In support of three drug regimens

Dr Laura Waters

Consultant Physician

CNWL, Mortimer Market Centre

London, UK

Question 1: is dual therapy….

Not as good as triple therapy?

The same as as triple therapy?

Better than triple therapy?

THE HISTORY OF 2DR VS 3DR

0

-0.5

-1

-1.5

-2

-2.5

-3

1987: NRTI monotherapy

RN

A C

han

ge (

Log

10

co

pie

s/m

L)

24 Week Response

0

-0.5

-1

-1.5

-2

-2.5

-3

1994: Two NRTI therapy

0

-0.5

-1

-1.5

-2

-2.5

-3

1997: 3-drug therapy

Introduction of 3DR D

eath

s p

er

10

0,0

00

p

op

ula

tio

n

40

30

20

10

0

Unintentional injury Cancer Heart disease Suicide Homicide Chronic liver disease HIV infection Stroke Diabetes

Available at: http://www.cdc.gov/hiv/library/slideSets/ [Accessed March 2014]

Mortality among persons 25–44 years old, USA: 1987–2010

Early trials of 3DR vs 2DR

1. Havlir et al. NEJM 1998;339(18):1261-8. 2. Montaner J et al. JAMA. 1998;279(12):930-937. 3. Collier AC et al. N Engl J Med 1996;334:1011-7. 4. Schapiro JM et al. J Infect Dis 1999; 179(1):249-53

INDUCTION MAINTENANCE1

ZDV/3TC + IDV

> mIDV or ZDV/3TC

INCAS: 1st LINE2

ZDV/ddI + NVP

> ZDV/ddI > ZDV + NVP

ACTG 229: NRTI EXPERIENCED3

SQV/ZDV/ddC

= ZDV/ddC > ZDV + SQV

2DR in the boosted PI era: ACTG 5142

Riddler SA et al. N Engl J Med. 2008 May 15;358(20):2095-106.

2DR worse for

Lipids (significantly) NNRTI resistance (66% vs 43%)

And where are we now?

• Normal life expectancy if well-controlled HIV

• Undetectable = untransmittable

95% 98% 97%

Diagnosed On treatment Virally suppressed

https://www.healthylondon.org/london-first-global-city-to-exceed-unaids-ambitions/

London: 1st global city to reach 95:95:95

Unmet needs

• Undiagnosed & late diagnosed HIV • Quality of life • Stigma • Long-term adherence • Co-morbidities & drug toxicities • Polypharmacy • Ageing • ART for people with limited options

ARGUMENTS FOR 2DR

Why revisit 2DR?

• More efficacious, high barrier agents

– Including unboosted

• Increasing concern about NRTI toxicities

• Lower costs?

• Fewer drugs must be a good thing, right?!

– Ageing, multi-morbidity, polypharmacy….

Tenofovir-DF vs abacavir

TDF ABC

NRTI: tenofovir-DF vs abacavir

mtDNA DNA

methylation

Telomerase & telomere length 1. Marsit CJ et al. Epigenetics. 2015;10(8):708-16; 2. Stella-Ascariz N et al. JAIDS 2017;74(1):91–94; 3. Montejano R et al. JAIDS 2018. 4. Stella-Ascariz N et al. J Infect Dis. 2018 Jul 3.

What if there was an NRTI that was heart AND renal AND bone friendly….?!

TAF ANGEL

The battle

No TAF TAF

QUESTION 1: DO 2DR = 3DR IN TERMS OF VIRAL SUPPRESSION?

Winners & Losers a non-exhaustive list of PI-based dual ART options

• First line – DRV/r + RAL* (NEAT-001)

– DRV/r + 3TC (ANDES)

• Switch – ATV/r + 3TC (ATLAS-M, SALT)

– DRV/r + 3TC (DUAL)

• First line – LPV/r + EFV (ACTG 5142)

– DRV/r + MVC (MODERN)

• Switch – DRV/r + MVC (MARCH)

– RAL + ATV (SPARTAN)

*with caveats

NEAT 001: DRV/r + RAL vs DRV/r + TDF/FTC primary endpoint = VF, death AIDS or serious non-AIDS

log rank p=0.12

0

0.25

0.50

0.75

1.00

402 395 393 361 350 340 331 215 90 12 400 383 375 346 327 315 306 210 89 11

0 8 18 32 48 64 80 96 112 128 144 Time (weeks) Numbers of patients

DRV/r + RAL DRV/r + TDF/FTC

Raffi F et al. Lancet 2014;384:1942-51

Estimated proportion reaching primary endpoint at W96 RAL: 17.8% vs TDF/FTC: 13.8%

Adjusted difference: 4% (95% CI: -0.8, 8.8%)

Kaplan-Meier estimates of % reaching endpoint at by baseline HIV RNA and CD4 Adjusted difference in

proportions of failure at W96 (%, 95% CI)

DRV/r + RAL

(%)

DRV/r + TDF/FTC

(%)

-5 0 10 15 20 25 30 35 40

Adjusted difference in proportions of failure at W96 (%, 95% CI)

Baseline HIV RNA < 100 000 copies/mL 0.1 (-3.8 ; 4.0) 7.3 7.4

Baseline HIV RNA > 100 000 copies/mL 9.6 (-0.1 ; 20.1) 27.3 36.8

CD4 cell count < 200 cells/mm3 22.3 (7.4 ; 37.1) 20.9 43.2

CD4 cell count > 200 cells/mm3 1.4 (-3.5 ; 6,3) 12.3 13.7

5

Raffi F et al. Lancet 2014;384:1942-51

• Resistance:

– No resistance in 3DR arm (n=49)

– 27% on 2DR had INSTI RAMs, 2% PI (n=61)

SWORD-1 and SWORD-2 Phase III Study design

Identically designed, randomised, multicenter, open-label, parallel-group, non-inferiority studies1–3

DTG + RPV (n=513)

Day 1

Screening

Week 148

CAR (n=511) DTG + RPV

VL <50 c/mL

on INI, NNRTI,

or PI + 2 NRTIs

1:1

DTG + RPV

Week 52

Early-switch phase Late-switch phase Continuation phase

Week 100

ClinicalTrials.gov. NCT02429791;

ClinicalTrials.gov. NCT02422797;

Llibre JM, et al. Lancet 2018;391:839–849.

