controls for 42148179person years to see who would develop MS On average the follow-up was 7 years

exposure outcome MS in HIVMS in

Controls

rate ratio(Relative

Risk)Protective

Effect low CI upr CI chi-sq p-value

HIVmultiple sclerosis 7 183 038 gt62 015 079 639 0011

NHS Data on UK Healthcare events 1999-2011

Sheet1

NHS Cohort gt One year after Exposure (HIV) Contact

Exposure OutcomeMS in

exposedMS in

Controls

Rate ratio (Relative

Risk)Protective

Effect Low CIHigh

CI Chi-sqP

value

HIVMultiple Sclerosis 4 158 022 80 007 065 81 0004

Assuming that HIV diagnosis was made on first contact assessmentof cohort after one year would probably account for effect of HIVtherapy on all exposed If no effect of HIV treatment then expect noreduction in Relative Risk

Cohort of HIV and Autoimmune Diseases-all casesexposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-valueHIV Addisons disease 1868 35 35 1008 7 1408 27231 0HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0HIV Coeliac disease 8127 7 156 045 018 092 423 00396HIV Crohns disease 12300 31 349 089 06 126 034 05606HIV ITP 4694 43 78 552 399 745 15331 0HIV Myxoedema 181453 85 1577 054 043 067 331 0HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492HIV Polymyositis 631 10 15 691 33 1279 4409 0HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381HIV Psoriasis 18690 65 473 137 106 175 624 00125

HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113HIV Scleroderma 1930 1 25 04 001 221 042 05189HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929

all

aged 0-14

15-34

35-54

55-64

65+

interval lt1yr

1-4

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
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  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 830 15 15 998 556 1655 11032 0
HIV Ankylosing spondylitis 1995 2 56 035 004 128 174 01866
HIV Autoimmune haemolytic anaemia 796 4 09 423 115 1088 687 00088
HIV Chronic active hepatitis 340 3 06 537 11 1582 668 00098
HIV Coeliac disease 3639 6 79 076 028 165 025 0616
HIV Crohns disease 5695 13 167 078 041 133 061 04355
HIV ITP 2142 15 32 473 265 783 4024 0
HIV Myxoedema 77911 43 698 062 045 083 992 00016
HIV Pernicious anaemia 7615 3 37 082 017 239 001 09271
HIV Polymyositis 302 8 08 1018 435 2031 5584 0
HIV Primary biliary cirrhosis 919 0 12 0 0 317 038 05375
HIV Psoriasis 8090 27 217 125 082 182 108 02985
HIV Rheumatoid arthritis 23991 17 266 064 037 102 314 00763
HIV Scleroderma 911 1 12 085 002 475 009 07639
HIV Sjogrens syndrome 1836 0 21 0 0 176 121 02704
HIV Systematic lupus erythematosus 1703 6 5 121 044 263 006 0813
HIV Thyrotoxicosis 11529 14 155 09 049 151 007 0797
HIV Ulcerative colitis 9323 30 282 106 072 152 006 08069
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 352 17 09 1992 1147 3236 27362 0
HIV Ankylosing spondylitis 767 1 11 088 002 493 012 07296
HIV Autoimmune haemolytic anaemia 306 7 04 1792 714 3736 9338 0
HIV Chronic active hepatitis 118 6 02 3067 1103 6878 13684 0
HIV Coeliac disease 1206 0 16 0 0 226 079 03752
HIV Crohns disease 1896 15 5 3 167 496 1787 0
HIV ITP 728 22 21 1068 665 1629 17803 0
HIV Myxoedema 28047 13 163 08 042 136 048 04889
HIV Pernicious anaemia 2773 1 09 106 003 593 021 06495
HIV Polymyositis 113 1 01 785 02 4461 108 02995
HIV Primary biliary cirrhosis 308 1 02 646 016 3624 077 03817
HIV Psoriasis 3072 22 61 361 226 548 3875 0
HIV Rheumatoid arthritis 9101 11 69 16 08 286 189 01697
HIV Scleroderma 294 0 03 0 0 1121 009 07682
HIV Sjogrens syndrome 565 2 05 436 053 1581 235 01253
HIV Systematic lupus erythematosus 608 1 12 082 002 461 007 07944
HIV Thyrotoxicosis 4243 5 43 118 038 275 001 09048
HIV Ulcerative colitis 3123 17 75 229 133 367 1101 00009
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 821 1 01 78 02 4358 108 02995
HIV Ankylosing spondylitis 1672 0 04 0 0 887 002 08966
HIV Autoimmune haemolytic anaemia 1142 1 02 418 011 2333 028 05943
HIV Chronic active hepatitis 300 1 01 1674 042 9401 323 00721
HIV Coeliac disease 3003 0 04 0 0 836 001 09297
HIV Crohns disease 4249 1 07 14 004 779 006 07988
HIV ITP 2750 4 05 823 224 2109 1866 0
HIV Myxoedema 111802 12 124 097 05 169 0 09748
HIV Pernicious anaemia 13040 0 15 0 0 253 063 04283
HIV Polymyositis 333 2 0 4371 527 15913 4594 0
HIV Primary biliary cirrhosis 1120 0 01 0 0 3586 153 02162
HIV Psoriasis 6100 2 15 131 016 472 0 09797
HIV Rheumatoid arthritis 30228 7 41 172 069 355 146 02269
HIV Scleroderma 909 0 01 0 0 3312 135 02449
HIV Sjogrens syndrome 1883 0 02 0 0 1969 052 04704
HIV Systematic lupus erythematosus 1056 0 02 0 0 1993 053 04648
HIV Thyrotoxicosis 15247 4 19 21 057 538 134 0247
HIV Ulcerative colitis 7697 5 16 317 103 74 541 002
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 326 3 03 893 183 2632 138 00002
HIV Ankylosing spondylitis 971 0 14 0 0 272 054 04621
HIV Autoimmune haemolytic anaemia 261 0 03 0 0 1419 022 06407
HIV Chronic active hepatitis 143 1 01 733 018 415 096 03272
HIV Coeliac disease 1492 0 11 0 0 331 034 05598
HIV Crohns disease 1923 1 24 042 001 234 032 05686
HIV ITP 712 3 09 329 068 964 274 00976
HIV Myxoedema 30859 11 201 055 027 098 368 00552
HIV Pernicious anaemia 1970 1 13 078 002 437 004 0844
HIV Polymyositis 135 2 01 1436 172 5288 1309 00003
HIV Primary biliary cirrhosis 377 1 02 575 015 3225 061 0435
HIV Psoriasis 3545 5 48 104 034 244 002 08955
HIV Rheumatoid arthritis 10250 4 88 045 012 116 214 01439
HIV Scleroderma 463 0 03 0 0 1449 023 06285
HIV Sjogrens syndrome 1053 1 05 2 005 1119 0 09991
HIV Systematic lupus erythematosus 715 0 06 0 0 606 002 0888
HIV Thyrotoxicosis 4076 4 35 115 031 295 0 0988
HIV Ulcerative colitis 3588 8 49 164 071 324 141 02348
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 458 20 2 1017 615 1589 14969 0
HIV Ankylosing spondylitis 1430 1 74 013 0 075 476 00291
HIV Autoimmune haemolytic anaemia 195 9 11 854 385 1655 5027 0
HIV Chronic active hepatitis 126 6 06 1068 385 2391 4141 0
HIV Coeliac disease 2230 5 96 052 017 122 173 01884
HIV Crohns disease 3262 22 203 108 068 164 007 07958
HIV ITP 694 23 44 533 335 806 7409 0
HIV Myxoedema 30770 47 922 051 037 068 2172 0
HIV Pernicious anaemia 1664 3 43 07 014 204 015 07013
HIV Polymyositis 127 3 1 316 064 945 246 01165
HIV Primary biliary cirrhosis 359 1 14 07 002 393 0 09501
HIV Psoriasis 6137 35 30 117 081 162 067 04141
HIV Rheumatoid arthritis 10968 21 365 057 036 088 617 0013
HIV Scleroderma 455 1 17 059 001 331 002 08849
HIV Sjogrens syndrome 995 1 29 034 001 192 068 04097
HIV Systematic lupus erythematosus 1279 7 63 112 045 231 001 09219
HIV Thyrotoxicosis 4589 18 191 094 056 149 002 08979
HIV Ulcerative colitis 5315 34 346 098 068 138 0 09893
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 213 11 1 1186 583 2166 9395 0
HIV Ankylosing spondylitis 486 2 27 074 009 269 002 09025
HIV Autoimmune haemolytic anaemia 66 2 03 627 074 2356 422 00398
HIV Chronic active hepatitis 39 2 02 1257 147 4856 1072 00011
HIV Coeliac disease 909 2 42 047 006 171 071 03994
HIV Crohns disease 2215 7 111 063 025 13 118 02778
HIV ITP 331 11 19 606 3 1098 4019 0
HIV Myxoedema 7241 15 325 046 026 076 896 00028
HIV Pernicious anaemia 472 0 17 0 0 212 089 03468
HIV Polymyositis 32 3 03 1034 203 3306 1533 00001
HIV Primary biliary cirrhosis 59 0 03 0 0 1176 01 07528
HIV Psoriasis 2551 23 109 213 135 32 1253 00004
HIV Rheumatoid arthritis 2238 7 95 073 03 152 043 05128
HIV Scleroderma 89 0 05 0 0 805 0 09596
HIV Sjogrens syndrome 160 0 07 0 0 564 004 08448
HIV Systematic lupus erythematosus 554 3 27 111 023 326 002 0899
HIV Thyrotoxicosis 1784 6 88 068 025 148 062 04293
HIV Ulcerative colitis 2667 15 151 1 056 165 001 09074
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 50 0 0 0 0 8184 44 00359
HIV Ankylosing spondylitis 10 0 0 0 0 71245 3898 0
HIV Autoimmune haemolytic anaemia 24 0 0 0 0 24127 1416 00002
HIV Chronic active hepatitis 17 0 0 0 0 12064 638 00115
HIV Coeliac disease 493 0 03 0 0 1306 017 06837
HIV Crohns disease 651 0 04 0 0 933 003 08691
HIV ITP 207 2 01 139 167 5086 1266 00004
HIV Myxoedema 781 0 05 0 0 704 0 09722
HIV Pernicious anaemia 14 0 0 0 0 84591 4915 0
HIV Polymyositis 4 0 0 0 0 6051 24878 0
HIV Primary biliary cirrhosis 2 0 0 0 0 0 0 0
HIV Psoriasis 357 0 01 0 0 2873 107 03016
HIV Rheumatoid arthritis 109 0 0 0 0 7558 409 00431
HIV Scleroderma 14 0 0 0 0 107299 626 0
HIV Sjogrens syndrome 10 0 0 0 0 396158 22105 0
HIV Systematic lupus erythematosus 64 0 0 0 0 7928 427 00387
HIV Thyrotoxicosis 173 0 01 0 0 3713 159 0207
HIV Ulcerative colitis 504 0 03 0 0 1346 018 06677
Cohort of HIV and Autoimmune Diseases-all cases
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1868 35 35 1008 7 1408 27231 0
HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147
HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0
HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0
HIV Coeliac disease 8127 7 156 045 018 092 423 00396
HIV Crohns disease 12300 31 349 089 06 126 034 05606
HIV ITP 4694 43 78 552 399 745 15331 0
HIV Myxoedema 181453 85 1577 054 043 067 331 0
HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492
HIV Polymyositis 631 10 15 691 33 1279 4409 0
HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381
HIV Psoriasis 18690 65 473 137 106 175 624 00125
HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113
HIV Scleroderma 1930 1 25 04 001 221 042 05189
HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396
HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218
HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879
HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929
Page 8: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

What do cohort studies show

bull A single study in Danish National Registry of Patients (Nexo Pederson Sorensen and Koch-Henriksen Epidem 2013242 332-333) Cohort from 1994-2011

bull 5018 first time HIV diagnosis followed for 31875 person yearsbull 50194 controls matched for age and sex followed for 393871

person yearsbull One person with HIV developed MS which was a non-

significant relative risk of around 03 (95CI 004-22)

bull Interesting but not convincing

What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral

therapybull They affect similar demographic populations in western

countriesbull Literature consists of 950000 peer reviewed publications on

HIVAIDS and gt270000 peer reviewed papers on MS They are two of the most studied and documented conditions in medical science

bull Only one case of a patient with both MS and HIV documented as treated with anti-retroviral therapy (Eur J Neurol 201118110-111)

bull Unable to find HIV patients who have MS in major HIV clinics in Europe US and Australia

bull Unusual to find no documentation or company advice for treating HIV patients who have MS with DMT especially interferon

Methodsbull Hospital Episode Statistics of all 55 million people in

the UK from 1999 to 2011bull Any contact with healthcare system including

admissions day cases and deaths Multiple contacts are linked to individual record

bull Database analyzed at Unit of Health-care Epidemiology Oxford University

bull Exposed (HIV) and unexposed matched on week of first contact age area of residence and socio-economic status

bull Relative risk calculated using MS as outcome (OHIVEHIV)(OCCECC)

Age distribution of people entering the HIV cohort the percentage female and the number of people entering the reference cohort1

Age (yrs) N entering HIV cohort

( of total) female N entering the

reference cohort 0-4

139 (07) 446 137461

5-9

168 (08) 452 172624 10-14

138 (07) 572 138003

15-19

173 (08) 590 216875 20-24

653 (31) 444 267177

25-29

2136 (101) 439 340834 30-34

4066 (192) 369 459410

35-39

4792 (226) 296 541994 40-44

3701 (175) 249 496704

45-49

2228 (105) 206 433194 50-54

1293 (61) 186 446510

55-59

776 (37) 174 482105 60-64

480 (23) 163 506958

65-69

274 (13) 212 503916 70-74

98 (05) 214 508750

75-79

37 (02) 270 485042 80-84

22 (01) 227 353716

85+

33 (02) 455 252837

All ages 21207 (100) 302 6744110

Following 21207 patients with HIV for 152618 person years and 6744301 controls for 42148179person years to see who would develop MS On average the follow-up was 7 years

exposure outcome MS in HIVMS in

Controls

rate ratio(Relative

Risk)Protective

Effect low CI upr CI chi-sq p-value

HIVmultiple sclerosis 7 183 038 gt62 015 079 639 0011

NHS Data on UK Healthcare events 1999-2011

Sheet1

NHS Cohort gt One year after Exposure (HIV) Contact

Exposure OutcomeMS in

exposedMS in

Controls

Rate ratio (Relative

Risk)Protective

Effect Low CIHigh

CI Chi-sqP

value

HIVMultiple Sclerosis 4 158 022 80 007 065 81 0004

Assuming that HIV diagnosis was made on first contact assessmentof cohort after one year would probably account for effect of HIVtherapy on all exposed If no effect of HIV treatment then expect noreduction in Relative Risk

Cohort of HIV and Autoimmune Diseases-all casesexposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-valueHIV Addisons disease 1868 35 35 1008 7 1408 27231 0HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0HIV Coeliac disease 8127 7 156 045 018 092 423 00396HIV Crohns disease 12300 31 349 089 06 126 034 05606HIV ITP 4694 43 78 552 399 745 15331 0HIV Myxoedema 181453 85 1577 054 043 067 331 0HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492HIV Polymyositis 631 10 15 691 33 1279 4409 0HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381HIV Psoriasis 18690 65 473 137 106 175 624 00125

HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113HIV Scleroderma 1930 1 25 04 001 221 042 05189HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929

all

aged 0-14

15-34

35-54

55-64

65+

interval lt1yr

1-4

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 830 15 15 998 556 1655 11032 0
HIV Ankylosing spondylitis 1995 2 56 035 004 128 174 01866
HIV Autoimmune haemolytic anaemia 796 4 09 423 115 1088 687 00088
HIV Chronic active hepatitis 340 3 06 537 11 1582 668 00098
HIV Coeliac disease 3639 6 79 076 028 165 025 0616
HIV Crohns disease 5695 13 167 078 041 133 061 04355
HIV ITP 2142 15 32 473 265 783 4024 0
HIV Myxoedema 77911 43 698 062 045 083 992 00016
HIV Pernicious anaemia 7615 3 37 082 017 239 001 09271
HIV Polymyositis 302 8 08 1018 435 2031 5584 0
HIV Primary biliary cirrhosis 919 0 12 0 0 317 038 05375
HIV Psoriasis 8090 27 217 125 082 182 108 02985
HIV Rheumatoid arthritis 23991 17 266 064 037 102 314 00763
HIV Scleroderma 911 1 12 085 002 475 009 07639
HIV Sjogrens syndrome 1836 0 21 0 0 176 121 02704
HIV Systematic lupus erythematosus 1703 6 5 121 044 263 006 0813
HIV Thyrotoxicosis 11529 14 155 09 049 151 007 0797
HIV Ulcerative colitis 9323 30 282 106 072 152 006 08069
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 352 17 09 1992 1147 3236 27362 0
HIV Ankylosing spondylitis 767 1 11 088 002 493 012 07296
HIV Autoimmune haemolytic anaemia 306 7 04 1792 714 3736 9338 0
HIV Chronic active hepatitis 118 6 02 3067 1103 6878 13684 0
HIV Coeliac disease 1206 0 16 0 0 226 079 03752
HIV Crohns disease 1896 15 5 3 167 496 1787 0
HIV ITP 728 22 21 1068 665 1629 17803 0
HIV Myxoedema 28047 13 163 08 042 136 048 04889
HIV Pernicious anaemia 2773 1 09 106 003 593 021 06495
HIV Polymyositis 113 1 01 785 02 4461 108 02995
HIV Primary biliary cirrhosis 308 1 02 646 016 3624 077 03817
HIV Psoriasis 3072 22 61 361 226 548 3875 0
HIV Rheumatoid arthritis 9101 11 69 16 08 286 189 01697
HIV Scleroderma 294 0 03 0 0 1121 009 07682
HIV Sjogrens syndrome 565 2 05 436 053 1581 235 01253
HIV Systematic lupus erythematosus 608 1 12 082 002 461 007 07944
HIV Thyrotoxicosis 4243 5 43 118 038 275 001 09048
HIV Ulcerative colitis 3123 17 75 229 133 367 1101 00009
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 821 1 01 78 02 4358 108 02995
HIV Ankylosing spondylitis 1672 0 04 0 0 887 002 08966
HIV Autoimmune haemolytic anaemia 1142 1 02 418 011 2333 028 05943
HIV Chronic active hepatitis 300 1 01 1674 042 9401 323 00721
HIV Coeliac disease 3003 0 04 0 0 836 001 09297
HIV Crohns disease 4249 1 07 14 004 779 006 07988
HIV ITP 2750 4 05 823 224 2109 1866 0
HIV Myxoedema 111802 12 124 097 05 169 0 09748
HIV Pernicious anaemia 13040 0 15 0 0 253 063 04283
HIV Polymyositis 333 2 0 4371 527 15913 4594 0
HIV Primary biliary cirrhosis 1120 0 01 0 0 3586 153 02162
HIV Psoriasis 6100 2 15 131 016 472 0 09797
HIV Rheumatoid arthritis 30228 7 41 172 069 355 146 02269
HIV Scleroderma 909 0 01 0 0 3312 135 02449
HIV Sjogrens syndrome 1883 0 02 0 0 1969 052 04704
HIV Systematic lupus erythematosus 1056 0 02 0 0 1993 053 04648
HIV Thyrotoxicosis 15247 4 19 21 057 538 134 0247
HIV Ulcerative colitis 7697 5 16 317 103 74 541 002
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 326 3 03 893 183 2632 138 00002
HIV Ankylosing spondylitis 971 0 14 0 0 272 054 04621
HIV Autoimmune haemolytic anaemia 261 0 03 0 0 1419 022 06407
HIV Chronic active hepatitis 143 1 01 733 018 415 096 03272
HIV Coeliac disease 1492 0 11 0 0 331 034 05598
HIV Crohns disease 1923 1 24 042 001 234 032 05686
HIV ITP 712 3 09 329 068 964 274 00976
HIV Myxoedema 30859 11 201 055 027 098 368 00552
HIV Pernicious anaemia 1970 1 13 078 002 437 004 0844
HIV Polymyositis 135 2 01 1436 172 5288 1309 00003
HIV Primary biliary cirrhosis 377 1 02 575 015 3225 061 0435
HIV Psoriasis 3545 5 48 104 034 244 002 08955
HIV Rheumatoid arthritis 10250 4 88 045 012 116 214 01439
HIV Scleroderma 463 0 03 0 0 1449 023 06285
HIV Sjogrens syndrome 1053 1 05 2 005 1119 0 09991
HIV Systematic lupus erythematosus 715 0 06 0 0 606 002 0888
HIV Thyrotoxicosis 4076 4 35 115 031 295 0 0988
HIV Ulcerative colitis 3588 8 49 164 071 324 141 02348
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 458 20 2 1017 615 1589 14969 0
HIV Ankylosing spondylitis 1430 1 74 013 0 075 476 00291
HIV Autoimmune haemolytic anaemia 195 9 11 854 385 1655 5027 0
HIV Chronic active hepatitis 126 6 06 1068 385 2391 4141 0
HIV Coeliac disease 2230 5 96 052 017 122 173 01884
HIV Crohns disease 3262 22 203 108 068 164 007 07958
HIV ITP 694 23 44 533 335 806 7409 0
HIV Myxoedema 30770 47 922 051 037 068 2172 0
HIV Pernicious anaemia 1664 3 43 07 014 204 015 07013
HIV Polymyositis 127 3 1 316 064 945 246 01165
HIV Primary biliary cirrhosis 359 1 14 07 002 393 0 09501
HIV Psoriasis 6137 35 30 117 081 162 067 04141
HIV Rheumatoid arthritis 10968 21 365 057 036 088 617 0013
HIV Scleroderma 455 1 17 059 001 331 002 08849
HIV Sjogrens syndrome 995 1 29 034 001 192 068 04097
HIV Systematic lupus erythematosus 1279 7 63 112 045 231 001 09219
HIV Thyrotoxicosis 4589 18 191 094 056 149 002 08979
HIV Ulcerative colitis 5315 34 346 098 068 138 0 09893
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 213 11 1 1186 583 2166 9395 0
HIV Ankylosing spondylitis 486 2 27 074 009 269 002 09025
HIV Autoimmune haemolytic anaemia 66 2 03 627 074 2356 422 00398
HIV Chronic active hepatitis 39 2 02 1257 147 4856 1072 00011
HIV Coeliac disease 909 2 42 047 006 171 071 03994
HIV Crohns disease 2215 7 111 063 025 13 118 02778
HIV ITP 331 11 19 606 3 1098 4019 0
HIV Myxoedema 7241 15 325 046 026 076 896 00028
HIV Pernicious anaemia 472 0 17 0 0 212 089 03468
HIV Polymyositis 32 3 03 1034 203 3306 1533 00001
HIV Primary biliary cirrhosis 59 0 03 0 0 1176 01 07528
HIV Psoriasis 2551 23 109 213 135 32 1253 00004
HIV Rheumatoid arthritis 2238 7 95 073 03 152 043 05128
HIV Scleroderma 89 0 05 0 0 805 0 09596
HIV Sjogrens syndrome 160 0 07 0 0 564 004 08448
HIV Systematic lupus erythematosus 554 3 27 111 023 326 002 0899
HIV Thyrotoxicosis 1784 6 88 068 025 148 062 04293
HIV Ulcerative colitis 2667 15 151 1 056 165 001 09074
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 50 0 0 0 0 8184 44 00359
HIV Ankylosing spondylitis 10 0 0 0 0 71245 3898 0
HIV Autoimmune haemolytic anaemia 24 0 0 0 0 24127 1416 00002
HIV Chronic active hepatitis 17 0 0 0 0 12064 638 00115
HIV Coeliac disease 493 0 03 0 0 1306 017 06837
HIV Crohns disease 651 0 04 0 0 933 003 08691
HIV ITP 207 2 01 139 167 5086 1266 00004
HIV Myxoedema 781 0 05 0 0 704 0 09722
HIV Pernicious anaemia 14 0 0 0 0 84591 4915 0
HIV Polymyositis 4 0 0 0 0 6051 24878 0
HIV Primary biliary cirrhosis 2 0 0 0 0 0 0 0
HIV Psoriasis 357 0 01 0 0 2873 107 03016
HIV Rheumatoid arthritis 109 0 0 0 0 7558 409 00431
HIV Scleroderma 14 0 0 0 0 107299 626 0
HIV Sjogrens syndrome 10 0 0 0 0 396158 22105 0
HIV Systematic lupus erythematosus 64 0 0 0 0 7928 427 00387
HIV Thyrotoxicosis 173 0 01 0 0 3713 159 0207
HIV Ulcerative colitis 504 0 03 0 0 1346 018 06677
Cohort of HIV and Autoimmune Diseases-all cases
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1868 35 35 1008 7 1408 27231 0
HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147
HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0
HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0
HIV Coeliac disease 8127 7 156 045 018 092 423 00396
HIV Crohns disease 12300 31 349 089 06 126 034 05606
HIV ITP 4694 43 78 552 399 745 15331 0
HIV Myxoedema 181453 85 1577 054 043 067 331 0
HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492
HIV Polymyositis 631 10 15 691 33 1279 4409 0
HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381
HIV Psoriasis 18690 65 473 137 106 175 624 00125
HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113
HIV Scleroderma 1930 1 25 04 001 221 042 05189
HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396
HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218
HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879
HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929
Page 9: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral

