Toronto I-II 4:00 pm

The use and misuse of cohort studies in guiding care

Jens LundgrenProfessor in the Department of International Health, Immunology and Microbiology at the University of Copenhagen and coordinator of theDAD study (Data Collection on Adverse Events of Anti-HIV Drugs)

Moderator: Colin KovaksAssistant Professor, Department of Medicine, University of Toronto, and a primary care physician currently practicing at the Maple Leaf Medical Clinic in Toronto

Use (and misuse) of cohort studies to inform treatment decisions

OHTN Research Conference 2013, Toronto17th November 2013

Professor Jens D. Lundgren MD DMScCopenhagen HIV Programme

Department of Infectious Diseases, Rigshospitalet, University of Copenhagen

Denmark

We all know !

• Zidovudine monotherapy should be used in early HIV• ART should be deferred to CD4 < 200 cells/µL• ART interruptions are healthy• d4T + ddI is a atoxic combination of ARV’s• IL-2 should be provided to well suppressed pts

remaining with a low CD4 count• Tenofovir does not adversely affect kidney function• Atazanavir/r causes no other adverse drug reaction

that increased levels of bilirubin

Expert opinion is a hall-mark of HIV medicine !Error rectified by continued research

HIV epidemic in eastern Europe and central Asia the fastest growing in the world:

Estimated number of people living with HIV in WHO-EURO Region, 1990-2011

Source: UNAIDS. Global report: UNAIDS report on the global AIDS epidemic 2012.

0.0200,000.0400,000.0600,000.0800,000.0

1,000,000.01,200,000.01,400,000.01,600,000.01,800,000.02,000,000.02,200,000.02,400,000.02,600,000.02,800,000.03,000,000.0

WHO European Region (total estimated)2.4 million

Eastern Europe and central Asia1.5 million

Western and central Europe860 000

The number of new cases of HIV infection in Russian citizens, 1987 -

2009

UNAIDS Country Report

*

*: numbers continue to increase in 2010/11 (app 70,000)20-25 million HIV tests per year – www. hivrussia.org

Infection increasing faster than treatment:

WHO European Region, 1985–2011

0200400600800

1 0001 2001 4001 6001 800

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

HIVAIDSAIDS deathsPeople on ART

Sources: ECDC/WHO. HIV/AIDS surveillance in Europe 2011. Stockholm: ECDC; 2012; Federal Scientific and Methodological Center for the Prevention and Control of AIDS, Russian Federation; Ukrainian AIDS Centre,

Ukraine; WHO/UNICEF/UNAIDS monitoring and reporting on the Health Sector Response to HIV/AIDS.

(diagnosed)

Treatment cascade in Europe

Infect

ed

Diagno

sed

In car

e*

On ART

Fully

suppre

ssed

0102030405060708090

100

All EuropeWestern EEastern E

% o

f all

infe

cted

*: incomplete data on number of persons in care in Eastern Europe

Durability of HIV suppression*: the key indicator to benchmark for good

ART care

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 20110.0

20.0

40.0

60.0

80.0

100.0South Central West NorthCentral East East

Prop

ortio

n of

FU

whe

re >

90%

FU

has

VL

< 50

0

*: % of follow-up (FU) on ART where >90% FU has VL < 500 EuroSIDA (unpublished)

Late presentation by year of presentation

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010/11

0

25

50

75

100

0

100

200

300

400

LPadvanced immunode-ficiencyAIDS

LP : CD4 < 350/AIDS; advanced immunodeficiency : CD4 < 200/AIDSN 7367 7404 8046 7756 8591 8663 8251 8618 9057 7548 3223

Year of presentation

Prop

ortio

n

Med

ian

CD4

at p

rese

ntat

ion

Crude odds ratio 0.96 (0.95 – 0.97) per calendar yearCrude odds ratio 0.95 (0.94 – 0.96) per calendar yearCrude odds ratio 0.94 (0.93 – 0.95) per calendar yearCrude 4.4 (3.8 – 5.0/mm3) per year increase in CD4 at presentation

COHERE: Mocroft et al, PLoS Med 2013

Testing strategies

• Existing approach• Self referral• Selected clinics in health system (ID, STD)

• Future approach• Community testing (ensure transferral to

care)• Provider-initiated testing

• Indicator conditions (in any clinic or general practitioner seeing persons with such conditions)

– Mononucleose-like illness, TB, viral hepatitis, STD, psoriasis, cervical dysplasia, esophageal candidiasis, malignant lymphoma, etc

Focus to get general practitioners

to test persons presenting with indicators

routinely

Guidelines Changebut not in Synchrony

De Cock & El-Sadr, NEJM 20132013

When to START ART ?