therapybull They affect similar demographic populations in western

countriesbull Literature consists of 950000 peer reviewed publications on

HIVAIDS and gt270000 peer reviewed papers on MS They are two of the most studied and documented conditions in medical science

bull Only one case of a patient with both MS and HIV documented as treated with anti-retroviral therapy (Eur J Neurol 201118110-111)

bull Unable to find HIV patients who have MS in major HIV clinics in Europe US and Australia

bull Unusual to find no documentation or company advice for treating HIV patients who have MS with DMT especially interferon

Methodsbull Hospital Episode Statistics of all 55 million people in

the UK from 1999 to 2011bull Any contact with healthcare system including

admissions day cases and deaths Multiple contacts are linked to individual record

bull Database analyzed at Unit of Health-care Epidemiology Oxford University

bull Exposed (HIV) and unexposed matched on week of first contact age area of residence and socio-economic status

bull Relative risk calculated using MS as outcome (OHIVEHIV)(OCCECC)

Age distribution of people entering the HIV cohort the percentage female and the number of people entering the reference cohort1

Age (yrs) N entering HIV cohort

( of total) female N entering the

reference cohort 0-4

139 (07) 446 137461

5-9

168 (08) 452 172624 10-14

138 (07) 572 138003

15-19

173 (08) 590 216875 20-24

653 (31) 444 267177

25-29

2136 (101) 439 340834 30-34

4066 (192) 369 459410

35-39

4792 (226) 296 541994 40-44

3701 (175) 249 496704

45-49

2228 (105) 206 433194 50-54

1293 (61) 186 446510

55-59

776 (37) 174 482105 60-64

480 (23) 163 506958

65-69

274 (13) 212 503916 70-74

98 (05) 214 508750

75-79

37 (02) 270 485042 80-84

22 (01) 227 353716

85+

33 (02) 455 252837

All ages 21207 (100) 302 6744110

Following 21207 patients with HIV for 152618 person years and 6744301 controls for 42148179person years to see who would develop MS On average the follow-up was 7 years

exposure outcome MS in HIVMS in

Controls

rate ratio(Relative

Risk)Protective

Effect low CI upr CI chi-sq p-value

HIVmultiple sclerosis 7 183 038 gt62 015 079 639 0011

NHS Data on UK Healthcare events 1999-2011

Sheet1

NHS Cohort gt One year after Exposure (HIV) Contact

Exposure OutcomeMS in

exposedMS in

Controls

Rate ratio (Relative

Risk)Protective

Effect Low CIHigh

CI Chi-sqP

value

HIVMultiple Sclerosis 4 158 022 80 007 065 81 0004

Assuming that HIV diagnosis was made on first contact assessmentof cohort after one year would probably account for effect of HIVtherapy on all exposed If no effect of HIV treatment then expect noreduction in Relative Risk

Cohort of HIV and Autoimmune Diseases-all casesexposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-valueHIV Addisons disease 1868 35 35 1008 7 1408 27231 0HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0HIV Coeliac disease 8127 7 156 045 018 092 423 00396HIV Crohns disease 12300 31 349 089 06 126 034 05606HIV ITP 4694 43 78 552 399 745 15331 0HIV Myxoedema 181453 85 1577 054 043 067 331 0HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492HIV Polymyositis 631 10 15 691 33 1279 4409 0HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381HIV Psoriasis 18690 65 473 137 106 175 624 00125

HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113HIV Scleroderma 1930 1 25 04 001 221 042 05189HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929

all

aged 0-14

15-34

35-54

55-64

65+

interval lt1yr

1-4

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 830 15 15 998 556 1655 11032 0
HIV Ankylosing spondylitis 1995 2 56 035 004 128 174 01866
HIV Autoimmune haemolytic anaemia 796 4 09 423 115 1088 687 00088
HIV Chronic active hepatitis 340 3 06 537 11 1582 668 00098
HIV Coeliac disease 3639 6 79 076 028 165 025 0616
HIV Crohns disease 5695 13 167 078 041 133 061 04355
HIV ITP 2142 15 32 473 265 783 4024 0
HIV Myxoedema 77911 43 698 062 045 083 992 00016
HIV Pernicious anaemia 7615 3 37 082 017 239 001 09271
HIV Polymyositis 302 8 08 1018 435 2031 5584 0
HIV Primary biliary cirrhosis 919 0 12 0 0 317 038 05375
HIV Psoriasis 8090 27 217 125 082 182 108 02985
HIV Rheumatoid arthritis 23991 17 266 064 037 102 314 00763
HIV Scleroderma 911 1 12 085 002 475 009 07639
HIV Sjogrens syndrome 1836 0 21 0 0 176 121 02704
HIV Systematic lupus erythematosus 1703 6 5 121 044 263 006 0813
HIV Thyrotoxicosis 11529 14 155 09 049 151 007 0797
HIV Ulcerative colitis 9323 30 282 106 072 152 006 08069
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 352 17 09 1992 1147 3236 27362 0
HIV Ankylosing spondylitis 767 1 11 088 002 493 012 07296
HIV Autoimmune haemolytic anaemia 306 7 04 1792 714 3736 9338 0
HIV Chronic active hepatitis 118 6 02 3067 1103 6878 13684 0
HIV Coeliac disease 1206 0 16 0 0 226 079 03752
HIV Crohns disease 1896 15 5 3 167 496 1787 0
HIV ITP 728 22 21 1068 665 1629 17803 0
HIV Myxoedema 28047 13 163 08 042 136 048 04889
HIV Pernicious anaemia 2773 1 09 106 003 593 021 06495
HIV Polymyositis 113 1 01 785 02 4461 108 02995
HIV Primary biliary cirrhosis 308 1 02 646 016 3624 077 03817
HIV Psoriasis 3072 22 61 361 226 548 3875 0
HIV Rheumatoid arthritis 9101 11 69 16 08 286 189 01697
HIV Scleroderma 294 0 03 0 0 1121 009 07682
HIV Sjogrens syndrome 565 2 05 436 053 1581 235 01253
HIV Systematic lupus erythematosus 608 1 12 082 002 461 007 07944
HIV Thyrotoxicosis 4243 5 43 118 038 275 001 09048
HIV Ulcerative colitis 3123 17 75 229 133 367 1101 00009
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 821 1 01 78 02 4358 108 02995
HIV Ankylosing spondylitis 1672 0 04 0 0 887 002 08966
HIV Autoimmune haemolytic anaemia 1142 1 02 418 011 2333 028 05943
HIV Chronic active hepatitis 300 1 01 1674 042 9401 323 00721
HIV Coeliac disease 3003 0 04 0 0 836 001 09297
HIV Crohns disease 4249 1 07 14 004 779 006 07988
HIV ITP 2750 4 05 823 224 2109 1866 0
HIV Myxoedema 111802 12 124 097 05 169 0 09748
HIV Pernicious anaemia 13040 0 15 0 0 253 063 04283
HIV Polymyositis 333 2 0 4371 527 15913 4594 0
HIV Primary biliary cirrhosis 1120 0 01 0 0 3586 153 02162
HIV Psoriasis 6100 2 15 131 016 472 0 09797
HIV Rheumatoid arthritis 30228 7 41 172 069 355 146 02269
HIV Scleroderma 909 0 01 0 0 3312 135 02449
HIV Sjogrens syndrome 1883 0 02 0 0 1969 052 04704
HIV Systematic lupus erythematosus 1056 0 02 0 0 1993 053 04648
HIV Thyrotoxicosis 15247 4 19 21 057 538 134 0247
HIV Ulcerative colitis 7697 5 16 317 103 74 541 002
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 326 3 03 893 183 2632 138 00002
HIV Ankylosing spondylitis 971 0 14 0 0 272 054 04621
HIV Autoimmune haemolytic anaemia 261 0 03 0 0 1419 022 06407
HIV Chronic active hepatitis 143 1 01 733 018 415 096 03272
HIV Coeliac disease 1492 0 11 0 0 331 034 05598
HIV Crohns disease 1923 1 24 042 001 234 032 05686
HIV ITP 712 3 09 329 068 964 274 00976
HIV Myxoedema 30859 11 201 055 027 098 368 00552
HIV Pernicious anaemia 1970 1 13 078 002 437 004 0844
HIV Polymyositis 135 2 01 1436 172 5288 1309 00003
HIV Primary biliary cirrhosis 377 1 02 575 015 3225 061 0435
HIV Psoriasis 3545 5 48 104 034 244 002 08955
HIV Rheumatoid arthritis 10250 4 88 045 012 116 214 01439
HIV Scleroderma 463 0 03 0 0 1449 023 06285
HIV Sjogrens syndrome 1053 1 05 2 005 1119 0 09991
HIV Systematic lupus erythematosus 715 0 06 0 0 606 002 0888
HIV Thyrotoxicosis 4076 4 35 115 031 295 0 0988
HIV Ulcerative colitis 3588 8 49 164 071 324 141 02348
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 458 20 2 1017 615 1589 14969 0
HIV Ankylosing spondylitis 1430 1 74 013 0 075 476 00291
HIV Autoimmune haemolytic anaemia 195 9 11 854 385 1655 5027 0
HIV Chronic active hepatitis 126 6 06 1068 385 2391 4141 0
HIV Coeliac disease 2230 5 96 052 017 122 173 01884
HIV Crohns disease 3262 22 203 108 068 164 007 07958
HIV ITP 694 23 44 533 335 806 7409 0
HIV Myxoedema 30770 47 922 051 037 068 2172 0
HIV Pernicious anaemia 1664 3 43 07 014 204 015 07013
HIV Polymyositis 127 3 1 316 064 945 246 01165
HIV Primary biliary cirrhosis 359 1 14 07 002 393 0 09501
HIV Psoriasis 6137 35 30 117 081 162 067 04141
HIV Rheumatoid arthritis 10968 21 365 057 036 088 617 0013
HIV Scleroderma 455 1 17 059 001 331 002 08849
HIV Sjogrens syndrome 995 1 29 034 001 192 068 04097
HIV Systematic lupus erythematosus 1279 7 63 112 045 231 001 09219
HIV Thyrotoxicosis 4589 18 191 094 056 149 002 08979
HIV Ulcerative colitis 5315 34 346 098 068 138 0 09893
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 213 11 1 1186 583 2166 9395 0
HIV Ankylosing spondylitis 486 2 27 074 009 269 002 09025
HIV Autoimmune haemolytic anaemia 66 2 03 627 074 2356 422 00398
HIV Chronic active hepatitis 39 2 02 1257 147 4856 1072 00011
HIV Coeliac disease 909 2 42 047 006 171 071 03994
HIV Crohns disease 2215 7 111 063 025 13 118 02778
HIV ITP 331 11 19 606 3 1098 4019 0
HIV Myxoedema 7241 15 325 046 026 076 896 00028
HIV Pernicious anaemia 472 0 17 0 0 212 089 03468
HIV Polymyositis 32 3 03 1034 203 3306 1533 00001
HIV Primary biliary cirrhosis 59 0 03 0 0 1176 01 07528
HIV Psoriasis 2551 23 109 213 135 32 1253 00004
HIV Rheumatoid arthritis 2238 7 95 073 03 152 043 05128
HIV Scleroderma 89 0 05 0 0 805 0 09596
HIV Sjogrens syndrome 160 0 07 0 0 564 004 08448
HIV Systematic lupus erythematosus 554 3 27 111 023 326 002 0899
HIV Thyrotoxicosis 1784 6 88 068 025 148 062 04293
HIV Ulcerative colitis 2667 15 151 1 056 165 001 09074
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 50 0 0 0 0 8184 44 00359
HIV Ankylosing spondylitis 10 0 0 0 0 71245 3898 0
HIV Autoimmune haemolytic anaemia 24 0 0 0 0 24127 1416 00002
HIV Chronic active hepatitis 17 0 0 0 0 12064 638 00115
HIV Coeliac disease 493 0 03 0 0 1306 017 06837
HIV Crohns disease 651 0 04 0 0 933 003 08691
HIV ITP 207 2 01 139 167 5086 1266 00004
HIV Myxoedema 781 0 05 0 0 704 0 09722
HIV Pernicious anaemia 14 0 0 0 0 84591 4915 0
HIV Polymyositis 4 0 0 0 0 6051 24878 0
HIV Primary biliary cirrhosis 2 0 0 0 0 0 0 0
HIV Psoriasis 357 0 01 0 0 2873 107 03016
HIV Rheumatoid arthritis 109 0 0 0 0 7558 409 00431
HIV Scleroderma 14 0 0 0 0 107299 626 0
HIV Sjogrens syndrome 10 0 0 0 0 396158 22105 0
HIV Systematic lupus erythematosus 64 0 0 0 0 7928 427 00387
HIV Thyrotoxicosis 173 0 01 0 0 3713 159 0207
HIV Ulcerative colitis 504 0 03 0 0 1346 018 06677
Cohort of HIV and Autoimmune Diseases-all cases
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1868 35 35 1008 7 1408 27231 0
HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147
HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0
HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0
HIV Coeliac disease 8127 7 156 045 018 092 423 00396
HIV Crohns disease 12300 31 349 089 06 126 034 05606
HIV ITP 4694 43 78 552 399 745 15331 0
HIV Myxoedema 181453 85 1577 054 043 067 331 0
HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492
HIV Polymyositis 631 10 15 691 33 1279 4409 0
HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381
HIV Psoriasis 18690 65 473 137 106 175 624 00125
HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113
HIV Scleroderma 1930 1 25 04 001 221 042 05189
HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396
HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218
HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879
HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929
Page 10: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Methodsbull Hospital Episode Statistics of all 55 million people in

the UK from 1999 to 2011bull Any contact with healthcare system including

admissions day cases and deaths Multiple contacts are linked to individual record

bull Database analyzed at Unit of Health-care Epidemiology Oxford University

bull Exposed (HIV) and unexposed matched on week of first contact age area of residence and socio-economic status

bull Relative risk calculated using MS as outcome (OHIVEHIV)(OCCECC)

Age distribution of people entering the HIV cohort the percentage female and the number of people entering the reference cohort1

Age (yrs) N entering HIV cohort

( of total) female N entering the

reference cohort 0-4

139 (07) 446 137461

5-9

168 (08) 452 172624 10-14

138 (07) 572 138003

15-19

173 (08) 590 216875 20-24

653 (31) 444 267177

25-29

2136 (101) 439 340834 30-34

4066 (192) 369 459410

35-39

4792 (226) 296 541994 40-44

3701 (175) 249 496704

45-49

2228 (105) 206 433194 50-54

1293 (61) 186 446510

55-59

776 (37) 174 482105 60-64

480 (23) 163 506958

65-69

274 (13) 212 503916 70-74

98 (05) 214 508750

75-79

37 (02) 270 485042 80-84

22 (01) 227 353716

85+

33 (02) 455 252837

All ages 21207 (100) 302 6744110

Following 21207 patients with HIV for 152618 person years and 6744301 controls for 42148179person years to see who would develop MS On average the follow-up was 7 years

exposure outcome MS in HIVMS in

Controls

rate ratio(Relative

Risk)Protective

Effect low CI upr CI chi-sq p-value

HIVmultiple sclerosis 7 183 038 gt62 015 079 639 0011

NHS Data on UK Healthcare events 1999-2011

Sheet1

NHS Cohort gt One year after Exposure (HIV) Contact

Exposure OutcomeMS in

exposedMS in

Controls

Rate ratio (Relative

Risk)Protective

Effect Low CIHigh

CI Chi-sqP

value

HIVMultiple Sclerosis 4 158 022 80 007 065 81 0004

Assuming that HIV diagnosis was made on first contact assessmentof cohort after one year would probably account for effect of HIVtherapy on all exposed If no effect of HIV treatment then expect noreduction in Relative Risk

Cohort of HIV and Autoimmune Diseases-all casesexposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-valueHIV Addisons disease 1868 35 35 1008 7 1408 27231 0HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0HIV Coeliac disease 8127 7 156 045 018 092 423 00396HIV Crohns disease 12300 31 349 089 06 126 034 05606HIV ITP 4694 43 78 552 399 745 15331 0HIV Myxoedema 181453 85 1577 054 043 067 331 0HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492HIV Polymyositis 631 10 15 691 33 1279 4409 0HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381HIV Psoriasis 18690 65 473 137 106 175 624 00125

HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113HIV Scleroderma 1930 1 25 04 001 221 042 05189HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929