Benefit toIndividual vs

individuals sexual partner vs

societal benefit

Use of ART to reduce transmission:

CD4 threshold vs coverage• Main determinant is coverage• If all infected on ART - very few transmissions• Realistic goal: rate of reproduction should be

below 1• Required coverage remains to be defined• If most transmissions occur prior to diagnosis,

elevating CD4 count for when to start ART will not be effective• Testing strategies are critical• If source of infection is often very recently infected

persons, not even the best testing strategy will work

Potential impact of cART on epidemic

Granich RM et al. Lancet 2009

Potential impact of cART on epidemic

Granich RM et al. Lancet 2009;373:48-57; Montaner JS. TasP-Workshop, Vancouver 2012.

Early vs delayed* ART of HIV+ persons living in sexual relationship with HIV-

person: HPTN 052

*: Early = CD4 350-550 cells/µL; delayed = CD4 < 250 cells/µL Cohen et al, NEJM 2011

Risk of HIV infection for HIV neg

In 28 of 38 infections, virus wasgenetically linked to virus from HIV+

HR=0.11 (0.04-0.33)Most :HeterosexualReported use of condoms

Uknowns from study: IDU ?No condoms ?MSM ? Population benefit ?

HIV among MSM in the UK – increasing incidence despite extensive ART coverage

• Observed increases in HIV incidence in last 10 years despite gradual larger ART coverage

• More condom-less sexual behaviour

Phillips et al. PLoS One 2013

00.20.40.60.8

11.21.41.61.8

2

1980 1985 1990 1995 2000 2005 2010

Observed

Without condomuse from 2000

Incidence (per 100 person-years)

HIV incidence in the UK among MSM:observed or if condom use ceased in

2000

Phillips et al. PLoS One 2013

Pilcher et al JID 2004; 189:1785–92Weeks after infection

2016 1814121086420

5%

4%

3%

2%

1%

0%

Tran

smis

sion

ris

k pe

r se

xual

act

When does HIV transmission occur?The role of primary HIV Infection

HIV among MSM in the UK – source of most new infections are from undiagnosed men:

more testing = less new infections

• Observed increases in HIV incidence in last 10 years despite gradual larger ART coverage

• More condom-less sexual behaviour• Source of new infections in 2010:

• 82% undiagnosed infection; diagnosed ART naive 10%, diagnosed ART experienced 7%

• If testing frequency increased to 68% of all MSM/yr (compared with currently 25%/yr)• Incidence projected to be reduced by 25%

Phillips et al. PLoS One 2013

CASCADE: Lodi et al; JID 2011

Natural history of HIV: CD4 count distributionaccording to time from infection

First, do no harm

• Primum non nocere• The doctor should not prescribe

medications unless s/he knows that the treatment is unlikely to be harmful

Doctor oath, year 1200

The case why early ART may cause net harm ?

• Low risk of morbidity and mortality in early HIV without ART• In particular among younger persons

• Overrepresented among persons with early HIV

• If ART is of benefit, high NNTB• ART may adversely affect several organ

functions• Risk is low – high NNTH

• If NNTH > NNTB = ART of net harm

• If correct (we will know in next 3-4 yrs) – major implications

HPTN 052 Update: Grinsztejn et al, WAC, July 2012

Non-AIDS events 9 12Diabetes mellitus 5 4Non AIDS malignancy 3 3Cardiovascular/Vascular 1 3Serious liver disease 0 2End stage renal disease 0 0

Number of subjects experiencing >1 eventDelayed Immediate

Any Primary event 77 (9%) 57 (6%)AIDS event 61 40Deaths 15 11Primary event associated 4 1Deaths from other causes 11 10

HR =1.37 ( 0.97 - 1.93 )

ART Initiation in Delayed Arm: 24% - CD4 count 229 (IQR: 197-249)

Do results support initiation of cART at CD4 >350 cells/mm3?

>550 450-559

350-449

250-349

<250

CD4 strata (cells/mm3)

Even

t ra

te

>550 450-559

350-449

250-349

<250

CD4 strata (cells/mm3)

Even

t ra

te

http://www.biomedcentral.com/1741-7015/11/148

It is the deferral strategy that defines the result of

a RCT of WTS ART(not the immediate)

Characteristics at entry and deferral strategies from RCTs

comparing deferred vs. immediate initiation of ART in ART-naive HIV+

persons Study Sample size

Median baseline

CD4 count(cells/ µL)

Deferral Strategy Median CD4 count at ART initiation in

the deferred armSMART 249 437 ART deferred until:

1. CD4 declined to < 250 cells/µL

2. CD4 percentage declined to < 15%

3. Symptoms of HIV disease developed

245

CIPRA HT-001

816 281 ART deferred until:1. CD4 declined to ≤ 200

cells/µL2. AIDS-defining illness

developed

166

HPNT 052

1761 428 ART deferred until:1. CD4 declined to ≤ 250

cells/µL2. AIDS-defining illness

developed

229

When to start ART ?Ability to provide a safe deferral strategy

1 Rosen et al, Plos Med 2011; Severe et al, NEJM 2010

Safe deferral strategy

Unsafe deferral strategy

Retention in care good poorAccess to repeat CD4 counts at sensible intervals

good poor

Diagnosed above CD4 treshold starts ART

As intended Later than intended

Consequences Deferral is possible to when evidence

document that benefits outweights harm from starting

ART

Earlier initiation of AT may outweigh

consequences of this unsafe deferral

strategy

Survival after ART initiated at different CD4 count levels between 200-500: ”causal”

modelling

The HIV-CAUSAL Collaboration, Ann Intern Med 2011

Proportionsurviving

”Use of more stingent criteria [e.g. GRADE], would likely reach the conclusion that evidence

insufficient to make firm recommendations[for starting ART at CD4 of 500 vs deferring to

350 cells/µL].”None of the studies reliable assessed non-fatal

potential harm.