all

aged 0-14

15-34

35-54

55-64

65+

interval lt1yr

1-4

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 830 15 15 998 556 1655 11032 0
HIV Ankylosing spondylitis 1995 2 56 035 004 128 174 01866
HIV Autoimmune haemolytic anaemia 796 4 09 423 115 1088 687 00088
HIV Chronic active hepatitis 340 3 06 537 11 1582 668 00098
HIV Coeliac disease 3639 6 79 076 028 165 025 0616
HIV Crohns disease 5695 13 167 078 041 133 061 04355
HIV ITP 2142 15 32 473 265 783 4024 0
HIV Myxoedema 77911 43 698 062 045 083 992 00016
HIV Pernicious anaemia 7615 3 37 082 017 239 001 09271
HIV Polymyositis 302 8 08 1018 435 2031 5584 0
HIV Primary biliary cirrhosis 919 0 12 0 0 317 038 05375
HIV Psoriasis 8090 27 217 125 082 182 108 02985
HIV Rheumatoid arthritis 23991 17 266 064 037 102 314 00763
HIV Scleroderma 911 1 12 085 002 475 009 07639
HIV Sjogrens syndrome 1836 0 21 0 0 176 121 02704
HIV Systematic lupus erythematosus 1703 6 5 121 044 263 006 0813
HIV Thyrotoxicosis 11529 14 155 09 049 151 007 0797
HIV Ulcerative colitis 9323 30 282 106 072 152 006 08069
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 352 17 09 1992 1147 3236 27362 0
HIV Ankylosing spondylitis 767 1 11 088 002 493 012 07296
HIV Autoimmune haemolytic anaemia 306 7 04 1792 714 3736 9338 0
HIV Chronic active hepatitis 118 6 02 3067 1103 6878 13684 0
HIV Coeliac disease 1206 0 16 0 0 226 079 03752
HIV Crohns disease 1896 15 5 3 167 496 1787 0
HIV ITP 728 22 21 1068 665 1629 17803 0
HIV Myxoedema 28047 13 163 08 042 136 048 04889
HIV Pernicious anaemia 2773 1 09 106 003 593 021 06495
HIV Polymyositis 113 1 01 785 02 4461 108 02995
HIV Primary biliary cirrhosis 308 1 02 646 016 3624 077 03817
HIV Psoriasis 3072 22 61 361 226 548 3875 0
HIV Rheumatoid arthritis 9101 11 69 16 08 286 189 01697
HIV Scleroderma 294 0 03 0 0 1121 009 07682
HIV Sjogrens syndrome 565 2 05 436 053 1581 235 01253
HIV Systematic lupus erythematosus 608 1 12 082 002 461 007 07944
HIV Thyrotoxicosis 4243 5 43 118 038 275 001 09048
HIV Ulcerative colitis 3123 17 75 229 133 367 1101 00009
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 821 1 01 78 02 4358 108 02995
HIV Ankylosing spondylitis 1672 0 04 0 0 887 002 08966
HIV Autoimmune haemolytic anaemia 1142 1 02 418 011 2333 028 05943
HIV Chronic active hepatitis 300 1 01 1674 042 9401 323 00721
HIV Coeliac disease 3003 0 04 0 0 836 001 09297
HIV Crohns disease 4249 1 07 14 004 779 006 07988
HIV ITP 2750 4 05 823 224 2109 1866 0
HIV Myxoedema 111802 12 124 097 05 169 0 09748
HIV Pernicious anaemia 13040 0 15 0 0 253 063 04283
HIV Polymyositis 333 2 0 4371 527 15913 4594 0
HIV Primary biliary cirrhosis 1120 0 01 0 0 3586 153 02162
HIV Psoriasis 6100 2 15 131 016 472 0 09797
HIV Rheumatoid arthritis 30228 7 41 172 069 355 146 02269
HIV Scleroderma 909 0 01 0 0 3312 135 02449
HIV Sjogrens syndrome 1883 0 02 0 0 1969 052 04704
HIV Systematic lupus erythematosus 1056 0 02 0 0 1993 053 04648
HIV Thyrotoxicosis 15247 4 19 21 057 538 134 0247
HIV Ulcerative colitis 7697 5 16 317 103 74 541 002
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 326 3 03 893 183 2632 138 00002
HIV Ankylosing spondylitis 971 0 14 0 0 272 054 04621
HIV Autoimmune haemolytic anaemia 261 0 03 0 0 1419 022 06407
HIV Chronic active hepatitis 143 1 01 733 018 415 096 03272
HIV Coeliac disease 1492 0 11 0 0 331 034 05598
HIV Crohns disease 1923 1 24 042 001 234 032 05686
HIV ITP 712 3 09 329 068 964 274 00976
HIV Myxoedema 30859 11 201 055 027 098 368 00552
HIV Pernicious anaemia 1970 1 13 078 002 437 004 0844
HIV Polymyositis 135 2 01 1436 172 5288 1309 00003
HIV Primary biliary cirrhosis 377 1 02 575 015 3225 061 0435
HIV Psoriasis 3545 5 48 104 034 244 002 08955
HIV Rheumatoid arthritis 10250 4 88 045 012 116 214 01439
HIV Scleroderma 463 0 03 0 0 1449 023 06285
HIV Sjogrens syndrome 1053 1 05 2 005 1119 0 09991
HIV Systematic lupus erythematosus 715 0 06 0 0 606 002 0888
HIV Thyrotoxicosis 4076 4 35 115 031 295 0 0988
HIV Ulcerative colitis 3588 8 49 164 071 324 141 02348
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 458 20 2 1017 615 1589 14969 0
HIV Ankylosing spondylitis 1430 1 74 013 0 075 476 00291
HIV Autoimmune haemolytic anaemia 195 9 11 854 385 1655 5027 0
HIV Chronic active hepatitis 126 6 06 1068 385 2391 4141 0
HIV Coeliac disease 2230 5 96 052 017 122 173 01884
HIV Crohns disease 3262 22 203 108 068 164 007 07958
HIV ITP 694 23 44 533 335 806 7409 0
HIV Myxoedema 30770 47 922 051 037 068 2172 0
HIV Pernicious anaemia 1664 3 43 07 014 204 015 07013
HIV Polymyositis 127 3 1 316 064 945 246 01165
HIV Primary biliary cirrhosis 359 1 14 07 002 393 0 09501
HIV Psoriasis 6137 35 30 117 081 162 067 04141
HIV Rheumatoid arthritis 10968 21 365 057 036 088 617 0013
HIV Scleroderma 455 1 17 059 001 331 002 08849
HIV Sjogrens syndrome 995 1 29 034 001 192 068 04097
HIV Systematic lupus erythematosus 1279 7 63 112 045 231 001 09219
HIV Thyrotoxicosis 4589 18 191 094 056 149 002 08979
HIV Ulcerative colitis 5315 34 346 098 068 138 0 09893
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 213 11 1 1186 583 2166 9395 0
HIV Ankylosing spondylitis 486 2 27 074 009 269 002 09025
HIV Autoimmune haemolytic anaemia 66 2 03 627 074 2356 422 00398
HIV Chronic active hepatitis 39 2 02 1257 147 4856 1072 00011
HIV Coeliac disease 909 2 42 047 006 171 071 03994
HIV Crohns disease 2215 7 111 063 025 13 118 02778
HIV ITP 331 11 19 606 3 1098 4019 0
HIV Myxoedema 7241 15 325 046 026 076 896 00028
HIV Pernicious anaemia 472 0 17 0 0 212 089 03468
HIV Polymyositis 32 3 03 1034 203 3306 1533 00001
HIV Primary biliary cirrhosis 59 0 03 0 0 1176 01 07528
HIV Psoriasis 2551 23 109 213 135 32 1253 00004
HIV Rheumatoid arthritis 2238 7 95 073 03 152 043 05128
HIV Scleroderma 89 0 05 0 0 805 0 09596
HIV Sjogrens syndrome 160 0 07 0 0 564 004 08448
HIV Systematic lupus erythematosus 554 3 27 111 023 326 002 0899
HIV Thyrotoxicosis 1784 6 88 068 025 148 062 04293
HIV Ulcerative colitis 2667 15 151 1 056 165 001 09074
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 50 0 0 0 0 8184 44 00359
HIV Ankylosing spondylitis 10 0 0 0 0 71245 3898 0
HIV Autoimmune haemolytic anaemia 24 0 0 0 0 24127 1416 00002
HIV Chronic active hepatitis 17 0 0 0 0 12064 638 00115
HIV Coeliac disease 493 0 03 0 0 1306 017 06837
HIV Crohns disease 651 0 04 0 0 933 003 08691
HIV ITP 207 2 01 139 167 5086 1266 00004
HIV Myxoedema 781 0 05 0 0 704 0 09722
HIV Pernicious anaemia 14 0 0 0 0 84591 4915 0
HIV Polymyositis 4 0 0 0 0 6051 24878 0
HIV Primary biliary cirrhosis 2 0 0 0 0 0 0 0
HIV Psoriasis 357 0 01 0 0 2873 107 03016
HIV Rheumatoid arthritis 109 0 0 0 0 7558 409 00431
HIV Scleroderma 14 0 0 0 0 107299 626 0
HIV Sjogrens syndrome 10 0 0 0 0 396158 22105 0
HIV Systematic lupus erythematosus 64 0 0 0 0 7928 427 00387
HIV Thyrotoxicosis 173 0 01 0 0 3713 159 0207
HIV Ulcerative colitis 504 0 03 0 0 1346 018 06677
Cohort of HIV and Autoimmune Diseases-all cases
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1868 35 35 1008 7 1408 27231 0
HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147
HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0
HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0
HIV Coeliac disease 8127 7 156 045 018 092 423 00396
HIV Crohns disease 12300 31 349 089 06 126 034 05606
HIV ITP 4694 43 78 552 399 745 15331 0
HIV Myxoedema 181453 85 1577 054 043 067 331 0
HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492
HIV Polymyositis 631 10 15 691 33 1279 4409 0
HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381
HIV Psoriasis 18690 65 473 137 106 175 624 00125
HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113
HIV Scleroderma 1930 1 25 04 001 221 042 05189
HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396
HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218
HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879
HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929
Page 11: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Age distribution of people entering the HIV cohort the percentage female and the number of people entering the reference cohort1

Age (yrs) N entering HIV cohort

( of total) female N entering the

reference cohort 0-4

139 (07) 446 137461

5-9

168 (08) 452 172624 10-14

138 (07) 572 138003

15-19

173 (08) 590 216875 20-24

653 (31) 444 267177

25-29

2136 (101) 439 340834 30-34

4066 (192) 369 459410

35-39

4792 (226) 296 541994 40-44

3701 (175) 249 496704

45-49

2228 (105) 206 433194 50-54

1293 (61) 186 446510

55-59

776 (37) 174 482105 60-64

480 (23) 163 506958

65-69

274 (13) 212 503916 70-74

98 (05) 214 508750

75-79

37 (02) 270 485042 80-84

22 (01) 227 353716

85+

33 (02) 455 252837

All ages 21207 (100) 302 6744110

Following 21207 patients with HIV for 152618 person years and 6744301 controls for 42148179person years to see who would develop MS On average the follow-up was 7 years

exposure outcome MS in HIVMS in

Controls

rate ratio(Relative

Risk)Protective

Effect low CI upr CI chi-sq p-value

HIVmultiple sclerosis 7 183 038 gt62 015 079 639 0011

NHS Data on UK Healthcare events 1999-2011

Sheet1

NHS Cohort gt One year after Exposure (HIV) Contact

Exposure OutcomeMS in

exposedMS in

Controls

Rate ratio (Relative

Risk)Protective

Effect Low CIHigh

CI Chi-sqP

value

HIVMultiple Sclerosis 4 158 022 80 007 065 81 0004

Assuming that HIV diagnosis was made on first contact assessmentof cohort after one year would probably account for effect of HIVtherapy on all exposed If no effect of HIV treatment then expect noreduction in Relative Risk

Cohort of HIV and Autoimmune Diseases-all casesexposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-valueHIV Addisons disease 1868 35 35 1008 7 1408 27231 0HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0HIV Coeliac disease 8127 7 156 045 018 092 423 00396HIV Crohns disease 12300 31 349 089 06 126 034 05606HIV ITP 4694 43 78 552 399 745 15331 0HIV Myxoedema 181453 85 1577 054 043 067 331 0HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492HIV Polymyositis 631 10 15 691 33 1279 4409 0HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381HIV Psoriasis 18690 65 473 137 106 175 624 00125

HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113HIV Scleroderma 1930 1 25 04 001 221 042 05189HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929

all

aged 0-14

15-34

35-54

55-64

65+

interval lt1yr

1-4

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 830 15 15 998 556 1655 11032 0
HIV Ankylosing spondylitis 1995 2 56 035 004 128 174 01866
HIV Autoimmune haemolytic anaemia 796 4 09 423 115 1088 687 00088
HIV Chronic active hepatitis 340 3 06 537 11 1582 668 00098
HIV Coeliac disease 3639 6 79 076 028 165 025 0616
HIV Crohns disease 5695 13 167 078 041 133 061 04355
HIV ITP 2142 15 32 473 265 783 4024 0
HIV Myxoedema 77911 43 698 062 045 083 992 00016
HIV Pernicious anaemia 7615 3 37 082 017 239 001 09271
HIV Polymyositis 302 8 08 1018 435 2031 5584 0
HIV Primary biliary cirrhosis 919 0 12 0 0 317 038 05375
HIV Psoriasis 8090 27 217 125 082 182 108 02985
HIV Rheumatoid arthritis 23991 17 266 064 037 102 314 00763
HIV Scleroderma 911 1 12 085 002 475 009 07639
HIV Sjogrens syndrome 1836 0 21 0 0 176 121 02704
HIV Systematic lupus erythematosus 1703 6 5 121 044 263 006 0813
HIV Thyrotoxicosis 11529 14 155 09 049 151 007 0797
HIV Ulcerative colitis 9323 30 282 106 072 152 006 08069
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 352 17 09 1992 1147 3236 27362 0
HIV Ankylosing spondylitis 767 1 11 088 002 493 012 07296
HIV Autoimmune haemolytic anaemia 306 7 04 1792 714 3736 9338 0
HIV Chronic active hepatitis 118 6 02 3067 1103 6878 13684 0
HIV Coeliac disease 1206 0 16 0 0 226 079 03752
HIV Crohns disease 1896 15 5 3 167 496 1787 0
HIV ITP 728 22 21 1068 665 1629 17803 0
HIV Myxoedema 28047 13 163 08 042 136 048 04889
HIV Pernicious anaemia 2773 1 09 106 003 593 021 06495
HIV Polymyositis 113 1 01 785 02 4461 108 02995
HIV Primary biliary cirrhosis 308 1 02 646 016 3624 077 03817
HIV Psoriasis 3072 22 61 361 226 548 3875 0
HIV Rheumatoid arthritis 9101 11 69 16 08 286 189 01697
HIV Scleroderma 294 0 03 0 0 1121 009 07682
HIV Sjogrens syndrome 565 2 05 436 053 1581 235 01253
HIV Systematic lupus erythematosus 608 1 12 082 002 461 007 07944
HIV Thyrotoxicosis 4243 5 43 118 038 275 001 09048
HIV Ulcerative colitis 3123 17 75 229 133 367 1101 00009
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 821 1 01 78 02 4358 108 02995
HIV Ankylosing spondylitis 1672 0 04 0 0 887 002 08966
HIV Autoimmune haemolytic anaemia 1142 1 02 418 011 2333 028 05943
HIV Chronic active hepatitis 300 1 01 1674 042 9401 323 00721
HIV Coeliac disease 3003 0 04 0 0 836 001 09297
HIV Crohns disease 4249 1 07 14 004 779 006 07988
HIV ITP 2750 4 05 823 224 2109 1866 0
HIV Myxoedema 111802 12 124 097 05 169 0 09748
HIV Pernicious anaemia 13040 0 15 0 0 253 063 04283
HIV Polymyositis 333 2 0 4371 527 15913 4594 0
HIV Primary biliary cirrhosis 1120 0 01 0 0 3586 153 02162
HIV Psoriasis 6100 2 15 131 016 472 0 09797
HIV Rheumatoid arthritis 30228 7 41 172 069 355 146 02269
HIV Scleroderma 909 0 01 0 0 3312 135 02449
HIV Sjogrens syndrome 1883 0 02 0 0 1969 052 04704
HIV Systematic lupus erythematosus 1056 0 02 0 0 1993 053 04648
HIV Thyrotoxicosis 15247 4 19 21 057 538 134 0247
HIV Ulcerative colitis 7697 5 16 317 103 74 541 002
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 326 3 03 893 183 2632 138 00002
HIV Ankylosing spondylitis 971 0 14 0 0 272 054 04621
HIV Autoimmune haemolytic anaemia 261 0 03 0 0 1419 022 06407
HIV Chronic active hepatitis 143 1 01 733 018 415 096 03272
HIV Coeliac disease 1492 0 11 0 0 331 034 05598
HIV Crohns disease 1923 1 24 042 001 234 032 05686
HIV ITP 712 3 09 329 068 964 274 00976
HIV Myxoedema 30859 11 201 055 027 098 368 00552
HIV Pernicious anaemia 1970 1 13 078 002 437 004 0844
HIV Polymyositis 135 2 01 1436 172 5288 1309 00003
HIV Primary biliary cirrhosis 377 1 02 575 015 3225 061 0435
HIV Psoriasis 3545 5 48 104 034 244 002 08955
HIV Rheumatoid arthritis 10250 4 88 045 012 116 214 01439
HIV Scleroderma 463 0 03 0 0 1449 023 06285
HIV Sjogrens syndrome 1053 1 05 2 005 1119 0 09991
HIV Systematic lupus erythematosus 715 0 06 0 0 606 002 0888
HIV Thyrotoxicosis 4076 4 35 115 031 295 0 0988
HIV Ulcerative colitis 3588 8 49 164 071 324 141 02348
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 458 20 2 1017 615 1589 14969 0
HIV Ankylosing spondylitis 1430 1 74 013 0 075 476 00291
HIV Autoimmune haemolytic anaemia 195 9 11 854 385 1655 5027 0
HIV Chronic active hepatitis 126 6 06 1068 385 2391 4141 0
HIV Coeliac disease 2230 5 96 052 017 122 173 01884
HIV Crohns disease 3262 22 203 108 068 164 007 07958
HIV ITP 694 23 44 533 335 806 7409 0
HIV Myxoedema 30770 47 922 051 037 068 2172 0
HIV Pernicious anaemia 1664 3 43 07 014 204 015 07013
HIV Polymyositis 127 3 1 316 064 945 246 01165
HIV Primary biliary cirrhosis 359 1 14 07 002 393 0 09501
HIV Psoriasis 6137 35 30 117 081 162 067 04141
HIV Rheumatoid arthritis 10968 21 365 057 036 088 617 0013
HIV Scleroderma 455 1 17 059 001 331 002 08849
HIV Sjogrens syndrome 995 1 29 034 001 192 068 04097
HIV Systematic lupus erythematosus 1279 7 63 112 045 231 001 09219
HIV Thyrotoxicosis 4589 18 191 094 056 149 002 08979
HIV Ulcerative colitis 5315 34 346 098 068 138 0 09893
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 213 11 1 1186 583 2166 9395 0
HIV Ankylosing spondylitis 486 2 27 074 009 269 002 09025
HIV Autoimmune haemolytic anaemia 66 2 03 627 074 2356 422 00398
HIV Chronic active hepatitis 39 2 02 1257 147 4856 1072 00011
HIV Coeliac disease 909 2 42 047 006 171 071 03994
HIV Crohns disease 2215 7 111 063 025 13 118 02778
HIV ITP 331 11 19 606 3 1098 4019 0
HIV Myxoedema 7241 15 325 046 026 076 896 00028
HIV Pernicious anaemia 472 0 17 0 0 212 089 03468
HIV Polymyositis 32 3 03 1034 203 3306 1533 00001
HIV Primary biliary cirrhosis 59 0 03 0 0 1176 01 07528
HIV Psoriasis 2551 23 109 213 135 32 1253 00004
HIV Rheumatoid arthritis 2238 7 95 073 03 152 043 05128
HIV Scleroderma 89 0 05 0 0 805 0 09596
HIV Sjogrens syndrome 160 0 07 0 0 564 004 08448
HIV Systematic lupus erythematosus 554 3 27 111 023 326 002 0899
HIV Thyrotoxicosis 1784 6 88 068 025 148 062 04293
HIV Ulcerative colitis 2667 15 151 1 056 165 001 09074
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 50 0 0 0 0 8184 44 00359
HIV Ankylosing spondylitis 10 0 0 0 0 71245 3898 0
HIV Autoimmune haemolytic anaemia 24 0 0 0 0 24127 1416 00002
HIV Chronic active hepatitis 17 0 0 0 0 12064 638 00115
HIV Coeliac disease 493 0 03 0 0 1306 017 06837
HIV Crohns disease 651 0 04 0 0 933 003 08691
HIV ITP 207 2 01 139 167 5086 1266 00004
HIV Myxoedema 781 0 05 0 0 704 0 09722
HIV Pernicious anaemia 14 0 0 0 0 84591 4915 0
HIV Polymyositis 4 0 0 0 0 6051 24878 0
HIV Primary biliary cirrhosis 2 0 0 0 0 0 0 0
HIV Psoriasis 357 0 01 0 0 2873 107 03016
HIV Rheumatoid arthritis 109 0 0 0 0 7558 409 00431
HIV Scleroderma 14 0 0 0 0 107299 626 0
HIV Sjogrens syndrome 10 0 0 0 0 396158 22105 0
HIV Systematic lupus erythematosus 64 0 0 0 0 7928 427 00387
HIV Thyrotoxicosis 173 0 01 0 0 3713 159 0207
HIV Ulcerative colitis 504 0 03 0 0 1346 018 06677
Cohort of HIV and Autoimmune Diseases-all cases
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1868 35 35 1008 7 1408 27231 0
HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147
HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0
HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0
HIV Coeliac disease 8127 7 156 045 018 092 423 00396
HIV Crohns disease 12300 31 349 089 06 126 034 05606
HIV ITP 4694 43 78 552 399 745 15331 0
HIV Myxoedema 181453 85 1577 054 043 067 331 0
HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492
HIV Polymyositis 631 10 15 691 33 1279 4409 0
HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381
HIV Psoriasis 18690 65 473 137 106 175 624 00125
HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113
HIV Scleroderma 1930 1 25 04 001 221 042 05189
HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396
HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218
HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879
HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929
Page 12: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Following 21207 patients with HIV for 152618 person years and 6744301 controls for 42148179person years to see who would develop MS On average the follow-up was 7 years

exposure outcome MS in HIVMS in

Controls

rate ratio(Relative

Risk)Protective

Effect low CI upr CI chi-sq p-value

HIVmultiple sclerosis 7 183 038 gt62 015 079 639 0011

NHS Data on UK Healthcare events 1999-2011

Sheet1

NHS Cohort gt One year after Exposure (HIV) Contact

Exposure OutcomeMS in

exposedMS in

Controls

Rate ratio (Relative

Risk)Protective

Effect Low CIHigh

CI Chi-sqP

value

HIVMultiple Sclerosis 4 158 022 80 007 065 81 0004

Assuming that HIV diagnosis was made on first contact assessmentof cohort after one year would probably account for effect of HIVtherapy on all exposed If no effect of HIV treatment then expect noreduction in Relative Risk

Cohort of HIV and Autoimmune Diseases-all casesexposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-valueHIV Addisons disease 1868 35 35 1008 7 1408 27231 0HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0HIV Coeliac disease 8127 7 156 045 018 092 423 00396HIV Crohns disease 12300 31 349 089 06 126 034 05606HIV ITP 4694 43 78 552 399 745 15331 0HIV Myxoedema 181453 85 1577 054 043 067 331 0HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492HIV Polymyositis 631 10 15 691 33 1279 4409 0HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381HIV Psoriasis 18690 65 473 137 106 175 624 00125

HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113HIV Scleroderma 1930 1 25 04 001 221 042 05189HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929

all

aged 0-14

15-34

35-54

55-64

65+

interval lt1yr

1-4

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 830 15 15 998 556 1655 11032 0
HIV Ankylosing spondylitis 1995 2 56 035 004 128 174 01866
HIV Autoimmune haemolytic anaemia 796 4 09 423 115 1088 687 00088
HIV Chronic active hepatitis 340 3 06 537 11 1582 668 00098
HIV Coeliac disease 3639 6 79 076 028 165 025 0616
HIV Crohns disease 5695 13 167 078 041 133 061 04355
HIV ITP 2142 15 32 473 265 783 4024 0
HIV Myxoedema 77911 43 698 062 045 083 992 00016
HIV Pernicious anaemia 7615 3 37 082 017 239 001 09271
HIV Polymyositis 302 8 08 1018 435 2031 5584 0
HIV Primary biliary cirrhosis 919 0 12 0 0 317 038 05375
HIV Psoriasis 8090 27 217 125 082 182 108 02985
HIV Rheumatoid arthritis 23991 17 266 064 037 102 314 00763
HIV Scleroderma 911 1 12 085 002 475 009 07639
HIV Sjogrens syndrome 1836 0 21 0 0 176 121 02704
HIV Systematic lupus erythematosus 1703 6 5 121 044 263 006 0813
HIV Thyrotoxicosis 11529 14 155 09 049 151 007 0797
HIV Ulcerative colitis 9323 30 282 106 072 152 006 08069
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 352 17 09 1992 1147 3236 27362 0
HIV Ankylosing spondylitis 767 1 11 088 002 493 012 07296
HIV Autoimmune haemolytic anaemia 306 7 04 1792 714 3736 9338 0
HIV Chronic active hepatitis 118 6 02 3067 1103 6878 13684 0
HIV Coeliac disease 1206 0 16 0 0 226 079 03752
HIV Crohns disease 1896 15 5 3 167 496 1787 0
HIV ITP 728 22 21 1068 665 1629 17803 0
HIV Myxoedema 28047 13 163 08 042 136 048 04889
HIV Pernicious anaemia 2773 1 09 106 003 593 021 06495
HIV Polymyositis 113 1 01 785 02 4461 108 02995
HIV Primary biliary cirrhosis 308 1 02 646 016 3624 077 03817
HIV Psoriasis 3072 22 61 361 226 548 3875 0
HIV Rheumatoid arthritis 9101 11 69 16 08 286 189 01697
HIV Scleroderma 294 0 03 0 0 1121 009 07682
HIV Sjogrens syndrome 565 2 05 436 053 1581 235 01253
HIV Systematic lupus erythematosus 608 1 12 082 002 461 007 07944
HIV Thyrotoxicosis 4243 5 43 118 038 275 001 09048
HIV Ulcerative colitis 3123 17 75 229 133 367 1101 00009
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 821 1 01 78 02 4358 108 02995
HIV Ankylosing spondylitis 1672 0 04 0 0 887 002 08966
HIV Autoimmune haemolytic anaemia 1142 1 02 418 011 2333 028 05943
HIV Chronic active hepatitis 300 1 01 1674 042 9401 323 00721
HIV Coeliac disease 3003 0 04 0 0 836 001 09297
HIV Crohns disease 4249 1 07 14 004 779 006 07988
HIV ITP 2750 4 05 823 224 2109 1866 0
HIV Myxoedema 111802 12 124 097 05 169 0 09748
HIV Pernicious anaemia 13040 0 15 0 0 253 063 04283
HIV Polymyositis 333 2 0 4371 527 15913 4594 0
HIV Primary biliary cirrhosis 1120 0 01 0 0 3586 153 02162
HIV Psoriasis 6100 2 15 131 016 472 0 09797
HIV Rheumatoid arthritis 30228 7 41 172 069 355 146 02269
HIV Scleroderma 909 0 01 0 0 3312 135 02449
HIV Sjogrens syndrome 1883 0 02 0 0 1969 052 04704
HIV Systematic lupus erythematosus 1056 0 02 0 0 1993 053 04648
HIV Thyrotoxicosis 15247 4 19 21 057 538 134 0247
HIV Ulcerative colitis 7697 5 16 317 103 74 541 002
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 326 3 03 893 183 2632 138 00002
HIV Ankylosing spondylitis 971 0 14 0 0 272 054 04621
HIV Autoimmune haemolytic anaemia 261 0 03 0 0 1419 022 06407
HIV Chronic active hepatitis 143 1 01 733 018 415 096 03272
HIV Coeliac disease 1492 0 11 0 0 331 034 05598
HIV Crohns disease 1923 1 24 042 001 234 032 05686
HIV ITP 712 3 09 329 068 964 274 00976
HIV Myxoedema 30859 11 201 055 027 098 368 00552
HIV Pernicious anaemia 1970 1 13 078 002 437 004 0844
HIV Polymyositis 135 2 01 1436 172 5288 1309 00003
HIV Primary biliary cirrhosis 377 1 02 575 015 3225 061 0435
HIV Psoriasis 3545 5 48 104 034 244 002 08955
HIV Rheumatoid arthritis 10250 4 88 045 012 116 214 01439
HIV Scleroderma 463 0 03 0 0 1449 023 06285
HIV Sjogrens syndrome 1053 1 05 2 005 1119 0 09991
HIV Systematic lupus erythematosus 715 0 06 0 0 606 002 0888
HIV Thyrotoxicosis 4076 4 35 115 031 295 0 0988
HIV Ulcerative colitis 3588 8 49 164 071 324 141 02348
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 458 20 2 1017 615 1589 14969 0
HIV Ankylosing spondylitis 1430 1 74 013 0 075 476 00291
HIV Autoimmune haemolytic anaemia 195 9 11 854 385 1655 5027 0
HIV Chronic active hepatitis 126 6 06 1068 385 2391 4141 0
HIV Coeliac disease 2230 5 96 052 017 122 173 01884
HIV Crohns disease 3262 22 203 108 068 164 007 07958
HIV ITP 694 23 44 533 335 806 7409 0
HIV Myxoedema 30770 47 922 051 037 068 2172 0
HIV Pernicious anaemia 1664 3 43 07 014 204 015 07013
HIV Polymyositis 127 3 1 316 064 945 246 01165
HIV Primary biliary cirrhosis 359 1 14 07 002 393 0 09501
HIV Psoriasis 6137 35 30 117 081 162 067 04141
HIV Rheumatoid arthritis 10968 21 365 057 036 088 617 0013
HIV Scleroderma 455 1 17 059 001 331 002 08849
HIV Sjogrens syndrome 995 1 29 034 001 192 068 04097
HIV Systematic lupus erythematosus 1279 7 63 112 045 231 001 09219
HIV Thyrotoxicosis 4589 18 191 094 056 149 002 08979
HIV Ulcerative colitis 5315 34 346 098 068 138 0 09893
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 213 11 1 1186 583 2166 9395 0
HIV Ankylosing spondylitis 486 2 27 074 009 269 002 09025
HIV Autoimmune haemolytic anaemia 66 2 03 627 074 2356 422 00398
HIV Chronic active hepatitis 39 2 02 1257 147 4856 1072 00011
HIV Coeliac disease 909 2 42 047 006 171 071 03994
HIV Crohns disease 2215 7 111 063 025 13 118 02778
HIV ITP 331 11 19 606 3 1098 4019 0
HIV Myxoedema 7241 15 325 046 026 076 896 00028
HIV Pernicious anaemia 472 0 17 0 0 212 089 03468
HIV Polymyositis 32 3 03 1034 203 3306 1533 00001
HIV Primary biliary cirrhosis 59 0 03 0 0 1176 01 07528
HIV Psoriasis 2551 23 109 213 135 32 1253 00004
HIV Rheumatoid arthritis 2238 7 95 073 03 152 043 05128
HIV Scleroderma 89 0 05 0 0 805 0 09596
HIV Sjogrens syndrome 160 0 07 0 0 564 004 08448
HIV Systematic lupus erythematosus 554 3 27 111 023 326 002 0899
HIV Thyrotoxicosis 1784 6 88 068 025 148 062 04293
HIV Ulcerative colitis 2667 15 151 1 056 165 001 09074
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 50 0 0 0 0 8184 44 00359
HIV Ankylosing spondylitis 10 0 0 0 0 71245 3898 0
HIV Autoimmune haemolytic anaemia 24 0 0 0 0 24127 1416 00002
HIV Chronic active hepatitis 17 0 0 0 0 12064 638 00115
HIV Coeliac disease 493 0 03 0 0 1306 017 06837
HIV Crohns disease 651 0 04 0 0 933 003 08691
HIV ITP 207 2 01 139 167 5086 1266 00004
HIV Myxoedema 781 0 05 0 0 704 0 09722
HIV Pernicious anaemia 14 0 0 0 0 84591 4915 0
HIV Polymyositis 4 0 0 0 0 6051 24878 0
HIV Primary biliary cirrhosis 2 0 0 0 0 0 0 0
HIV Psoriasis 357 0 01 0 0 2873 107 03016
HIV Rheumatoid arthritis 109 0 0 0 0 7558 409 00431
HIV Scleroderma 14 0 0 0 0 107299 626 0
HIV Sjogrens syndrome 10 0 0 0 0 396158 22105 0
HIV Systematic lupus erythematosus 64 0 0 0 0 7928 427 00387
HIV Thyrotoxicosis 173 0 01 0 0 3713 159 0207
HIV Ulcerative colitis 504 0 03 0 0 1346 018 06677
Cohort of HIV and Autoimmune Diseases-all cases
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1868 35 35 1008 7 1408 27231 0
HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147
HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0
HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0
HIV Coeliac disease 8127 7 156 045 018 092 423 00396
HIV Crohns disease 12300 31 349 089 06 126 034 05606
HIV ITP 4694 43 78 552 399 745 15331 0
HIV Myxoedema 181453 85 1577 054 043 067 331 0
HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492
HIV Polymyositis 631 10 15 691 33 1279 4409 0
HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381
HIV Psoriasis 18690 65 473 137 106 175 624 00125
HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113
HIV Scleroderma 1930 1 25 04 001 221 042 05189
HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396
HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218
HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879
HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929
Page 13: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

exposure outcome MS in HIVMS in

Controls

rate ratio(Relative

Risk)Protective

Effect low CI upr CI chi-sq p-value

HIVmultiple sclerosis 7 183 038 gt62 015 079 639 0011

NHS Data on UK Healthcare events 1999-2011

Sheet1

NHS Cohort gt One year after Exposure (HIV) Contact

Exposure OutcomeMS in

exposedMS in

Controls

Rate ratio (Relative

Risk)Protective

Effect Low CIHigh

CI Chi-sqP

value

HIVMultiple Sclerosis 4 158 022 80 007 065 81 0004

Assuming that HIV diagnosis was made on first contact assessmentof cohort after one year would probably account for effect of HIVtherapy on all exposed If no effect of HIV treatment then expect noreduction in Relative Risk

Cohort of HIV and Autoimmune Diseases-all casesexposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-valueHIV Addisons disease 1868 35 35 1008 7 1408 27231 0HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0HIV Coeliac disease 8127 7 156 045 018 092 423 00396HIV Crohns disease 12300 31 349 089 06 126 034 05606HIV ITP 4694 43 78 552 399 745 15331 0HIV Myxoedema 181453 85 1577 054 043 067 331 0HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492HIV Polymyositis 631 10 15 691 33 1279 4409 0HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381HIV Psoriasis 18690 65 473 137 106 175 624 00125

HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113HIV Scleroderma 1930 1 25 04 001 221 042 05189HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929

all

aged 0-14

15-34

35-54

55-64

65+

interval lt1yr

1-4

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 830 15 15 998 556 1655 11032 0
HIV Ankylosing spondylitis 1995 2 56 035 004 128 174 01866
HIV Autoimmune haemolytic anaemia 796 4 09 423 115 1088 687 00088
HIV Chronic active hepatitis 340 3 06 537 11 1582 668 00098
HIV Coeliac disease 3639 6 79 076 028 165 025 0616
HIV Crohns disease 5695 13 167 078 041 133 061 04355
HIV ITP 2142 15 32 473 265 783 4024 0
HIV Myxoedema 77911 43 698 062 045 083 992 00016
HIV Pernicious anaemia 7615 3 37 082 017 239 001 09271
HIV Polymyositis 302 8 08 1018 435 2031 5584 0
HIV Primary biliary cirrhosis 919 0 12 0 0 317 038 05375
HIV Psoriasis 8090 27 217 125 082 182 108 02985
HIV Rheumatoid arthritis 23991 17 266 064 037 102 314 00763
HIV Scleroderma 911 1 12 085 002 475 009 07639
HIV Sjogrens syndrome 1836 0 21 0 0 176 121 02704
HIV Systematic lupus erythematosus 1703 6 5 121 044 263 006 0813
HIV Thyrotoxicosis 11529 14 155 09 049 151 007 0797
HIV Ulcerative colitis 9323 30 282 106 072 152 006 08069
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 352 17 09 1992 1147 3236 27362 0
HIV Ankylosing spondylitis 767 1 11 088 002 493 012 07296
HIV Autoimmune haemolytic anaemia 306 7 04 1792 714 3736 9338 0
HIV Chronic active hepatitis 118 6 02 3067 1103 6878 13684 0
HIV Coeliac disease 1206 0 16 0 0 226 079 03752
HIV Crohns disease 1896 15 5 3 167 496 1787 0
HIV ITP 728 22 21 1068 665 1629 17803 0
HIV Myxoedema 28047 13 163 08 042 136 048 04889
HIV Pernicious anaemia 2773 1 09 106 003 593 021 06495
HIV Polymyositis 113 1 01 785 02 4461 108 02995
HIV Primary biliary cirrhosis 308 1 02 646 016 3624 077 03817
HIV Psoriasis 3072 22 61 361 226 548 3875 0
HIV Rheumatoid arthritis 9101 11 69 16 08 286 189 01697
HIV Scleroderma 294 0 03 0 0 1121 009 07682
HIV Sjogrens syndrome 565 2 05 436 053 1581 235 01253
HIV Systematic lupus erythematosus 608 1 12 082 002 461 007 07944
HIV Thyrotoxicosis 4243 5 43 118 038 275 001 09048
HIV Ulcerative colitis 3123 17 75 229 133 367 1101 00009
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 821 1 01 78 02 4358 108 02995
HIV Ankylosing spondylitis 1672 0 04 0 0 887 002 08966
HIV Autoimmune haemolytic anaemia 1142 1 02 418 011 2333 028 05943
HIV Chronic active hepatitis 300 1 01 1674 042 9401 323 00721
HIV Coeliac disease 3003 0 04 0 0 836 001 09297
HIV Crohns disease 4249 1 07 14 004 779 006 07988
HIV ITP 2750 4 05 823 224 2109 1866 0
HIV Myxoedema 111802 12 124 097 05 169 0 09748
HIV Pernicious anaemia 13040 0 15 0 0 253 063 04283
HIV Polymyositis 333 2 0 4371 527 15913 4594 0
HIV Primary biliary cirrhosis 1120 0 01 0 0 3586 153 02162
HIV Psoriasis 6100 2 15 131 016 472 0 09797
HIV Rheumatoid arthritis 30228 7 41 172 069 355 146 02269
HIV Scleroderma 909 0 01 0 0 3312 135 02449
HIV Sjogrens syndrome 1883 0 02 0 0 1969 052 04704
HIV Systematic lupus erythematosus 1056 0 02 0 0 1993 053 04648
HIV Thyrotoxicosis 15247 4 19 21 057 538 134 0247
HIV Ulcerative colitis 7697 5 16 317 103 74 541 002
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 326 3 03 893 183 2632 138 00002
HIV Ankylosing spondylitis 971 0 14 0 0 272 054 04621
HIV Autoimmune haemolytic anaemia 261 0 03 0 0 1419 022 06407
HIV Chronic active hepatitis 143 1 01 733 018 415 096 03272
HIV Coeliac disease 1492 0 11 0 0 331 034 05598
HIV Crohns disease 1923 1 24 042 001 234 032 05686
HIV ITP 712 3 09 329 068 964 274 00976
HIV Myxoedema 30859 11 201 055 027 098 368 00552
HIV Pernicious anaemia 1970 1 13 078 002 437 004 0844
HIV Polymyositis 135 2 01 1436 172 5288 1309 00003
HIV Primary biliary cirrhosis 377 1 02 575 015 3225 061 0435
HIV Psoriasis 3545 5 48 104 034 244 002 08955
HIV Rheumatoid arthritis 10250 4 88 045 012 116 214 01439
HIV Scleroderma 463 0 03 0 0 1449 023 06285
HIV Sjogrens syndrome 1053 1 05 2 005 1119 0 09991
HIV Systematic lupus erythematosus 715 0 06 0 0 606 002 0888
HIV Thyrotoxicosis 4076 4 35 115 031 295 0 0988
HIV Ulcerative colitis 3588 8 49 164 071 324 141 02348
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 458 20 2 1017 615 1589 14969 0
HIV Ankylosing spondylitis 1430 1 74 013 0 075 476 00291
HIV Autoimmune haemolytic anaemia 195 9 11 854 385 1655 5027 0
HIV Chronic active hepatitis 126 6 06 1068 385 2391 4141 0
HIV Coeliac disease 2230 5 96 052 017 122 173 01884
HIV Crohns disease 3262 22 203 108 068 164 007 07958
HIV ITP 694 23 44 533 335 806 7409 0
HIV Myxoedema 30770 47 922 051 037 068 2172 0
HIV Pernicious anaemia 1664 3 43 07 014 204 015 07013
HIV Polymyositis 127 3 1 316 064 945 246 01165
HIV Primary biliary cirrhosis 359 1 14 07 002 393 0 09501
HIV Psoriasis 6137 35 30 117 081 162 067 04141
HIV Rheumatoid arthritis 10968 21 365 057 036 088 617 0013
HIV Scleroderma 455 1 17 059 001 331 002 08849
HIV Sjogrens syndrome 995 1 29 034 001 192 068 04097
HIV Systematic lupus erythematosus 1279 7 63 112 045 231 001 09219
HIV Thyrotoxicosis 4589 18 191 094 056 149 002 08979
HIV Ulcerative colitis 5315 34 346 098 068 138 0 09893
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 213 11 1 1186 583 2166 9395 0
HIV Ankylosing spondylitis 486 2 27 074 009 269 002 09025
HIV Autoimmune haemolytic anaemia 66 2 03 627 074 2356 422 00398
HIV Chronic active hepatitis 39 2 02 1257 147 4856 1072 00011
HIV Coeliac disease 909 2 42 047 006 171 071 03994
HIV Crohns disease 2215 7 111 063 025 13 118 02778
HIV ITP 331 11 19 606 3 1098 4019 0
HIV Myxoedema 7241 15 325 046 026 076 896 00028
HIV Pernicious anaemia 472 0 17 0 0 212 089 03468
HIV Polymyositis 32 3 03 1034 203 3306 1533 00001
HIV Primary biliary cirrhosis 59 0 03 0 0 1176 01 07528
HIV Psoriasis 2551 23 109 213 135 32 1253 00004
HIV Rheumatoid arthritis 2238 7 95 073 03 152 043 05128
HIV Scleroderma 89 0 05 0 0 805 0 09596
HIV Sjogrens syndrome 160 0 07 0 0 564 004 08448
HIV Systematic lupus erythematosus 554 3 27 111 023 326 002 0899
HIV Thyrotoxicosis 1784 6 88 068 025 148 062 04293
HIV Ulcerative colitis 2667 15 151 1 056 165 001 09074
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 50 0 0 0 0 8184 44 00359
HIV Ankylosing spondylitis 10 0 0 0 0 71245 3898 0
HIV Autoimmune haemolytic anaemia 24 0 0 0 0 24127 1416 00002
HIV Chronic active hepatitis 17 0 0 0 0 12064 638 00115
HIV Coeliac disease 493 0 03 0 0 1306 017 06837
HIV Crohns disease 651 0 04 0 0 933 003 08691
HIV ITP 207 2 01 139 167 5086 1266 00004
HIV Myxoedema 781 0 05 0 0 704 0 09722
HIV Pernicious anaemia 14 0 0 0 0 84591 4915 0
HIV Polymyositis 4 0 0 0 0 6051 24878 0
HIV Primary biliary cirrhosis 2 0 0 0 0 0 0 0
HIV Psoriasis 357 0 01 0 0 2873 107 03016
HIV Rheumatoid arthritis 109 0 0 0 0 7558 409 00431
HIV Scleroderma 14 0 0 0 0 107299 626 0
HIV Sjogrens syndrome 10 0 0 0 0 396158 22105 0
HIV Systematic lupus erythematosus 64 0 0 0 0 7928 427 00387
HIV Thyrotoxicosis 173 0 01 0 0 3713 159 0207
HIV Ulcerative colitis 504 0 03 0 0 1346 018 06677
Cohort of HIV and Autoimmune Diseases-all cases
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1868 35 35 1008 7 1408 27231 0
HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147
HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0
HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0
HIV Coeliac disease 8127 7 156 045 018 092 423 00396
HIV Crohns disease 12300 31 349 089 06 126 034 05606
HIV ITP 4694 43 78 552 399 745 15331 0
HIV Myxoedema 181453 85 1577 054 043 067 331 0
HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492
HIV Polymyositis 631 10 15 691 33 1279 4409 0
HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381
HIV Psoriasis 18690 65 473 137 106 175 624 00125
HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113
HIV Scleroderma 1930 1 25 04 001 221 042 05189
HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396
HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218
HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879
HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929
Page 14: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

NHS Cohort gt One year after Exposure (HIV) Contact

Exposure OutcomeMS in

exposedMS in

Controls

Rate ratio (Relative

Risk)Protective

Effect Low CIHigh

CI Chi-sqP

value

HIVMultiple Sclerosis 4 158 022 80 007 065 81 0004

Assuming that HIV diagnosis was made on first contact assessmentof cohort after one year would probably account for effect of HIVtherapy on all exposed If no effect of HIV treatment then expect noreduction in Relative Risk

Cohort of HIV and Autoimmune Diseases-all casesexposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-valueHIV Addisons disease 1868 35 35 1008 7 1408 27231 0HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0HIV Coeliac disease 8127 7 156 045 018 092 423 00396HIV Crohns disease 12300 31 349 089 06 126 034 05606HIV ITP 4694 43 78 552 399 745 15331 0HIV Myxoedema 181453 85 1577 054 043 067 331 0HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492HIV Polymyositis 631 10 15 691 33 1279 4409 0HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381HIV Psoriasis 18690 65 473 137 106 175 624 00125

HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113HIV Scleroderma 1930 1 25 04 001 221 042 05189HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929

all

aged 0-14

15-34

35-54

55-64

65+

interval lt1yr

1-4

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 830 15 15 998 556 1655 11032 0
HIV Ankylosing spondylitis 1995 2 56 035 004 128 174 01866
HIV Autoimmune haemolytic anaemia 796 4 09 423 115 1088 687 00088
HIV Chronic active hepatitis 340 3 06 537 11 1582 668 00098
HIV Coeliac disease 3639 6 79 076 028 165 025 0616
HIV Crohns disease 5695 13 167 078 041 133 061 04355
HIV ITP 2142 15 32 473 265 783 4024 0
HIV Myxoedema 77911 43 698 062 045 083 992 00016
HIV Pernicious anaemia 7615 3 37 082 017 239 001 09271
HIV Polymyositis 302 8 08 1018 435 2031 5584 0
HIV Primary biliary cirrhosis 919 0 12 0 0 317 038 05375
HIV Psoriasis 8090 27 217 125 082 182 108 02985
HIV Rheumatoid arthritis 23991 17 266 064 037 102 314 00763
HIV Scleroderma 911 1 12 085 002 475 009 07639
HIV Sjogrens syndrome 1836 0 21 0 0 176 121 02704
HIV Systematic lupus erythematosus 1703 6 5 121 044 263 006 0813
HIV Thyrotoxicosis 11529 14 155 09 049 151 007 0797
HIV Ulcerative colitis 9323 30 282 106 072 152 006 08069
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 352 17 09 1992 1147 3236 27362 0
HIV Ankylosing spondylitis 767 1 11 088 002 493 012 07296
HIV Autoimmune haemolytic anaemia 306 7 04 1792 714 3736 9338 0
HIV Chronic active hepatitis 118 6 02 3067 1103 6878 13684 0
HIV Coeliac disease 1206 0 16 0 0 226 079 03752
HIV Crohns disease 1896 15 5 3 167 496 1787 0
HIV ITP 728 22 21 1068 665 1629 17803 0
HIV Myxoedema 28047 13 163 08 042 136 048 04889
HIV Pernicious anaemia 2773 1 09 106 003 593 021 06495
HIV Polymyositis 113 1 01 785 02 4461 108 02995
HIV Primary biliary cirrhosis 308 1 02 646 016 3624 077 03817
HIV Psoriasis 3072 22 61 361 226 548 3875 0
HIV Rheumatoid arthritis 9101 11 69 16 08 286 189 01697
HIV Scleroderma 294 0 03 0 0 1121 009 07682
HIV Sjogrens syndrome 565 2 05 436 053 1581 235 01253
HIV Systematic lupus erythematosus 608 1 12 082 002 461 007 07944
HIV Thyrotoxicosis 4243 5 43 118 038 275 001 09048
HIV Ulcerative colitis 3123 17 75 229 133 367 1101 00009
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 821 1 01 78 02 4358 108 02995
HIV Ankylosing spondylitis 1672 0 04 0 0 887 002 08966
HIV Autoimmune haemolytic anaemia 1142 1 02 418 011 2333 028 05943
HIV Chronic active hepatitis 300 1 01 1674 042 9401 323 00721
HIV Coeliac disease 3003 0 04 0 0 836 001 09297
HIV Crohns disease 4249 1 07 14 004 779 006 07988
HIV ITP 2750 4 05 823 224 2109 1866 0
HIV Myxoedema 111802 12 124 097 05 169 0 09748
HIV Pernicious anaemia 13040 0 15 0 0 253 063 04283
HIV Polymyositis 333 2 0 4371 527 15913 4594 0
HIV Primary biliary cirrhosis 1120 0 01 0 0 3586 153 02162
HIV Psoriasis 6100 2 15 131 016 472 0 09797
HIV Rheumatoid arthritis 30228 7 41 172 069 355 146 02269
HIV Scleroderma 909 0 01 0 0 3312 135 02449
HIV Sjogrens syndrome 1883 0 02 0 0 1969 052 04704
HIV Systematic lupus erythematosus 1056 0 02 0 0 1993 053 04648
HIV Thyrotoxicosis 15247 4 19 21 057 538 134 0247
HIV Ulcerative colitis 7697 5 16 317 103 74 541 002
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 326 3 03 893 183 2632 138 00002
HIV Ankylosing spondylitis 971 0 14 0 0 272 054 04621
HIV Autoimmune haemolytic anaemia 261 0 03 0 0 1419 022 06407
HIV Chronic active hepatitis 143 1 01 733 018 415 096 03272
HIV Coeliac disease 1492 0 11 0 0 331 034 05598
HIV Crohns disease 1923 1 24 042 001 234 032 05686
HIV ITP 712 3 09 329 068 964 274 00976
HIV Myxoedema 30859 11 201 055 027 098 368 00552
HIV Pernicious anaemia 1970 1 13 078 002 437 004 0844
HIV Polymyositis 135 2 01 1436 172 5288 1309 00003
HIV Primary biliary cirrhosis 377 1 02 575 015 3225 061 0435
HIV Psoriasis 3545 5 48 104 034 244 002 08955
HIV Rheumatoid arthritis 10250 4 88 045 012 116 214 01439
HIV Scleroderma 463 0 03 0 0 1449 023 06285
HIV Sjogrens syndrome 1053 1 05 2 005 1119 0 09991
HIV Systematic lupus erythematosus 715 0 06 0 0 606 002 0888
HIV Thyrotoxicosis 4076 4 35 115 031 295 0 0988
HIV Ulcerative colitis 3588 8 49 164 071 324 141 02348
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 458 20 2 1017 615 1589 14969 0
HIV Ankylosing spondylitis 1430 1 74 013 0 075 476 00291
HIV Autoimmune haemolytic anaemia 195 9 11 854 385 1655 5027 0
HIV Chronic active hepatitis 126 6 06 1068 385 2391 4141 0
HIV Coeliac disease 2230 5 96 052 017 122 173 01884
HIV Crohns disease 3262 22 203 108 068 164 007 07958
HIV ITP 694 23 44 533 335 806 7409 0
HIV Myxoedema 30770 47 922 051 037 068 2172 0
HIV Pernicious anaemia 1664 3 43 07 014 204 015 07013
HIV Polymyositis 127 3 1 316 064 945 246 01165
HIV Primary biliary cirrhosis 359 1 14 07 002 393 0 09501
HIV Psoriasis 6137 35 30 117 081 162 067 04141
HIV Rheumatoid arthritis 10968 21 365 057 036 088 617 0013
HIV Scleroderma 455 1 17 059 001 331 002 08849
HIV Sjogrens syndrome 995 1 29 034 001 192 068 04097
HIV Systematic lupus erythematosus 1279 7 63 112 045 231 001 09219
HIV Thyrotoxicosis 4589 18 191 094 056 149 002 08979
HIV Ulcerative colitis 5315 34 346 098 068 138 0 09893
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 213 11 1 1186 583 2166 9395 0
HIV Ankylosing spondylitis 486 2 27 074 009 269 002 09025
HIV Autoimmune haemolytic anaemia 66 2 03 627 074 2356 422 00398
HIV Chronic active hepatitis 39 2 02 1257 147 4856 1072 00011
HIV Coeliac disease 909 2 42 047 006 171 071 03994
HIV Crohns disease 2215 7 111 063 025 13 118 02778
HIV ITP 331 11 19 606 3 1098 4019 0
HIV Myxoedema 7241 15 325 046 026 076 896 00028
HIV Pernicious anaemia 472 0 17 0 0 212 089 03468
HIV Polymyositis 32 3 03 1034 203 3306 1533 00001
HIV Primary biliary cirrhosis 59 0 03 0 0 1176 01 07528
HIV Psoriasis 2551 23 109 213 135 32 1253 00004
HIV Rheumatoid arthritis 2238 7 95 073 03 152 043 05128
HIV Scleroderma 89 0 05 0 0 805 0 09596
HIV Sjogrens syndrome 160 0 07 0 0 564 004 08448
HIV Systematic lupus erythematosus 554 3 27 111 023 326 002 0899
HIV Thyrotoxicosis 1784 6 88 068 025 148 062 04293
HIV Ulcerative colitis 2667 15 151 1 056 165 001 09074
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 50 0 0 0 0 8184 44 00359
HIV Ankylosing spondylitis 10 0 0 0 0 71245 3898 0
HIV Autoimmune haemolytic anaemia 24 0 0 0 0 24127 1416 00002
HIV Chronic active hepatitis 17 0 0 0 0 12064 638 00115
HIV Coeliac disease 493 0 03 0 0 1306 017 06837
HIV Crohns disease 651 0 04 0 0 933 003 08691
HIV ITP 207 2 01 139 167 5086 1266 00004
HIV Myxoedema 781 0 05 0 0 704 0 09722
HIV Pernicious anaemia 14 0 0 0 0 84591 4915 0
HIV Polymyositis 4 0 0 0 0 6051 24878 0
HIV Primary biliary cirrhosis 2 0 0 0 0 0 0 0
HIV Psoriasis 357 0 01 0 0 2873 107 03016
HIV Rheumatoid arthritis 109 0 0 0 0 7558 409 00431
HIV Scleroderma 14 0 0 0 0 107299 626 0
HIV Sjogrens syndrome 10 0 0 0 0 396158 22105 0
HIV Systematic lupus erythematosus 64 0 0 0 0 7928 427 00387
HIV Thyrotoxicosis 173 0 01 0 0 3713 159 0207
HIV Ulcerative colitis 504 0 03 0 0 1346 018 06677
Cohort of HIV and Autoimmune Diseases-all cases
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1868 35 35 1008 7 1408 27231 0
HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147
HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0
HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0
HIV Coeliac disease 8127 7 156 045 018 092 423 00396
HIV Crohns disease 12300 31 349 089 06 126 034 05606
HIV ITP 4694 43 78 552 399 745 15331 0
HIV Myxoedema 181453 85 1577 054 043 067 331 0
HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492
HIV Polymyositis 631 10 15 691 33 1279 4409 0
HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381
HIV Psoriasis 18690 65 473 137 106 175 624 00125
HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113
HIV Scleroderma 1930 1 25 04 001 221 042 05189
HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396
HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218
HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879
HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929
Page 15: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Cohort of HIV and Autoimmune Diseases-all casesexposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-valueHIV Addisons disease 1868 35 35 1008 7 1408 27231 0HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0HIV Coeliac disease 8127 7 156 045 018 092 423 00396HIV Crohns disease 12300 31 349 089 06 126 034 05606HIV ITP 4694 43 78 552 399 745 15331 0HIV Myxoedema 181453 85 1577 054 043 067 331 0HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492HIV Polymyositis 631 10 15 691 33 1279 4409 0HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381HIV Psoriasis 18690 65 473 137 106 175 624 00125

HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113HIV Scleroderma 1930 1 25 04 001 221 042 05189HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929

all

aged 0-14

15-34

35-54

55-64

65+

interval lt1yr

1-4

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 830 15 15 998 556 1655 11032 0
HIV Ankylosing spondylitis 1995 2 56 035 004 128 174 01866
HIV Autoimmune haemolytic anaemia 796 4 09 423 115 1088 687 00088
HIV Chronic active hepatitis 340 3 06 537 11 1582 668 00098
HIV Coeliac disease 3639 6 79 076 028 165 025 0616
HIV Crohns disease 5695 13 167 078 041 133 061 04355
HIV ITP 2142 15 32 473 265 783 4024 0
HIV Myxoedema 77911 43 698 062 045 083 992 00016
HIV Pernicious anaemia 7615 3 37 082 017 239 001 09271
HIV Polymyositis 302 8 08 1018 435 2031 5584 0
HIV Primary biliary cirrhosis 919 0 12 0 0 317 038 05375
HIV Psoriasis 8090 27 217 125 082 182 108 02985
HIV Rheumatoid arthritis 23991 17 266 064 037 102 314 00763
HIV Scleroderma 911 1 12 085 002 475 009 07639
HIV Sjogrens syndrome 1836 0 21 0 0 176 121 02704
HIV Systematic lupus erythematosus 1703 6 5 121 044 263 006 0813
HIV Thyrotoxicosis 11529 14 155 09 049 151 007 0797
HIV Ulcerative colitis 9323 30 282 106 072 152 006 08069
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 352 17 09 1992 1147 3236 27362 0
HIV Ankylosing spondylitis 767 1 11 088 002 493 012 07296
HIV Autoimmune haemolytic anaemia 306 7 04 1792 714 3736 9338 0
HIV Chronic active hepatitis 118 6 02 3067 1103 6878 13684 0
HIV Coeliac disease 1206 0 16 0 0 226 079 03752
HIV Crohns disease 1896 15 5 3 167 496 1787 0
HIV ITP 728 22 21 1068 665 1629 17803 0
HIV Myxoedema 28047 13 163 08 042 136 048 04889
HIV Pernicious anaemia 2773 1 09 106 003 593 021 06495
HIV Polymyositis 113 1 01 785 02 4461 108 02995
HIV Primary biliary cirrhosis 308 1 02 646 016 3624 077 03817
HIV Psoriasis 3072 22 61 361 226 548 3875 0
HIV Rheumatoid arthritis 9101 11 69 16 08 286 189 01697
HIV Scleroderma 294 0 03 0 0 1121 009 07682
HIV Sjogrens syndrome 565 2 05 436 053 1581 235 01253
HIV Systematic lupus erythematosus 608 1 12 082 002 461 007 07944
HIV Thyrotoxicosis 4243 5 43 118 038 275 001 09048
HIV Ulcerative colitis 3123 17 75 229 133 367 1101 00009
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 821 1 01 78 02 4358 108 02995
HIV Ankylosing spondylitis 1672 0 04 0 0 887 002 08966
HIV Autoimmune haemolytic anaemia 1142 1 02 418 011 2333 028 05943
HIV Chronic active hepatitis 300 1 01 1674 042 9401 323 00721
HIV Coeliac disease 3003 0 04 0 0 836 001 09297
HIV Crohns disease 4249 1 07 14 004 779 006 07988
HIV ITP 2750 4 05 823 224 2109 1866 0
HIV Myxoedema 111802 12 124 097 05 169 0 09748
HIV Pernicious anaemia 13040 0 15 0 0 253 063 04283
HIV Polymyositis 333 2 0 4371 527 15913 4594 0
HIV Primary biliary cirrhosis 1120 0 01 0 0 3586 153 02162
HIV Psoriasis 6100 2 15 131 016 472 0 09797
HIV Rheumatoid arthritis 30228 7 41 172 069 355 146 02269
HIV Scleroderma 909 0 01 0 0 3312 135 02449
HIV Sjogrens syndrome 1883 0 02 0 0 1969 052 04704
HIV Systematic lupus erythematosus 1056 0 02 0 0 1993 053 04648
HIV Thyrotoxicosis 15247 4 19 21 057 538 134 0247
HIV Ulcerative colitis 7697 5 16 317 103 74 541 002
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 326 3 03 893 183 2632 138 00002
HIV Ankylosing spondylitis 971 0 14 0 0 272 054 04621
HIV Autoimmune haemolytic anaemia 261 0 03 0 0 1419 022 06407
HIV Chronic active hepatitis 143 1 01 733 018 415 096 03272
HIV Coeliac disease 1492 0 11 0 0 331 034 05598
HIV Crohns disease 1923 1 24 042 001 234 032 05686
HIV ITP 712 3 09 329 068 964 274 00976
HIV Myxoedema 30859 11 201 055 027 098 368 00552
HIV Pernicious anaemia 1970 1 13 078 002 437 004 0844
HIV Polymyositis 135 2 01 1436 172 5288 1309 00003
HIV Primary biliary cirrhosis 377 1 02 575 015 3225 061 0435
HIV Psoriasis 3545 5 48 104 034 244 002 08955
HIV Rheumatoid arthritis 10250 4 88 045 012 116 214 01439
HIV Scleroderma 463 0 03 0 0 1449 023 06285
HIV Sjogrens syndrome 1053 1 05 2 005 1119 0 09991
HIV Systematic lupus erythematosus 715 0 06 0 0 606 002 0888
HIV Thyrotoxicosis 4076 4 35 115 031 295 0 0988
HIV Ulcerative colitis 3588 8 49 164 071 324 141 02348
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 458 20 2 1017 615 1589 14969 0
HIV Ankylosing spondylitis 1430 1 74 013 0 075 476 00291
HIV Autoimmune haemolytic anaemia 195 9 11 854 385 1655 5027 0
HIV Chronic active hepatitis 126 6 06 1068 385 2391 4141 0
HIV Coeliac disease 2230 5 96 052 017 122 173 01884
HIV Crohns disease 3262 22 203 108 068 164 007 07958
HIV ITP 694 23 44 533 335 806 7409 0
HIV Myxoedema 30770 47 922 051 037 068 2172 0
HIV Pernicious anaemia 1664 3 43 07 014 204 015 07013
HIV Polymyositis 127 3 1 316 064 945 246 01165
HIV Primary biliary cirrhosis 359 1 14 07 002 393 0 09501
HIV Psoriasis 6137 35 30 117 081 162 067 04141
HIV Rheumatoid arthritis 10968 21 365 057 036 088 617 0013
HIV Scleroderma 455 1 17 059 001 331 002 08849
HIV Sjogrens syndrome 995 1 29 034 001 192 068 04097
HIV Systematic lupus erythematosus 1279 7 63 112 045 231 001 09219
HIV Thyrotoxicosis 4589 18 191 094 056 149 002 08979
HIV Ulcerative colitis 5315 34 346 098 068 138 0 09893
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 213 11 1 1186 583 2166 9395 0
HIV Ankylosing spondylitis 486 2 27 074 009 269 002 09025
HIV Autoimmune haemolytic anaemia 66 2 03 627 074 2356 422 00398
HIV Chronic active hepatitis 39 2 02 1257 147 4856 1072 00011
HIV Coeliac disease 909 2 42 047 006 171 071 03994
HIV Crohns disease 2215 7 111 063 025 13 118 02778
HIV ITP 331 11 19 606 3 1098 4019 0
HIV Myxoedema 7241 15 325 046 026 076 896 00028
HIV Pernicious anaemia 472 0 17 0 0 212 089 03468
HIV Polymyositis 32 3 03 1034 203 3306 1533 00001
HIV Primary biliary cirrhosis 59 0 03 0 0 1176 01 07528
HIV Psoriasis 2551 23 109 213 135 32 1253 00004
HIV Rheumatoid arthritis 2238 7 95 073 03 152 043 05128
HIV Scleroderma 89 0 05 0 0 805 0 09596
HIV Sjogrens syndrome 160 0 07 0 0 564 004 08448
HIV Systematic lupus erythematosus 554 3 27 111 023 326 002 0899
HIV Thyrotoxicosis 1784 6 88 068 025 148 062 04293
HIV Ulcerative colitis 2667 15 151 1 056 165 001 09074
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 50 0 0 0 0 8184 44 00359
HIV Ankylosing spondylitis 10 0 0 0 0 71245 3898 0
HIV Autoimmune haemolytic anaemia 24 0 0 0 0 24127 1416 00002
HIV Chronic active hepatitis 17 0 0 0 0 12064 638 00115
HIV Coeliac disease 493 0 03 0 0 1306 017 06837
HIV Crohns disease 651 0 04 0 0 933 003 08691
HIV ITP 207 2 01 139 167 5086 1266 00004
HIV Myxoedema 781 0 05 0 0 704 0 09722
HIV Pernicious anaemia 14 0 0 0 0 84591 4915 0
HIV Polymyositis 4 0 0 0 0 6051 24878 0
HIV Primary biliary cirrhosis 2 0 0 0 0 0 0 0
HIV Psoriasis 357 0 01 0 0 2873 107 03016
HIV Rheumatoid arthritis 109 0 0 0 0 7558 409 00431
HIV Scleroderma 14 0 0 0 0 107299 626 0
HIV Sjogrens syndrome 10 0 0 0 0 396158 22105 0
HIV Systematic lupus erythematosus 64 0 0 0 0 7928 427 00387
HIV Thyrotoxicosis 173 0 01 0 0 3713 159 0207
HIV Ulcerative colitis 504 0 03 0 0 1346 018 06677
Cohort of HIV and Autoimmune Diseases-all cases
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1868 35 35 1008 7 1408 27231 0
HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147
HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0
HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0
HIV Coeliac disease 8127 7 156 045 018 092 423 00396
HIV Crohns disease 12300 31 349 089 06 126 034 05606
HIV ITP 4694 43 78 552 399 745 15331 0
HIV Myxoedema 181453 85 1577 054 043 067 331 0
HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492
HIV Polymyositis 631 10 15 691 33 1279 4409 0
HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381
HIV Psoriasis 18690 65 473 137 106 175 624 00125
HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113
HIV Scleroderma 1930 1 25 04 001 221 042 05189
HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396
HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218
HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879
HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929
Page 16: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