The choice to make for asymptomatic treatment naïve patients

Start ART Start ART Start ART

Prognostic evaluation

Prognostic evaluation

Prognostic evaluation

Talk in 2003

Data Released from WHO-lead meta-analysis

Guideline AIDS or HIV-

Related Symptoms

CD4+ Cell Count

< 200/mm3

CD4+ Cell Count 200-350/mm3

CD4+ Cell Count 350-500/mm3

CD4+ Cell Count > 500

cells/mm3

DHHS-USA, 2013 Yes Yes Yes Yes1 Yes2

International AIDS Society-USA, 2012

Yes Yes Yes Yes1 Yes2

British HIV Association, 2012

Yes Yes Yes Defer 3 Defer3

European AIDS Clinical Society, 2013

Yes Yes Yes Consider3 Consider3

World Health Organization, 2013

Yes Yes Yes Consider4 Defer5(1) Strong strength recommendation based on observational data (A-II)(2) Moderate strength recommendation based on expert opinion (B-III).(3 ) But treat all HIV+ pregnant women, HBV co-infection, HCV co-infection, HIVAN, HIV related neurocognitive disorders, ITP, non-AIDS cancers and serodiscordant couples

(4) But treat individuals with CD4 < 350 a priority.(5) But treat all HIV+ pregnant women ,TB co-infection with active disease and HBV co-infection with severe liver disease, and serodiscordant copuls

Major Guidelines for ART Initiation

Where is the evidence?

Observational Analyses of Outcome From Deferred vs Immediate ART:

Lack of Consistency

StudyCD4

comparison (cells/mm3)

Relative Hazard (deferred vs. immediate)(95% confidence interval)

AIDS/all-cause mortality

All-cause mortality

NA-ACCORD (NEJM 2009)

<500 vs. >500 n/a 1.94 (1.37, 2.79)<350 vs. 351-

500n/a 1.69 (1.26, 2.26)

When to Start (Lancet 2009)

351-450 vs. 451-550

0.99 (0.76, 1.29) 0.93 (0.60, 1.44)

251-350 vs. 351-450

1.28 (1.04, 1.57) 1.13 (0.80, 1.60)

CASCADE Collaboration (Arch Intern Med 2011)

<500 cs. 500-799 0.91 (0.56, 1.49) 0.98 (0.47, 2.04)<350 vs. 350-

4991.33 (0.88, 2.04) 1.96 (1.25, 3.03)

HIV-CAUSAL (AIM 2011)

<350 vs. 351-500

1.38 (1.23, 1.56) 1.01 (0.84, 1.22)

Transmission on ART – low or zero ?:largely unknown for anal sex

http://www.biomedcentral.com/1741-7015/11/148

Modest evidence to start ART when CD4 < 250/200 cells/µL

D:A:D Lancet 2008

Unanticipated association between abacavir useand raised risk of myocardial infarction

ART exposure and AIDS- and non-AIDS-defining cancer

Adjusted for age, sex, cohort, HIV mode of acquisition, ethnic group, calendar year, body mass index, any prior cancer, prior AIDS diagnosis, prior AIDS cancer, smoking status, HCV and HBV status

AIDS-defining cancer (n = 1,151) Non-AIDS-defining cancer (n = 1,091)

aRR

and

95%

CI

0.8

1.1

1.0

Any cART PI NNRTI0.8

ART exposure (/year)

1.1

1.0

Any cART PI NNRTI0.8

aRR

and

95%

CI

ART exposure (/year)

D:A:D: Bruyand et al CROI 2013 Also Chao et al, AIDS 2012, Piketty et al J Clin Oncol 2012

Acknowledgements

• RFH group: A Phillips, A Mocroft, C Sabin, F Nakagawa, F Lampe, L Shepherd, D Grint, A Schultze, et al

• CHIP: O Kirk, L Peters, L Ryom, J Grarup, D Podlekareva, D Raben, M Mansfield, J Lazarus et al

• WHO-EURO: M Donoghoe, I Eramova, B Drachmann, et al

• J Rockstroh, G Faetkenheuer• EuroSIDA for EuroCoord colleagues last 20 years

What’s next?6:30 p.m. Reception/Networking

(Foyer)