all

aged 0-14

15-34

35-54

55-64

65+

interval lt1yr

1-4

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 830 15 15 998 556 1655 11032 0
HIV Ankylosing spondylitis 1995 2 56 035 004 128 174 01866
HIV Autoimmune haemolytic anaemia 796 4 09 423 115 1088 687 00088
HIV Chronic active hepatitis 340 3 06 537 11 1582 668 00098
HIV Coeliac disease 3639 6 79 076 028 165 025 0616
HIV Crohns disease 5695 13 167 078 041 133 061 04355
HIV ITP 2142 15 32 473 265 783 4024 0
HIV Myxoedema 77911 43 698 062 045 083 992 00016
HIV Pernicious anaemia 7615 3 37 082 017 239 001 09271
HIV Polymyositis 302 8 08 1018 435 2031 5584 0
HIV Primary biliary cirrhosis 919 0 12 0 0 317 038 05375
HIV Psoriasis 8090 27 217 125 082 182 108 02985
HIV Rheumatoid arthritis 23991 17 266 064 037 102 314 00763
HIV Scleroderma 911 1 12 085 002 475 009 07639
HIV Sjogrens syndrome 1836 0 21 0 0 176 121 02704
HIV Systematic lupus erythematosus 1703 6 5 121 044 263 006 0813
HIV Thyrotoxicosis 11529 14 155 09 049 151 007 0797
HIV Ulcerative colitis 9323 30 282 106 072 152 006 08069
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 352 17 09 1992 1147 3236 27362 0
HIV Ankylosing spondylitis 767 1 11 088 002 493 012 07296
HIV Autoimmune haemolytic anaemia 306 7 04 1792 714 3736 9338 0
HIV Chronic active hepatitis 118 6 02 3067 1103 6878 13684 0
HIV Coeliac disease 1206 0 16 0 0 226 079 03752
HIV Crohns disease 1896 15 5 3 167 496 1787 0
HIV ITP 728 22 21 1068 665 1629 17803 0
HIV Myxoedema 28047 13 163 08 042 136 048 04889
HIV Pernicious anaemia 2773 1 09 106 003 593 021 06495
HIV Polymyositis 113 1 01 785 02 4461 108 02995
HIV Primary biliary cirrhosis 308 1 02 646 016 3624 077 03817
HIV Psoriasis 3072 22 61 361 226 548 3875 0
HIV Rheumatoid arthritis 9101 11 69 16 08 286 189 01697
HIV Scleroderma 294 0 03 0 0 1121 009 07682
HIV Sjogrens syndrome 565 2 05 436 053 1581 235 01253
HIV Systematic lupus erythematosus 608 1 12 082 002 461 007 07944
HIV Thyrotoxicosis 4243 5 43 118 038 275 001 09048
HIV Ulcerative colitis 3123 17 75 229 133 367 1101 00009
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 821 1 01 78 02 4358 108 02995
HIV Ankylosing spondylitis 1672 0 04 0 0 887 002 08966
HIV Autoimmune haemolytic anaemia 1142 1 02 418 011 2333 028 05943
HIV Chronic active hepatitis 300 1 01 1674 042 9401 323 00721
HIV Coeliac disease 3003 0 04 0 0 836 001 09297
HIV Crohns disease 4249 1 07 14 004 779 006 07988
HIV ITP 2750 4 05 823 224 2109 1866 0
HIV Myxoedema 111802 12 124 097 05 169 0 09748
HIV Pernicious anaemia 13040 0 15 0 0 253 063 04283
HIV Polymyositis 333 2 0 4371 527 15913 4594 0
HIV Primary biliary cirrhosis 1120 0 01 0 0 3586 153 02162
HIV Psoriasis 6100 2 15 131 016 472 0 09797
HIV Rheumatoid arthritis 30228 7 41 172 069 355 146 02269
HIV Scleroderma 909 0 01 0 0 3312 135 02449
HIV Sjogrens syndrome 1883 0 02 0 0 1969 052 04704
HIV Systematic lupus erythematosus 1056 0 02 0 0 1993 053 04648
HIV Thyrotoxicosis 15247 4 19 21 057 538 134 0247
HIV Ulcerative colitis 7697 5 16 317 103 74 541 002
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 326 3 03 893 183 2632 138 00002
HIV Ankylosing spondylitis 971 0 14 0 0 272 054 04621
HIV Autoimmune haemolytic anaemia 261 0 03 0 0 1419 022 06407
HIV Chronic active hepatitis 143 1 01 733 018 415 096 03272
HIV Coeliac disease 1492 0 11 0 0 331 034 05598
HIV Crohns disease 1923 1 24 042 001 234 032 05686
HIV ITP 712 3 09 329 068 964 274 00976
HIV Myxoedema 30859 11 201 055 027 098 368 00552
HIV Pernicious anaemia 1970 1 13 078 002 437 004 0844
HIV Polymyositis 135 2 01 1436 172 5288 1309 00003
HIV Primary biliary cirrhosis 377 1 02 575 015 3225 061 0435
HIV Psoriasis 3545 5 48 104 034 244 002 08955
HIV Rheumatoid arthritis 10250 4 88 045 012 116 214 01439
HIV Scleroderma 463 0 03 0 0 1449 023 06285
HIV Sjogrens syndrome 1053 1 05 2 005 1119 0 09991
HIV Systematic lupus erythematosus 715 0 06 0 0 606 002 0888
HIV Thyrotoxicosis 4076 4 35 115 031 295 0 0988
HIV Ulcerative colitis 3588 8 49 164 071 324 141 02348
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 458 20 2 1017 615 1589 14969 0
HIV Ankylosing spondylitis 1430 1 74 013 0 075 476 00291
HIV Autoimmune haemolytic anaemia 195 9 11 854 385 1655 5027 0
HIV Chronic active hepatitis 126 6 06 1068 385 2391 4141 0
HIV Coeliac disease 2230 5 96 052 017 122 173 01884
HIV Crohns disease 3262 22 203 108 068 164 007 07958
HIV ITP 694 23 44 533 335 806 7409 0
HIV Myxoedema 30770 47 922 051 037 068 2172 0
HIV Pernicious anaemia 1664 3 43 07 014 204 015 07013
HIV Polymyositis 127 3 1 316 064 945 246 01165
HIV Primary biliary cirrhosis 359 1 14 07 002 393 0 09501
HIV Psoriasis 6137 35 30 117 081 162 067 04141
HIV Rheumatoid arthritis 10968 21 365 057 036 088 617 0013
HIV Scleroderma 455 1 17 059 001 331 002 08849
HIV Sjogrens syndrome 995 1 29 034 001 192 068 04097
HIV Systematic lupus erythematosus 1279 7 63 112 045 231 001 09219
HIV Thyrotoxicosis 4589 18 191 094 056 149 002 08979
HIV Ulcerative colitis 5315 34 346 098 068 138 0 09893
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 213 11 1 1186 583 2166 9395 0
HIV Ankylosing spondylitis 486 2 27 074 009 269 002 09025
HIV Autoimmune haemolytic anaemia 66 2 03 627 074 2356 422 00398
HIV Chronic active hepatitis 39 2 02 1257 147 4856 1072 00011
HIV Coeliac disease 909 2 42 047 006 171 071 03994
HIV Crohns disease 2215 7 111 063 025 13 118 02778
HIV ITP 331 11 19 606 3 1098 4019 0
HIV Myxoedema 7241 15 325 046 026 076 896 00028
HIV Pernicious anaemia 472 0 17 0 0 212 089 03468
HIV Polymyositis 32 3 03 1034 203 3306 1533 00001
HIV Primary biliary cirrhosis 59 0 03 0 0 1176 01 07528
HIV Psoriasis 2551 23 109 213 135 32 1253 00004
HIV Rheumatoid arthritis 2238 7 95 073 03 152 043 05128
HIV Scleroderma 89 0 05 0 0 805 0 09596
HIV Sjogrens syndrome 160 0 07 0 0 564 004 08448
HIV Systematic lupus erythematosus 554 3 27 111 023 326 002 0899
HIV Thyrotoxicosis 1784 6 88 068 025 148 062 04293
HIV Ulcerative colitis 2667 15 151 1 056 165 001 09074
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 50 0 0 0 0 8184 44 00359
HIV Ankylosing spondylitis 10 0 0 0 0 71245 3898 0
HIV Autoimmune haemolytic anaemia 24 0 0 0 0 24127 1416 00002
HIV Chronic active hepatitis 17 0 0 0 0 12064 638 00115
HIV Coeliac disease 493 0 03 0 0 1306 017 06837
HIV Crohns disease 651 0 04 0 0 933 003 08691
HIV ITP 207 2 01 139 167 5086 1266 00004
HIV Myxoedema 781 0 05 0 0 704 0 09722
HIV Pernicious anaemia 14 0 0 0 0 84591 4915 0
HIV Polymyositis 4 0 0 0 0 6051 24878 0
HIV Primary biliary cirrhosis 2 0 0 0 0 0 0 0
HIV Psoriasis 357 0 01 0 0 2873 107 03016
HIV Rheumatoid arthritis 109 0 0 0 0 7558 409 00431
HIV Scleroderma 14 0 0 0 0 107299 626 0
HIV Sjogrens syndrome 10 0 0 0 0 396158 22105 0
HIV Systematic lupus erythematosus 64 0 0 0 0 7928 427 00387
HIV Thyrotoxicosis 173 0 01 0 0 3713 159 0207
HIV Ulcerative colitis 504 0 03 0 0 1346 018 06677
Cohort of HIV and Autoimmune Diseases-all cases
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1868 35 35 1008 7 1408 27231 0
HIV Ankylosing spondylitis 4569 3 119 025 005 073 596 00147
HIV Autoimmune haemolytic anaemia 1688 12 19 622 321 1089 4713 0
HIV Chronic active hepatitis 625 10 1 1031 492 191 7386 0
HIV Coeliac disease 8127 7 156 045 018 092 423 00396
HIV Crohns disease 12300 31 349 089 06 126 034 05606
HIV ITP 4694 43 78 552 399 745 15331 0
HIV Myxoedema 181453 85 1577 054 043 067 331 0
HIV Pernicious anaemia 17160 4 88 046 012 117 208 01492
HIV Polymyositis 631 10 15 691 33 1279 4409 0
HIV Primary biliary cirrhosis 1917 2 2 099 012 357 011 07381
HIV Psoriasis 18690 65 473 137 106 175 624 00125
HIV Rheumatoid arthritis 53793 39 59 066 047 09 643 00113
HIV Scleroderma 1930 1 25 04 001 221 042 05189
HIV Sjogrens syndrome 4101 2 42 047 006 17 072 0396
HIV Systematic lupus erythematosus 3668 10 98 102 049 188 001 09218
HIV Thyrotoxicosis 25869 32 334 096 066 135 002 0879
HIV Ulcerative colitis 19771 62 564 11 084 141 047 04929
Page 17: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

aged 0-14

15-34

35-54

55-64

65+

interval lt1yr

1-4

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 830 15 15 998 556 1655 11032 0
HIV Ankylosing spondylitis 1995 2 56 035 004 128 174 01866
HIV Autoimmune haemolytic anaemia 796 4 09 423 115 1088 687 00088
HIV Chronic active hepatitis 340 3 06 537 11 1582 668 00098
HIV Coeliac disease 3639 6 79 076 028 165 025 0616
HIV Crohns disease 5695 13 167 078 041 133 061 04355
HIV ITP 2142 15 32 473 265 783 4024 0
HIV Myxoedema 77911 43 698 062 045 083 992 00016
HIV Pernicious anaemia 7615 3 37 082 017 239 001 09271
HIV Polymyositis 302 8 08 1018 435 2031 5584 0
HIV Primary biliary cirrhosis 919 0 12 0 0 317 038 05375
HIV Psoriasis 8090 27 217 125 082 182 108 02985
HIV Rheumatoid arthritis 23991 17 266 064 037 102 314 00763
HIV Scleroderma 911 1 12 085 002 475 009 07639
HIV Sjogrens syndrome 1836 0 21 0 0 176 121 02704
HIV Systematic lupus erythematosus 1703 6 5 121 044 263 006 0813
HIV Thyrotoxicosis 11529 14 155 09 049 151 007 0797
HIV Ulcerative colitis 9323 30 282 106 072 152 006 08069
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 352 17 09 1992 1147 3236 27362 0
HIV Ankylosing spondylitis 767 1 11 088 002 493 012 07296
HIV Autoimmune haemolytic anaemia 306 7 04 1792 714 3736 9338 0
HIV Chronic active hepatitis 118 6 02 3067 1103 6878 13684 0
HIV Coeliac disease 1206 0 16 0 0 226 079 03752
HIV Crohns disease 1896 15 5 3 167 496 1787 0
HIV ITP 728 22 21 1068 665 1629 17803 0
HIV Myxoedema 28047 13 163 08 042 136 048 04889
HIV Pernicious anaemia 2773 1 09 106 003 593 021 06495
HIV Polymyositis 113 1 01 785 02 4461 108 02995
HIV Primary biliary cirrhosis 308 1 02 646 016 3624 077 03817
HIV Psoriasis 3072 22 61 361 226 548 3875 0
HIV Rheumatoid arthritis 9101 11 69 16 08 286 189 01697
HIV Scleroderma 294 0 03 0 0 1121 009 07682
HIV Sjogrens syndrome 565 2 05 436 053 1581 235 01253
HIV Systematic lupus erythematosus 608 1 12 082 002 461 007 07944
HIV Thyrotoxicosis 4243 5 43 118 038 275 001 09048
HIV Ulcerative colitis 3123 17 75 229 133 367 1101 00009
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 821 1 01 78 02 4358 108 02995
HIV Ankylosing spondylitis 1672 0 04 0 0 887 002 08966
HIV Autoimmune haemolytic anaemia 1142 1 02 418 011 2333 028 05943
HIV Chronic active hepatitis 300 1 01 1674 042 9401 323 00721
HIV Coeliac disease 3003 0 04 0 0 836 001 09297
HIV Crohns disease 4249 1 07 14 004 779 006 07988
HIV ITP 2750 4 05 823 224 2109 1866 0
HIV Myxoedema 111802 12 124 097 05 169 0 09748
HIV Pernicious anaemia 13040 0 15 0 0 253 063 04283
HIV Polymyositis 333 2 0 4371 527 15913 4594 0
HIV Primary biliary cirrhosis 1120 0 01 0 0 3586 153 02162
HIV Psoriasis 6100 2 15 131 016 472 0 09797
HIV Rheumatoid arthritis 30228 7 41 172 069 355 146 02269
HIV Scleroderma 909 0 01 0 0 3312 135 02449
HIV Sjogrens syndrome 1883 0 02 0 0 1969 052 04704
HIV Systematic lupus erythematosus 1056 0 02 0 0 1993 053 04648
HIV Thyrotoxicosis 15247 4 19 21 057 538 134 0247
HIV Ulcerative colitis 7697 5 16 317 103 74 541 002
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 326 3 03 893 183 2632 138 00002
HIV Ankylosing spondylitis 971 0 14 0 0 272 054 04621
HIV Autoimmune haemolytic anaemia 261 0 03 0 0 1419 022 06407
HIV Chronic active hepatitis 143 1 01 733 018 415 096 03272
HIV Coeliac disease 1492 0 11 0 0 331 034 05598
HIV Crohns disease 1923 1 24 042 001 234 032 05686
HIV ITP 712 3 09 329 068 964 274 00976
HIV Myxoedema 30859 11 201 055 027 098 368 00552
HIV Pernicious anaemia 1970 1 13 078 002 437 004 0844
HIV Polymyositis 135 2 01 1436 172 5288 1309 00003
HIV Primary biliary cirrhosis 377 1 02 575 015 3225 061 0435
HIV Psoriasis 3545 5 48 104 034 244 002 08955
HIV Rheumatoid arthritis 10250 4 88 045 012 116 214 01439
HIV Scleroderma 463 0 03 0 0 1449 023 06285
HIV Sjogrens syndrome 1053 1 05 2 005 1119 0 09991
HIV Systematic lupus erythematosus 715 0 06 0 0 606 002 0888
HIV Thyrotoxicosis 4076 4 35 115 031 295 0 0988
HIV Ulcerative colitis 3588 8 49 164 071 324 141 02348
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 458 20 2 1017 615 1589 14969 0
HIV Ankylosing spondylitis 1430 1 74 013 0 075 476 00291
HIV Autoimmune haemolytic anaemia 195 9 11 854 385 1655 5027 0
HIV Chronic active hepatitis 126 6 06 1068 385 2391 4141 0
HIV Coeliac disease 2230 5 96 052 017 122 173 01884
HIV Crohns disease 3262 22 203 108 068 164 007 07958
HIV ITP 694 23 44 533 335 806 7409 0
HIV Myxoedema 30770 47 922 051 037 068 2172 0
HIV Pernicious anaemia 1664 3 43 07 014 204 015 07013
HIV Polymyositis 127 3 1 316 064 945 246 01165
HIV Primary biliary cirrhosis 359 1 14 07 002 393 0 09501
HIV Psoriasis 6137 35 30 117 081 162 067 04141
HIV Rheumatoid arthritis 10968 21 365 057 036 088 617 0013
HIV Scleroderma 455 1 17 059 001 331 002 08849
HIV Sjogrens syndrome 995 1 29 034 001 192 068 04097
HIV Systematic lupus erythematosus 1279 7 63 112 045 231 001 09219
HIV Thyrotoxicosis 4589 18 191 094 056 149 002 08979
HIV Ulcerative colitis 5315 34 346 098 068 138 0 09893
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 213 11 1 1186 583 2166 9395 0
HIV Ankylosing spondylitis 486 2 27 074 009 269 002 09025
HIV Autoimmune haemolytic anaemia 66 2 03 627 074 2356 422 00398
HIV Chronic active hepatitis 39 2 02 1257 147 4856 1072 00011
HIV Coeliac disease 909 2 42 047 006 171 071 03994
HIV Crohns disease 2215 7 111 063 025 13 118 02778
HIV ITP 331 11 19 606 3 1098 4019 0
HIV Myxoedema 7241 15 325 046 026 076 896 00028
HIV Pernicious anaemia 472 0 17 0 0 212 089 03468
HIV Polymyositis 32 3 03 1034 203 3306 1533 00001
HIV Primary biliary cirrhosis 59 0 03 0 0 1176 01 07528
HIV Psoriasis 2551 23 109 213 135 32 1253 00004
HIV Rheumatoid arthritis 2238 7 95 073 03 152 043 05128
HIV Scleroderma 89 0 05 0 0 805 0 09596
HIV Sjogrens syndrome 160 0 07 0 0 564 004 08448
HIV Systematic lupus erythematosus 554 3 27 111 023 326 002 0899
HIV Thyrotoxicosis 1784 6 88 068 025 148 062 04293
HIV Ulcerative colitis 2667 15 151 1 056 165 001 09074
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 50 0 0 0 0 8184 44 00359
HIV Ankylosing spondylitis 10 0 0 0 0 71245 3898 0
HIV Autoimmune haemolytic anaemia 24 0 0 0 0 24127 1416 00002
HIV Chronic active hepatitis 17 0 0 0 0 12064 638 00115
HIV Coeliac disease 493 0 03 0 0 1306 017 06837
HIV Crohns disease 651 0 04 0 0 933 003 08691
HIV ITP 207 2 01 139 167 5086 1266 00004
HIV Myxoedema 781 0 05 0 0 704 0 09722
HIV Pernicious anaemia 14 0 0 0 0 84591 4915 0
HIV Polymyositis 4 0 0 0 0 6051 24878 0
HIV Primary biliary cirrhosis 2 0 0 0 0 0 0 0
HIV Psoriasis 357 0 01 0 0 2873 107 03016
HIV Rheumatoid arthritis 109 0 0 0 0 7558 409 00431
HIV Scleroderma 14 0 0 0 0 107299 626 0
HIV Sjogrens syndrome 10 0 0 0 0 396158 22105 0
HIV Systematic lupus erythematosus 64 0 0 0 0 7928 427 00387
HIV Thyrotoxicosis 173 0 01 0 0 3713 159 0207
HIV Ulcerative colitis 504 0 03 0 0 1346 018 06677
Page 18: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

15-34

35-54

55-64

65+

interval lt1yr

1-4

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 830 15 15 998 556 1655 11032 0
HIV Ankylosing spondylitis 1995 2 56 035 004 128 174 01866
HIV Autoimmune haemolytic anaemia 796 4 09 423 115 1088 687 00088
HIV Chronic active hepatitis 340 3 06 537 11 1582 668 00098
HIV Coeliac disease 3639 6 79 076 028 165 025 0616
HIV Crohns disease 5695 13 167 078 041 133 061 04355
HIV ITP 2142 15 32 473 265 783 4024 0
HIV Myxoedema 77911 43 698 062 045 083 992 00016
HIV Pernicious anaemia 7615 3 37 082 017 239 001 09271
HIV Polymyositis 302 8 08 1018 435 2031 5584 0
HIV Primary biliary cirrhosis 919 0 12 0 0 317 038 05375
HIV Psoriasis 8090 27 217 125 082 182 108 02985
HIV Rheumatoid arthritis 23991 17 266 064 037 102 314 00763
HIV Scleroderma 911 1 12 085 002 475 009 07639
HIV Sjogrens syndrome 1836 0 21 0 0 176 121 02704
HIV Systematic lupus erythematosus 1703 6 5 121 044 263 006 0813
HIV Thyrotoxicosis 11529 14 155 09 049 151 007 0797
HIV Ulcerative colitis 9323 30 282 106 072 152 006 08069
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 352 17 09 1992 1147 3236 27362 0
HIV Ankylosing spondylitis 767 1 11 088 002 493 012 07296
HIV Autoimmune haemolytic anaemia 306 7 04 1792 714 3736 9338 0
HIV Chronic active hepatitis 118 6 02 3067 1103 6878 13684 0
HIV Coeliac disease 1206 0 16 0 0 226 079 03752
HIV Crohns disease 1896 15 5 3 167 496 1787 0
HIV ITP 728 22 21 1068 665 1629 17803 0
HIV Myxoedema 28047 13 163 08 042 136 048 04889
HIV Pernicious anaemia 2773 1 09 106 003 593 021 06495
HIV Polymyositis 113 1 01 785 02 4461 108 02995
HIV Primary biliary cirrhosis 308 1 02 646 016 3624 077 03817
HIV Psoriasis 3072 22 61 361 226 548 3875 0
HIV Rheumatoid arthritis 9101 11 69 16 08 286 189 01697
HIV Scleroderma 294 0 03 0 0 1121 009 07682
HIV Sjogrens syndrome 565 2 05 436 053 1581 235 01253
HIV Systematic lupus erythematosus 608 1 12 082 002 461 007 07944
HIV Thyrotoxicosis 4243 5 43 118 038 275 001 09048
HIV Ulcerative colitis 3123 17 75 229 133 367 1101 00009
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 821 1 01 78 02 4358 108 02995
HIV Ankylosing spondylitis 1672 0 04 0 0 887 002 08966
HIV Autoimmune haemolytic anaemia 1142 1 02 418 011 2333 028 05943
HIV Chronic active hepatitis 300 1 01 1674 042 9401 323 00721
HIV Coeliac disease 3003 0 04 0 0 836 001 09297
HIV Crohns disease 4249 1 07 14 004 779 006 07988
HIV ITP 2750 4 05 823 224 2109 1866 0
HIV Myxoedema 111802 12 124 097 05 169 0 09748
HIV Pernicious anaemia 13040 0 15 0 0 253 063 04283
HIV Polymyositis 333 2 0 4371 527 15913 4594 0
HIV Primary biliary cirrhosis 1120 0 01 0 0 3586 153 02162
HIV Psoriasis 6100 2 15 131 016 472 0 09797
HIV Rheumatoid arthritis 30228 7 41 172 069 355 146 02269
HIV Scleroderma 909 0 01 0 0 3312 135 02449
HIV Sjogrens syndrome 1883 0 02 0 0 1969 052 04704
HIV Systematic lupus erythematosus 1056 0 02 0 0 1993 053 04648
HIV Thyrotoxicosis 15247 4 19 21 057 538 134 0247
HIV Ulcerative colitis 7697 5 16 317 103 74 541 002
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 326 3 03 893 183 2632 138 00002
HIV Ankylosing spondylitis 971 0 14 0 0 272 054 04621
HIV Autoimmune haemolytic anaemia 261 0 03 0 0 1419 022 06407
HIV Chronic active hepatitis 143 1 01 733 018 415 096 03272
HIV Coeliac disease 1492 0 11 0 0 331 034 05598
HIV Crohns disease 1923 1 24 042 001 234 032 05686
HIV ITP 712 3 09 329 068 964 274 00976
HIV Myxoedema 30859 11 201 055 027 098 368 00552
HIV Pernicious anaemia 1970 1 13 078 002 437 004 0844
HIV Polymyositis 135 2 01 1436 172 5288 1309 00003
HIV Primary biliary cirrhosis 377 1 02 575 015 3225 061 0435
HIV Psoriasis 3545 5 48 104 034 244 002 08955
HIV Rheumatoid arthritis 10250 4 88 045 012 116 214 01439
HIV Scleroderma 463 0 03 0 0 1449 023 06285
HIV Sjogrens syndrome 1053 1 05 2 005 1119 0 09991
HIV Systematic lupus erythematosus 715 0 06 0 0 606 002 0888
HIV Thyrotoxicosis 4076 4 35 115 031 295 0 0988
HIV Ulcerative colitis 3588 8 49 164 071 324 141 02348
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 458 20 2 1017 615 1589 14969 0
HIV Ankylosing spondylitis 1430 1 74 013 0 075 476 00291
HIV Autoimmune haemolytic anaemia 195 9 11 854 385 1655 5027 0
HIV Chronic active hepatitis 126 6 06 1068 385 2391 4141 0
HIV Coeliac disease 2230 5 96 052 017 122 173 01884
HIV Crohns disease 3262 22 203 108 068 164 007 07958
HIV ITP 694 23 44 533 335 806 7409 0
HIV Myxoedema 30770 47 922 051 037 068 2172 0
HIV Pernicious anaemia 1664 3 43 07 014 204 015 07013
HIV Polymyositis 127 3 1 316 064 945 246 01165
HIV Primary biliary cirrhosis 359 1 14 07 002 393 0 09501
HIV Psoriasis 6137 35 30 117 081 162 067 04141
HIV Rheumatoid arthritis 10968 21 365 057 036 088 617 0013
HIV Scleroderma 455 1 17 059 001 331 002 08849
HIV Sjogrens syndrome 995 1 29 034 001 192 068 04097
HIV Systematic lupus erythematosus 1279 7 63 112 045 231 001 09219
HIV Thyrotoxicosis 4589 18 191 094 056 149 002 08979
HIV Ulcerative colitis 5315 34 346 098 068 138 0 09893
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 213 11 1 1186 583 2166 9395 0
HIV Ankylosing spondylitis 486 2 27 074 009 269 002 09025
HIV Autoimmune haemolytic anaemia 66 2 03 627 074 2356 422 00398
HIV Chronic active hepatitis 39 2 02 1257 147 4856 1072 00011
HIV Coeliac disease 909 2 42 047 006 171 071 03994
HIV Crohns disease 2215 7 111 063 025 13 118 02778
HIV ITP 331 11 19 606 3 1098 4019 0
HIV Myxoedema 7241 15 325 046 026 076 896 00028
HIV Pernicious anaemia 472 0 17 0 0 212 089 03468
HIV Polymyositis 32 3 03 1034 203 3306 1533 00001
HIV Primary biliary cirrhosis 59 0 03 0 0 1176 01 07528
HIV Psoriasis 2551 23 109 213 135 32 1253 00004
HIV Rheumatoid arthritis 2238 7 95 073 03 152 043 05128
HIV Scleroderma 89 0 05 0 0 805 0 09596
HIV Sjogrens syndrome 160 0 07 0 0 564 004 08448
HIV Systematic lupus erythematosus 554 3 27 111 023 326 002 0899
HIV Thyrotoxicosis 1784 6 88 068 025 148 062 04293
HIV Ulcerative colitis 2667 15 151 1 056 165 001 09074
Page 19: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

35-54

55-64

65+

interval lt1yr

1-4

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 830 15 15 998 556 1655 11032 0
HIV Ankylosing spondylitis 1995 2 56 035 004 128 174 01866
HIV Autoimmune haemolytic anaemia 796 4 09 423 115 1088 687 00088
HIV Chronic active hepatitis 340 3 06 537 11 1582 668 00098
HIV Coeliac disease 3639 6 79 076 028 165 025 0616
HIV Crohns disease 5695 13 167 078 041 133 061 04355
HIV ITP 2142 15 32 473 265 783 4024 0
HIV Myxoedema 77911 43 698 062 045 083 992 00016
HIV Pernicious anaemia 7615 3 37 082 017 239 001 09271
HIV Polymyositis 302 8 08 1018 435 2031 5584 0
HIV Primary biliary cirrhosis 919 0 12 0 0 317 038 05375
HIV Psoriasis 8090 27 217 125 082 182 108 02985
HIV Rheumatoid arthritis 23991 17 266 064 037 102 314 00763
HIV Scleroderma 911 1 12 085 002 475 009 07639
HIV Sjogrens syndrome 1836 0 21 0 0 176 121 02704
HIV Systematic lupus erythematosus 1703 6 5 121 044 263 006 0813
HIV Thyrotoxicosis 11529 14 155 09 049 151 007 0797
HIV Ulcerative colitis 9323 30 282 106 072 152 006 08069
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 352 17 09 1992 1147 3236 27362 0
HIV Ankylosing spondylitis 767 1 11 088 002 493 012 07296
HIV Autoimmune haemolytic anaemia 306 7 04 1792 714 3736 9338 0
HIV Chronic active hepatitis 118 6 02 3067 1103 6878 13684 0
HIV Coeliac disease 1206 0 16 0 0 226 079 03752
HIV Crohns disease 1896 15 5 3 167 496 1787 0
HIV ITP 728 22 21 1068 665 1629 17803 0
HIV Myxoedema 28047 13 163 08 042 136 048 04889
HIV Pernicious anaemia 2773 1 09 106 003 593 021 06495
HIV Polymyositis 113 1 01 785 02 4461 108 02995
HIV Primary biliary cirrhosis 308 1 02 646 016 3624 077 03817
HIV Psoriasis 3072 22 61 361 226 548 3875 0
HIV Rheumatoid arthritis 9101 11 69 16 08 286 189 01697
HIV Scleroderma 294 0 03 0 0 1121 009 07682
HIV Sjogrens syndrome 565 2 05 436 053 1581 235 01253
HIV Systematic lupus erythematosus 608 1 12 082 002 461 007 07944
HIV Thyrotoxicosis 4243 5 43 118 038 275 001 09048
HIV Ulcerative colitis 3123 17 75 229 133 367 1101 00009
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 821 1 01 78 02 4358 108 02995
HIV Ankylosing spondylitis 1672 0 04 0 0 887 002 08966
HIV Autoimmune haemolytic anaemia 1142 1 02 418 011 2333 028 05943
HIV Chronic active hepatitis 300 1 01 1674 042 9401 323 00721
HIV Coeliac disease 3003 0 04 0 0 836 001 09297
HIV Crohns disease 4249 1 07 14 004 779 006 07988
HIV ITP 2750 4 05 823 224 2109 1866 0
HIV Myxoedema 111802 12 124 097 05 169 0 09748
HIV Pernicious anaemia 13040 0 15 0 0 253 063 04283
HIV Polymyositis 333 2 0 4371 527 15913 4594 0
HIV Primary biliary cirrhosis 1120 0 01 0 0 3586 153 02162
HIV Psoriasis 6100 2 15 131 016 472 0 09797
HIV Rheumatoid arthritis 30228 7 41 172 069 355 146 02269
HIV Scleroderma 909 0 01 0 0 3312 135 02449
HIV Sjogrens syndrome 1883 0 02 0 0 1969 052 04704
HIV Systematic lupus erythematosus 1056 0 02 0 0 1993 053 04648
HIV Thyrotoxicosis 15247 4 19 21 057 538 134 0247
HIV Ulcerative colitis 7697 5 16 317 103 74 541 002
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 326 3 03 893 183 2632 138 00002
HIV Ankylosing spondylitis 971 0 14 0 0 272 054 04621
HIV Autoimmune haemolytic anaemia 261 0 03 0 0 1419 022 06407
HIV Chronic active hepatitis 143 1 01 733 018 415 096 03272
HIV Coeliac disease 1492 0 11 0 0 331 034 05598
HIV Crohns disease 1923 1 24 042 001 234 032 05686
HIV ITP 712 3 09 329 068 964 274 00976
HIV Myxoedema 30859 11 201 055 027 098 368 00552
HIV Pernicious anaemia 1970 1 13 078 002 437 004 0844
HIV Polymyositis 135 2 01 1436 172 5288 1309 00003
HIV Primary biliary cirrhosis 377 1 02 575 015 3225 061 0435
HIV Psoriasis 3545 5 48 104 034 244 002 08955
HIV Rheumatoid arthritis 10250 4 88 045 012 116 214 01439
HIV Scleroderma 463 0 03 0 0 1449 023 06285
HIV Sjogrens syndrome 1053 1 05 2 005 1119 0 09991
HIV Systematic lupus erythematosus 715 0 06 0 0 606 002 0888
HIV Thyrotoxicosis 4076 4 35 115 031 295 0 0988
HIV Ulcerative colitis 3588 8 49 164 071 324 141 02348
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 458 20 2 1017 615 1589 14969 0
HIV Ankylosing spondylitis 1430 1 74 013 0 075 476 00291
HIV Autoimmune haemolytic anaemia 195 9 11 854 385 1655 5027 0
HIV Chronic active hepatitis 126 6 06 1068 385 2391 4141 0
HIV Coeliac disease 2230 5 96 052 017 122 173 01884
HIV Crohns disease 3262 22 203 108 068 164 007 07958
HIV ITP 694 23 44 533 335 806 7409 0
HIV Myxoedema 30770 47 922 051 037 068 2172 0
HIV Pernicious anaemia 1664 3 43 07 014 204 015 07013
HIV Polymyositis 127 3 1 316 064 945 246 01165
HIV Primary biliary cirrhosis 359 1 14 07 002 393 0 09501
HIV Psoriasis 6137 35 30 117 081 162 067 04141
HIV Rheumatoid arthritis 10968 21 365 057 036 088 617 0013
HIV Scleroderma 455 1 17 059 001 331 002 08849
HIV Sjogrens syndrome 995 1 29 034 001 192 068 04097
HIV Systematic lupus erythematosus 1279 7 63 112 045 231 001 09219
HIV Thyrotoxicosis 4589 18 191 094 056 149 002 08979
HIV Ulcerative colitis 5315 34 346 098 068 138 0 09893
Page 20: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

55-64

65+

interval lt1yr

1-4

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 830 15 15 998 556 1655 11032 0
HIV Ankylosing spondylitis 1995 2 56 035 004 128 174 01866
HIV Autoimmune haemolytic anaemia 796 4 09 423 115 1088 687 00088
HIV Chronic active hepatitis 340 3 06 537 11 1582 668 00098
HIV Coeliac disease 3639 6 79 076 028 165 025 0616
HIV Crohns disease 5695 13 167 078 041 133 061 04355
HIV ITP 2142 15 32 473 265 783 4024 0
HIV Myxoedema 77911 43 698 062 045 083 992 00016
HIV Pernicious anaemia 7615 3 37 082 017 239 001 09271
HIV Polymyositis 302 8 08 1018 435 2031 5584 0
HIV Primary biliary cirrhosis 919 0 12 0 0 317 038 05375
HIV Psoriasis 8090 27 217 125 082 182 108 02985
HIV Rheumatoid arthritis 23991 17 266 064 037 102 314 00763
HIV Scleroderma 911 1 12 085 002 475 009 07639
HIV Sjogrens syndrome 1836 0 21 0 0 176 121 02704
HIV Systematic lupus erythematosus 1703 6 5 121 044 263 006 0813
HIV Thyrotoxicosis 11529 14 155 09 049 151 007 0797
HIV Ulcerative colitis 9323 30 282 106 072 152 006 08069
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 352 17 09 1992 1147 3236 27362 0
HIV Ankylosing spondylitis 767 1 11 088 002 493 012 07296
HIV Autoimmune haemolytic anaemia 306 7 04 1792 714 3736 9338 0
HIV Chronic active hepatitis 118 6 02 3067 1103 6878 13684 0
HIV Coeliac disease 1206 0 16 0 0 226 079 03752
HIV Crohns disease 1896 15 5 3 167 496 1787 0
HIV ITP 728 22 21 1068 665 1629 17803 0
HIV Myxoedema 28047 13 163 08 042 136 048 04889
HIV Pernicious anaemia 2773 1 09 106 003 593 021 06495
HIV Polymyositis 113 1 01 785 02 4461 108 02995
HIV Primary biliary cirrhosis 308 1 02 646 016 3624 077 03817
HIV Psoriasis 3072 22 61 361 226 548 3875 0
HIV Rheumatoid arthritis 9101 11 69 16 08 286 189 01697
HIV Scleroderma 294 0 03 0 0 1121 009 07682
HIV Sjogrens syndrome 565 2 05 436 053 1581 235 01253
HIV Systematic lupus erythematosus 608 1 12 082 002 461 007 07944
HIV Thyrotoxicosis 4243 5 43 118 038 275 001 09048
HIV Ulcerative colitis 3123 17 75 229 133 367 1101 00009
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 821 1 01 78 02 4358 108 02995
HIV Ankylosing spondylitis 1672 0 04 0 0 887 002 08966
HIV Autoimmune haemolytic anaemia 1142 1 02 418 011 2333 028 05943
HIV Chronic active hepatitis 300 1 01 1674 042 9401 323 00721
HIV Coeliac disease 3003 0 04 0 0 836 001 09297
HIV Crohns disease 4249 1 07 14 004 779 006 07988
HIV ITP 2750 4 05 823 224 2109 1866 0
HIV Myxoedema 111802 12 124 097 05 169 0 09748
HIV Pernicious anaemia 13040 0 15 0 0 253 063 04283
HIV Polymyositis 333 2 0 4371 527 15913 4594 0
HIV Primary biliary cirrhosis 1120 0 01 0 0 3586 153 02162
HIV Psoriasis 6100 2 15 131 016 472 0 09797
HIV Rheumatoid arthritis 30228 7 41 172 069 355 146 02269
HIV Scleroderma 909 0 01 0 0 3312 135 02449
HIV Sjogrens syndrome 1883 0 02 0 0 1969 052 04704
HIV Systematic lupus erythematosus 1056 0 02 0 0 1993 053 04648
HIV Thyrotoxicosis 15247 4 19 21 057 538 134 0247
HIV Ulcerative colitis 7697 5 16 317 103 74 541 002
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 326 3 03 893 183 2632 138 00002
HIV Ankylosing spondylitis 971 0 14 0 0 272 054 04621
HIV Autoimmune haemolytic anaemia 261 0 03 0 0 1419 022 06407
HIV Chronic active hepatitis 143 1 01 733 018 415 096 03272
HIV Coeliac disease 1492 0 11 0 0 331 034 05598
HIV Crohns disease 1923 1 24 042 001 234 032 05686
HIV ITP 712 3 09 329 068 964 274 00976
HIV Myxoedema 30859 11 201 055 027 098 368 00552
HIV Pernicious anaemia 1970 1 13 078 002 437 004 0844
HIV Polymyositis 135 2 01 1436 172 5288 1309 00003
HIV Primary biliary cirrhosis 377 1 02 575 015 3225 061 0435
HIV Psoriasis 3545 5 48 104 034 244 002 08955
HIV Rheumatoid arthritis 10250 4 88 045 012 116 214 01439
HIV Scleroderma 463 0 03 0 0 1449 023 06285
HIV Sjogrens syndrome 1053 1 05 2 005 1119 0 09991
HIV Systematic lupus erythematosus 715 0 06 0 0 606 002 0888
HIV Thyrotoxicosis 4076 4 35 115 031 295 0 0988
HIV Ulcerative colitis 3588 8 49 164 071 324 141 02348
Page 21: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

65+

interval lt1yr

1-4

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 830 15 15 998 556 1655 11032 0
HIV Ankylosing spondylitis 1995 2 56 035 004 128 174 01866
HIV Autoimmune haemolytic anaemia 796 4 09 423 115 1088 687 00088
HIV Chronic active hepatitis 340 3 06 537 11 1582 668 00098
HIV Coeliac disease 3639 6 79 076 028 165 025 0616
HIV Crohns disease 5695 13 167 078 041 133 061 04355
HIV ITP 2142 15 32 473 265 783 4024 0
HIV Myxoedema 77911 43 698 062 045 083 992 00016
HIV Pernicious anaemia 7615 3 37 082 017 239 001 09271
HIV Polymyositis 302 8 08 1018 435 2031 5584 0
HIV Primary biliary cirrhosis 919 0 12 0 0 317 038 05375
HIV Psoriasis 8090 27 217 125 082 182 108 02985
HIV Rheumatoid arthritis 23991 17 266 064 037 102 314 00763
HIV Scleroderma 911 1 12 085 002 475 009 07639
HIV Sjogrens syndrome 1836 0 21 0 0 176 121 02704
HIV Systematic lupus erythematosus 1703 6 5 121 044 263 006 0813
HIV Thyrotoxicosis 11529 14 155 09 049 151 007 0797
HIV Ulcerative colitis 9323 30 282 106 072 152 006 08069
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 352 17 09 1992 1147 3236 27362 0
HIV Ankylosing spondylitis 767 1 11 088 002 493 012 07296
HIV Autoimmune haemolytic anaemia 306 7 04 1792 714 3736 9338 0
HIV Chronic active hepatitis 118 6 02 3067 1103 6878 13684 0
HIV Coeliac disease 1206 0 16 0 0 226 079 03752
HIV Crohns disease 1896 15 5 3 167 496 1787 0
HIV ITP 728 22 21 1068 665 1629 17803 0
HIV Myxoedema 28047 13 163 08 042 136 048 04889
HIV Pernicious anaemia 2773 1 09 106 003 593 021 06495
HIV Polymyositis 113 1 01 785 02 4461 108 02995
HIV Primary biliary cirrhosis 308 1 02 646 016 3624 077 03817
HIV Psoriasis 3072 22 61 361 226 548 3875 0
HIV Rheumatoid arthritis 9101 11 69 16 08 286 189 01697
HIV Scleroderma 294 0 03 0 0 1121 009 07682
HIV Sjogrens syndrome 565 2 05 436 053 1581 235 01253
HIV Systematic lupus erythematosus 608 1 12 082 002 461 007 07944
HIV Thyrotoxicosis 4243 5 43 118 038 275 001 09048
HIV Ulcerative colitis 3123 17 75 229 133 367 1101 00009
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 821 1 01 78 02 4358 108 02995
HIV Ankylosing spondylitis 1672 0 04 0 0 887 002 08966
HIV Autoimmune haemolytic anaemia 1142 1 02 418 011 2333 028 05943
HIV Chronic active hepatitis 300 1 01 1674 042 9401 323 00721
HIV Coeliac disease 3003 0 04 0 0 836 001 09297
HIV Crohns disease 4249 1 07 14 004 779 006 07988
HIV ITP 2750 4 05 823 224 2109 1866 0
HIV Myxoedema 111802 12 124 097 05 169 0 09748
HIV Pernicious anaemia 13040 0 15 0 0 253 063 04283
HIV Polymyositis 333 2 0 4371 527 15913 4594 0
HIV Primary biliary cirrhosis 1120 0 01 0 0 3586 153 02162
HIV Psoriasis 6100 2 15 131 016 472 0 09797
HIV Rheumatoid arthritis 30228 7 41 172 069 355 146 02269
HIV Scleroderma 909 0 01 0 0 3312 135 02449
HIV Sjogrens syndrome 1883 0 02 0 0 1969 052 04704
HIV Systematic lupus erythematosus 1056 0 02 0 0 1993 053 04648
HIV Thyrotoxicosis 15247 4 19 21 057 538 134 0247
HIV Ulcerative colitis 7697 5 16 317 103 74 541 002
Page 22: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

interval lt1yr

1-4

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 830 15 15 998 556 1655 11032 0
HIV Ankylosing spondylitis 1995 2 56 035 004 128 174 01866
HIV Autoimmune haemolytic anaemia 796 4 09 423 115 1088 687 00088
HIV Chronic active hepatitis 340 3 06 537 11 1582 668 00098
HIV Coeliac disease 3639 6 79 076 028 165 025 0616
HIV Crohns disease 5695 13 167 078 041 133 061 04355
HIV ITP 2142 15 32 473 265 783 4024 0
HIV Myxoedema 77911 43 698 062 045 083 992 00016
HIV Pernicious anaemia 7615 3 37 082 017 239 001 09271
HIV Polymyositis 302 8 08 1018 435 2031 5584 0
HIV Primary biliary cirrhosis 919 0 12 0 0 317 038 05375
HIV Psoriasis 8090 27 217 125 082 182 108 02985
HIV Rheumatoid arthritis 23991 17 266 064 037 102 314 00763
HIV Scleroderma 911 1 12 085 002 475 009 07639
HIV Sjogrens syndrome 1836 0 21 0 0 176 121 02704
HIV Systematic lupus erythematosus 1703 6 5 121 044 263 006 0813
HIV Thyrotoxicosis 11529 14 155 09 049 151 007 0797
HIV Ulcerative colitis 9323 30 282 106 072 152 006 08069
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 352 17 09 1992 1147 3236 27362 0
HIV Ankylosing spondylitis 767 1 11 088 002 493 012 07296
HIV Autoimmune haemolytic anaemia 306 7 04 1792 714 3736 9338 0
HIV Chronic active hepatitis 118 6 02 3067 1103 6878 13684 0
HIV Coeliac disease 1206 0 16 0 0 226 079 03752
HIV Crohns disease 1896 15 5 3 167 496 1787 0
HIV ITP 728 22 21 1068 665 1629 17803 0
HIV Myxoedema 28047 13 163 08 042 136 048 04889
HIV Pernicious anaemia 2773 1 09 106 003 593 021 06495
HIV Polymyositis 113 1 01 785 02 4461 108 02995
HIV Primary biliary cirrhosis 308 1 02 646 016 3624 077 03817
HIV Psoriasis 3072 22 61 361 226 548 3875 0
HIV Rheumatoid arthritis 9101 11 69 16 08 286 189 01697
HIV Scleroderma 294 0 03 0 0 1121 009 07682
HIV Sjogrens syndrome 565 2 05 436 053 1581 235 01253
HIV Systematic lupus erythematosus 608 1 12 082 002 461 007 07944
HIV Thyrotoxicosis 4243 5 43 118 038 275 001 09048
HIV Ulcerative colitis 3123 17 75 229 133 367 1101 00009
Page 23: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

1-4

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 830 15 15 998 556 1655 11032 0
HIV Ankylosing spondylitis 1995 2 56 035 004 128 174 01866
HIV Autoimmune haemolytic anaemia 796 4 09 423 115 1088 687 00088
HIV Chronic active hepatitis 340 3 06 537 11 1582 668 00098
HIV Coeliac disease 3639 6 79 076 028 165 025 0616
HIV Crohns disease 5695 13 167 078 041 133 061 04355
HIV ITP 2142 15 32 473 265 783 4024 0
HIV Myxoedema 77911 43 698 062 045 083 992 00016
HIV Pernicious anaemia 7615 3 37 082 017 239 001 09271
HIV Polymyositis 302 8 08 1018 435 2031 5584 0
HIV Primary biliary cirrhosis 919 0 12 0 0 317 038 05375
HIV Psoriasis 8090 27 217 125 082 182 108 02985
HIV Rheumatoid arthritis 23991 17 266 064 037 102 314 00763
HIV Scleroderma 911 1 12 085 002 475 009 07639
HIV Sjogrens syndrome 1836 0 21 0 0 176 121 02704
HIV Systematic lupus erythematosus 1703 6 5 121 044 263 006 0813
HIV Thyrotoxicosis 11529 14 155 09 049 151 007 0797
HIV Ulcerative colitis 9323 30 282 106 072 152 006 08069
Page 24: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

5+

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 686 3 11 271 056 796 175 01859
HIV Ankylosing spondylitis 1807 0 52 0 0 071 421 00401
HIV Autoimmune haemolytic anaemia 586 1 06 169 004 943 001 09035
HIV Chronic active hepatitis 167 1 02 466 012 2633 038 05397
HIV Coeliac disease 3282 1 61 016 0 091 346 00628
HIV Crohns disease 4709 3 132 023 005 066 717 00074
HIV ITP 1824 6 25 236 087 515 344 00636
HIV Myxoedema 75495 29 716 04 027 058 2479 0
HIV Pernicious anaemia 6772 0 42 0 0 089 322 00729
HIV Polymyositis 216 1 05 188 005 1057 0 09632
HIV Primary biliary cirrhosis 690 1 07 142 004 794 006 08079
HIV Psoriasis 7528 16 196 082 047 133 048 0489
HIV Rheumatoid arthritis 20701 11 254 043 022 077 763 00058
HIV Scleroderma 725 0 1 0 0 362 026 0607
HIV Sjogrens syndrome 1700 0 17 0 0 218 084 03586
HIV Systematic lupus erythematosus 1357 3 36 083 017 243 0 09495
HIV Thyrotoxicosis 10097 13 136 095 051 163 0 09755
HIV Ulcerative colitis 7325 15 207 072 04 119 131 02521
Page 25: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

1+

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1516 18 26 69 408 1094 8394 0
HIV Ankylosing spondylitis 3802 2 108 019 002 067 638 00116
HIV Autoimmune haemolytic anaemia 1382 5 15 325 105 761 568 00171
HIV Chronic active hepatitis 507 4 08 517 14 1332 953 0002
HIV Coeliac disease 6921 7 14 05 02 103 302 00822
HIV Crohns disease 10404 16 299 053 031 087 603 00141
HIV ITP 3966 21 57 368 227 563 3813 0
HIV Myxoedema 153406 72 1414 051 04 064 3362 0
HIV Pernicious anaemia 14387 3 78 038 008 112 24 01217
HIV Polymyositis 518 9 13 682 31 1305 3841 0
HIV Primary biliary cirrhosis 1609 1 19 053 001 298 007 0787
HIV Psoriasis 15618 43 412 104 075 141 004 08421
HIV Rheumatoid arthritis 44692 28 521 054 036 078 1067 00011
HIV Scleroderma 1636 1 22 046 001 254 022 06394
HIV Sjogrens syndrome 3536 0 38 0 0 097 286 0091
HIV Systematic lupus erythematosus 3060 9 86 105 048 199 0 09745
HIV Thyrotoxicosis 21626 27 291 093 061 135 009 07631
HIV Ulcerative colitis 16648 45 489 092 067 123 024 06256
Page 26: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

males

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 761 22 2 1108 69 169 18634 0
HIV Ankylosing spondylitis 2883 3 97 031 006 091 395 0047
HIV Autoimmune haemolytic anaemia 777 9 15 619 282 118 3371 0
HIV Chronic active hepatitis 190 7 07 1106 439 2324 5245 0
HIV Coeliac disease 3136 4 81 05 013 127 158 02085
HIV Crohns disease 5938 27 231 117 077 171 051 04754
HIV ITP 2190 32 52 628 428 889 13471 0
HIV Myxoedema 38856 52 60 087 065 114 095 0331
HIV Pernicious anaemia 5428 2 38 052 006 189 046 04974
HIV Polymyositis 236 7 1 732 291 1531 3116 0
HIV Primary biliary cirrhosis 312 1 09 115 003 648 016 06935
HIV Psoriasis 9428 58 344 169 128 219 1556 00001
HIV Rheumatoid arthritis 16087 28 31 09 06 131 02 06538
HIV Scleroderma 349 0 1 0 0 366 026 06107
HIV Sjogrens syndrome 461 2 12 17 02 617 009 07682
HIV Systematic lupus erythematosus 559 1 25 04 001 226 038 05355
HIV Thyrotoxicosis 5601 16 141 114 065 185 014 07078
HIV Ulcerative colitis 10536 57 408 14 106 181 605 00139
Page 27: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

females

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
HIV b4 autos
exposure outcome obs in ref cohort obs exp rate ratio low CI upr CI chi-sq p-value
HIV Addisons disease 1107 13 15 881 468 1513 814 0
HIV Ankylosing spondylitis 1686 0 22 0 0 164 136 02435
HIV Autoimmune haemolytic anaemia 911 3 05 638 131 187 873 00031
HIV Chronic active hepatitis 435 3 03 915 188 2693 143 00002
HIV Coeliac disease 4991 3 76 04 008 116 218 01395
HIV Crohns disease 6362 4 119 034 009 086 457 00325
HIV ITP 2504 11 27 411 205 737 2278 0
HIV Myxoedema 142597 33 977 034 023 047 4221 0
HIV Pernicious anaemia 11732 2 49 04 005 146 121 02717
HIV Polymyositis 395 3 05 622 128 183 837 00038
HIV Primary biliary cirrhosis 1605 1 12 086 002 482 01 07507
HIV Psoriasis 9262 7 129 054 022 111 229 01305
HIV Rheumatoid arthritis 37706 11 28 039 02 07 969 00018
HIV Scleroderma 1581 1 15 066 002 369 0 09916
HIV Sjogrens syndrome 3640 0 31 0 0 12 215 01424
HIV Systematic lupus erythematosus 3109 9 73 123 056 233 019 06667
HIV Thyrotoxicosis 20268 16 193 083 047 135 04 05258
HIV Ulcerative colitis 9235 5 155 032 01 075 65 00108
Page 28: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

The CHARCOT PROJECTINSPIRE

Isentress (Raltegravir)Pilot Study in Relapsing MS

bull Aims to investigate the concept of HERV+-EBV or herpes viruses as an etiology or trigger for MS

bull Disease controlling rather than disease modifying therapy

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 29: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

INSPIRE Design

bull Pilot study enrolling patients with active RRMS as defined by +ve Gd-enhanced MRI or documented relapse in previous 12 months

bull Baseline (3 months) followed by treatment (3 months)

bull Open label treatment phase with Raltegravir 400mg twice a day

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 30: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

INSPIRE Design 2bull 1deg Outcome number and rate of development

of Gd-enhanced lesionsbull 2deg outcomes are disability and quality-of-lifeStatistical considerations19 subjects need to complete trial to achieve 95 significance with 80 power for a 40 reduction in MS lesions compared with baseline (according to Sormani et al)

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 31: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Trial design

change in gradient

change(in means)

V1 V2(screening before

visit)

V3 V4 V5 V6 V7 V8after

Raltegravirdispensed

A statistically significantchange in means is not inthis situation consistent

with a reduction inoutcome values due tointervention

3

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 32: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Trial design

QOL QOL QOL QOL QOL QOL QOL

MSFC MSFC MSFC MSFC MSFC MSFC MSFCEDSS EDSS EDSS EDSS EDSS

blood blood blood blood blood blood blood blood

MRI MRI MRI MRI MRI MRI MRI

V1 V2 V3 V4 V5 V6 V7 V8(screening before after

visit)

bull Exploratory studybull Danger of Type II error of missing a real association arguably greater than

danger of Type I error of highlighting a spurious association

4

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 33: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

DATA

bull Patient socio-demographic and baseline

bull MRI

bull Viral and biomarkers

bull Disability

bull Quality of life

bull Laboratory safety tests

2

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 34: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Patient socio-demographic and baseline

N mean min maxITTAge at baselineyrs 20 4073 3115 5299Height cm 18 16904 15600 18300Weight kg 18 7873 5190 10970Baseline EDSS 20 240 000 400Number of relapses in past year 20 150 100 300

PPAge at baselineyrs 16 4162 3115 5299Height cm 14 16891 15600 18000Weight kg 14 7790 5190 10830Baseline EDSS 16 225 000 350Number of relapses in past year 16 144 100 300

6

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
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  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 35: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Patient adherenceITT PP

Visit mean

6 Number of tablets dispensed 60 60Number of tablets returned 235 269Adherence percentagea 9608 9552

7 Number of tablets dispensed 63 6375Number of tablets returned 72 675Adherence percentagea 88 8875

8 Number of tablets dispensed 597 5963Number of tablets returned 81 863Adherence percentagea 824 805

Over all three visits Number of tablets dispensed 609 6113Number of tablets returned 588 602Adherence percentagea 8883 8826

a100(tablets dispensed - tablets returned)tablets dispensed

7

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
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  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
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  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 36: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

MRI Total T1 Gd-enhancing lesionsTotal T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Change Weightedrate rate in rate rate ratiob

ITT (n=20) 289 302 012 103PP (n=16) 251 233 -018 092

aChanges calculated after-before or afterbeforebRatios averaged on log scale before back-transforming substituting 01 for zero rates Weighted ratios pooled byweighting for total subject counts

Poisson regression analysis after vs before

ITT rate ratio after vs before as 104(95 CI 85 129) P=0681PP rate ratio after vs before as093(95 CI 072 120) P=0577

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0659PP test of difference in gradients P=0463

8

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 37: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

MRI New T1 Gd-enhancing lesionsNew T1 (Gad enhanced) lesion rates

Before (visits 34 and 5) After (visits 67 and 8) Within-patient changea

Mean monthly Mean monthly Changerate rate in rate

ITT (n=20) 143 167 023PP (n=16) 098 115 017

aChanges calculated after-before or afterbefore

Poisson regression analysis after vs beforeITT rate ratio after vs before as 116(95 CI 087 155) P=0314PP rate ratio after vs before as 116 (95 CI079 172) P=0456

Poisson regression analysis gradient after vs gradient beforeITT test of difference in gradients P=0562PP test of difference in gradients P=0137

9

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 38: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

MRI T1 Gd lesions

ITT Patients in order of difference in rate

010008010019010015010001010016010009010028010027010003010005010007010010010011010013010014010017010023

010012010020010024

-4 -2 0 2difference in rate lesions per month

Difference after - before

4

13

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 39: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

MRI lesions summary

Lesion outcomes provide no statistical evidence consistent with aneffect of raltegravir

14

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 40: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Viral and biomarker data Before vs AfterBaselines (visit 2) Before (345) After (678)

Variable N mean sd N mean sd mean sd

MSRV A CtGAPDH Ct(dim-less) 20 094 01 20 093 007 20 092 007MSRV M CtGAPDH Ct(dim-less) 20 133 006 20 133 006 20 132 007TB HE23 CtGAPDH Ct(dim-less) 20 127 014 20 124 013 20 124 013HERV-W A CtGAPDH Ct(dim-less) 20 116 016 20 118 01 20 118 009HERV-W M CtGAPDH Ct(dim-less) 20 147 021 20 144 015 20 145 013TB HE1113 CtGAPDH Ct(dim-less) 20 127 01 20 128 006 20 129 006IL-8 pgmL 20 2805 8683 20 852 232 20 934 286HERV-WMSRV Gag Flix B cells (d-less) 13 118 011 19 119 01 18 115 006HERV-HF Gag Flix B cells (d-less) 12 114 01 17 108 007 20 112 011HERV-HF Env (H1) Flix B cells (d-less) 11 112 007 18 106 005 17 11 008HERV-HF Env (H3) Flix B cells (d-less) 19 156 024 20 147 015 20 152 016HERV-HF Env (W1) Flix B cells (d-less) 18 131 013 20 123 01 20 123 01HERV-HF Env (W3) Flix B cells (d-less) 17 125 015 20 122 009 20 124 017prop of B cells in sample () 19 914 38 20 859 306 20 905 379prop of monocytes in sample () 19 1533 92 20 1808 641 20 1609 623

HERV-WMSRV Gag Flix monocytes (d-less) 11 114 009 16 116 005 15 115 007MSRV F Gag Flix monocytes (d-less) 13 116 01 17 111 005 16 122 019Env (H1) Flix monocytes (d-less) 15 115 012 18 112 008 17 115 006Env (H3) Flix monocytes (d-less) 19 159 018 20 155 019 20 157 02Env (W1) Flix monocytes (d-less) 15 115 01 19 111 007 19 108 005Env (W3) Flix monocytes (d-less) 13 116 008 19 112 007 18 116 009HCRP ngmL 20 178383 21238 20 189945 176902 20 243527 224115CD163 ngmL 20 45667 15463 20 4239 10536 20 44257 12468EBV Copiesmicrolitre 16 21371 79687 16 238 6672 15 668 21274

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 41: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Viral and biomarker data Before vs AfterHERV-WMSRV Gag Flix B cellsSignificant drop in means in ITT and PPNo significant change in gradient but steeper gradient before

HERV-WMSRV Gag Flix B cellsPP Individual subjects and fitted line

Significant overall drop notattributable to intervention

Similar story for

Env (W1) Flix monocytes

2 3 4 5 6 7 8monthly visits

Solid line fitted by modelA significant drop in means cannot be explained by intervention since decline is steeper before

17

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 42: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

MRI PP Persisting T1 Gd-enhancing lesionsBefore After Within-patient changea

Mean rate Mean rate Change in ratePP (n=16) 153 119 -034

80 of total reductionoccurs before theintervention

attributing the overallreduction to the interventioneven if reduction weresignificant would not be

-013 (P=0469)

P=0762-003 (P=0835)

credible

11

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 43: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

MRI T2 lesions

T2 lesion counts Observed at visits 5 (before) and 8 (after)

Before After Within-patient changea

Mean count Mean count Mean count changeP=0472

weighted ratiob

ITT 445PP 313

465 020P=0462331 019

105107

aChanges calculated after-before or afterbeforebWithin-patient ratios averaged on log scale before back transforming substituting 01 for zero counts Weighted meanratios pooled on log scale by weighting for lesion counts

12

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 44: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Viral and biomarker data change vs T1 Gd lesion changePositive correlation

HERV-WMSRV Gag Flix B cells r=046 P=0057 ITT r=048 P=0086 PP

9

10

Additional analysis

A higher T1 Gd lesioncount at any visit isassociated with higher714

1619

28 27

20

1712

values of HERV-WMSRVGag Flix B cells at that visitP=0029 (ITT)

15

8 1

-3 -2 -1 0 1 2change in T1 lesion rate

Suggestion of decrease in HERV-WMSRV Gag Flix B cells associated with decrease in Gd-enhanced lesion rate PP r=-048 P=0086

23

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 45: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Patients with a decrease in lesion count (eg patient 8) tend to have a decrease or a greater decrease in the biomarker than patients with an increase in lesion count (eg patient 20)

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 46: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Viral and biomarker data summary

Some statistically significant changes in gradient before vs after wereobserved However whether these are consistent with an effect ofraltegravir depends partly on biological plausibility

A very small number of statistically significant correlations wereobserved between changes in these measures and changes in T1 Gdlesion counts their interpretation is again heavily dependent onbiological plausibility

Because of the number of measurestests any significant resultsshould be treated with caution Since results are singled out on thebasis of statistical significance rather than prior hypothesis Type Ierror is likely

25

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 47: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Viral and biomarker data Before vs AfterHCRP ngmLSignificant increase in means in ITT and PPNo significant change in (positive) gradient similar slightly steeper gradient after

ITT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 1221482 1495142 082 0414 -1708943 4151908after | 1406076 1495142 094 0347 -1524349 4336501

------------------------------------------------------------------------------

Significant overall increase not credibly attributable to intervention since the gradientbefore though non-significant is too similar to the gradient after intervention

18

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 48: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Quality of life data summary

A number of measures showed statistically significant improvementsin well-being or a slowing of deterioration in the period aftercompared to before intervention

Although consistent with an effect of raltegravir this is most crediblyattributable to the placebo effect of patients receiving an unblindedintervention rather than to any action of the drug

The study design of not having a control group or a cross-over designmitigated against determining the possible effect of the interventionon Q0L

31

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 49: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Viral and biomarker data Before vs AfterEnv (W3) Flix monocytesNon-significant decline before becomes borderline significant increase afterand significant change in gradient

Env (W3) Flix monocytesITT Individual subjects and fitted line

-002 P=0200

As before biologicalplausibility important bothfor change displayed andfor negative correlation

with Gd T1 lesions

+002 P=0055

P=0047

2 3 4 5 6 7 8monthly visits

Significant change in gradient in ITT (P=0047) and borderline in PP (P=0089)Change in means after - before negatively correlated withchange in rate of Gd enhancing T1 lesions r=-054 P=0015

21

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 50: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521 Highly significant improvement

PASAT------------------------------------------------------------------------------

| gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 2478954 4594816 540 0000 1578387 3379522after | 6377749 4534625 141 0160 -2509954 1526545

------------------------------------------------------------------------------

bull There is a significant gradient changebull But rate of improvement substantially greater before than after intervention

27

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 51: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Quality of life data

Summary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092

PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542

PQ - SF36 - General Health Scale (GH) 20 -467

PQ - SF36 - Vitality Scale (VT) 20 506 PQ - SF36 - Social Functioning Scale (SF) 20 245 PQ - SF36 - Role Emotional Scale (RE) 20 -862 no statistically significant changes

PQ - SF36 - Mental Health Scale (MH) 20 572 PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407PQ - MSIS - Total Score 20 -210 no statistically significant changes

PQ - MSWS-12 - MSWS Total Score 20 -035

30

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 52: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Quality of life dataSummary of changes after-before

change inITT n means

PQ - SF36 - Physical Functional Score (PF) 20 -092PQ - SF36 - Role-Physical Scale (RP) 20 -948PQ - SF36 - Bodily Pain Scale (BP) 20 -542PQ - SF36 - General Health Scale (GH) 20 -467PQ - SF36 - Vitality Scale (VT) 20 506

+ = improvement

PQ - SF36 - Social Functioning Scale (SF) 20 245PQ - SF36 - Role Emotional Scale (RE) 20 -862PQ - SF36 - Mental Health Scale (MH) 20 572PQ - PFA - Patient Fatigue Assessment 20 -151PQ - PPA - Patient Pain Assessment 19 407 - = improvementPQ - MSIS - Total Score 20 -210PQ - MSWS-12 - MSWS Total Score 20 -035

29

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 53: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Disability data

Summary of changes after-before

N mean sdEDSS 20 014 045 Neither change nor gradient change significant

MSFC 20 023 028 [Both change and change in gradient significant]9HPT peg speed 20 0003 0003 Highly significant improvementWalk speed (fs) 20 -004 047 Neither change nor gradient change significantPASAT score 20 466 521

9HPT peg speed------------------------------------------------------------------------------

ITT | gradient SE z P-value [95 Conf Interval]-------------+----------------------------------------------------------------

before | 0009916 0002372 418 0000 0005267 0014565after | 000545 0002363 231 0021 0000818 0010082

------------------------------------------------------------------------------

bull No significant gradient changebull But rate of improvement substantially greater before than after intervention

26

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
  • Diapositive numeacutero 36
  • Diapositive numeacutero 37
  • Diapositive numeacutero 38
  • Diapositive numeacutero 39
  • Diapositive numeacutero 40
  • Diapositive numeacutero 41
  • Diapositive numeacutero 42
  • Diapositive numeacutero 43
  • Diapositive numeacutero 44
  • Diapositive numeacutero 45
  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 54: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Acknowledgementsbull Unit for Healthcare Epidemiology Oxford

ndash Raph Goldacrendash Michael Goldacrendash David Yeates

bull QMULbull Gavin Giovannoni

bull The Albion Centrebull Hubert Maruszak

bull UCLbull Robin Weiss

Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
  • Diapositive numeacutero 30
  • Diapositive numeacutero 31
  • Diapositive numeacutero 32
  • Diapositive numeacutero 34
  • Diapositive numeacutero 35
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  • Acknowledgements
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Laboratory safety tests

32

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
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  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54
Page 56: INSPIRE: Raltegravir (Isentress) Pilot Study in Relapsing MS · Ross CA et al., BMJ, 1965. Mumps virus . Millar JH et al., Br Med J., 1971. Rubella . Horikawa Y et al., Lancet., 1973

Laboratory safety tests significant changes

ITT change gradient gradient change inbefore after gradient

ADJUSTED CALCIUM SERUM +002 -000003 +0008 P=0406 increase could bep=0025 pgt09 p=0149 due intervention

CHLORIDE SERUM -075 +014 -031 p=0194 decrease could bep=0055 p=0503 p=0103 due to intervention

CHOLESTEROL SERUM +028 +008 +003 p=0437 increase notp=0004 p=0059 p=0521 plausibly duehellip

GLUCOSE PLASMA -018 +008 -015 p=0072 gradient changep=0196 p=0284 p=0037 could be duehellip

LDL CHOLESTEROL SERUM +017 +006 +0004 p=0432 increase notp=0018 p=0162 pgt09 plausibly duehellip

PLATELET COUNT +686 -027 +259 p=0352 increase could bep=0040 p=0880 p=0129 duehellip

WHITE BLOOD COUNT PP +022 +006 +010 p=0827 increase notp=0049 p=0579 p=0331 plausibly due

33

  • Diapositive numeacutero 1
  • Diapositive numeacutero 2
  • Dr Jean-Martin Charcot
  • Diapositive numeacutero 4
  • Diapositive numeacutero 5
  • Diapositive numeacutero 6
  • Viruses and MS
  • Are human endogenous retroviruses pathogenic An approach to testing the hypothesis
  • How HERVs may induce autoimmune response
  • Diapositive numeacutero 10
  • Diapositive numeacutero 11
  • Diapositive numeacutero 12
  • Diapositive numeacutero 13
  • How many cases of HIV and MS have been reported
  • What do cohort studies show
  • What is the Risk of Developing Multiple Sclerosis if you have HIV and are on HIV Anti-retroviral therapy
  • Methods
  • Diapositive numeacutero 18
  • Diapositive numeacutero 19
  • NHS Data on UK Healthcare events 1999-2011
  • NHS Cohort gt One year after Exposure (HIV) Contact
  • Diapositive numeacutero 22
  • The CHARCOT PROJECTINSPIRE Isentress (Raltegravir)Pilot Study in Relapsing MS
  • INSPIRE Design
  • INSPIRE Design 2
  • Diapositive numeacutero 26
  • Diapositive numeacutero 27
  • Diapositive numeacutero 28
  • Diapositive numeacutero 29
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  • Diapositive numeacutero 47
  • Diapositive numeacutero 48
  • Diapositive numeacutero 49
  • Diapositive numeacutero 50
  • Acknowledgements
  • Diapositive numeacutero 52
  • Diapositive numeacutero 53
  • Diapositive numeacutero 54

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