SWORD-1 and SWORD-2: Virologic efficacy through 100 weeks

Switch to DTG/ABC/3TC , Week 24–Week 48 (n=244)b

95 89

93

0

20

40

60

80

100

Virologic success

HIV

-1 R

NA

<50

c/m

L, %

Early-switch group

Late-switch group

DTG + RPV, Day 1 to Week 100 (n=513) DTG + RPV, Day 1 to Week 48 (n=513)

DTG + RPV, Week 52 to Week 100 (n=477)

Aboud M, et al. AIDS 2018; Poster THPEB047; Llibre JM, et al. Lancet 2018;391:839–849. Van Wyk J et al. BHIVA 2019

• Confirmed virological withdrawals: – 10/990 (1%)

• CVWs with emergent resistance: – 3/990 (0.3%), all 2DR – All with ≥1 NNRTI RAM

• Benefit? – Improved proximal tubular

function (urine RBP & B2M)

Year 3: 3 additional CVR

2 with emergent NNRTI RAMs

GEMINI: snapshot ITT-E to W48

Adapted from: Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.

70 85 89

90 93

91 93

72

87 89 88

93

90 91

0

20

40

60

80

100

0 4 8 12 16 20 24 28 32 36 40 44 48HIV

-1 R

NA

<5

0 c

/mL,

%

Study visit

DTG + 3TC (n=716)

DTG + TDF/FTC (n=717)

Adjusted Rx difference (95% CI)

DTG + TDF/FTC DTG + 3TC

-10 -8 -6 -4 -2 0 2 4 6 8 10

-4.4 1.1

-1.7

Percentage-point difference

-1.3

-3.9 1.2

ITT-E

PP

98 98 98 98 99 98 97 100

0

20

40

60

80

100

Wit

ho

ut

TR

DF,

%

TRDF Analysis

566

576

>100,000 ≤100,000 >200 ≤200 Baseline HIV-1

RNA, c/mL

Baseline CD4+

cell count, cell/mm3

91 93 94 93 92

79

90 93

0

20

40

60

80

100

HIV

-1 R

NA

<5

0 c

/mL

, %

Snapshot Analysis

• 2% of participants in each arm had baseline HIV-1 RNA >500,000 c/mL • Treatment related discontinuation = failure (TRDF) population accounts for confirmed virologic withdrawal (CVW), withdrawal

due to lack of efficacy, withdrawal due to treatment-related AE, and participants who met protocol-defined stopping criteria • DTG + 3TC CD4 <200 Snapshot non-response (n=13): 1 CVW, 3 with VL >50 in window (2 of 3 re-suppressed), 2 discontinued due to AE (TB, Chagas disease), 2 protocol violations, 2 lost to follow-up, 1 withdrew consent, 1

withdrew to start HCV treatment, 1 change in ART (incarcerated) • DTG + TDF/FTC < 200 Snapshot non-response (n=4):1 investigator discretion, 1 withdrew consent, 1 lost to follow-up, 1 VL >50 (re-suppressed)

DTG + 3TC DTG + TDF/FTC

>100,000 ≤100,000 >200 ≤200 Baseline HIV-1

RNA, c/mL

Baseline CD4+

cell count, cell/mm3

553

564

138

140

149

153

642

653

647

662

62

63

55

55

526

576

531

564

129

140

138

153

605

653

618

662

50

63

51

55

GEMINI: W48 snapshot and TRDF analysis stratified by baseline HIV-1 RNA and CD4

Adapted from: Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.

GEMINI: snapshot VL <50 at W48 (pooled ITT-E, by baseline HIV-RNA)

80

83

89

90

94

85

89

88

92

91

0 20 40 60 80 100

>500,000 c/mL

>400,000 c/mL

>250,000 c/mL

>100,000 c/mL

≤100,000 c/mL

HIV-1 RNA <50 c/mL, %

Ba

se

line

vira

l lo

ad

str

ata

4,6

5,6

-0,9

1,9

-2,8

-30 -20 -10 0 10 20 30 40

Difference in proportion, % (95% CI)

DTG + 3TC (N=716) DTG + TDF/FTC (N=717)

138/153

41/46

20/24

12/15

531/564

DTG + TDF/FTC DTG + 3TC

129/140

45/51

16/18

11/13

526/576

Eron et al. HIV DART and Emerging Viruses 2018. Oral Presentation #7.

Sensitive virological markers TND = target not detected

Suppressed switch studies

• ASPIRE: RCT cART vs DTG/3TC

– No change by single copy assay at W24 or W48

• SWORD 1 & 2

– Target not detected analysis

First line studies

• GEMINI

– Similar time to TND both arms overall but faster on 2DR in VL >100K group

– Similar findings for % TND

Taiwo B et al. Glasgow; 2018 O213. Li J et al Abstract O145, Glasgow 2018; Underwood M et al. Glasgow 2018 Eron et al. HIV DART and Emerging Viruses 2018. O7; CROI 2019, poster 0490

Virologic success, n (%) DTG+RPV

N=402 CAR

N=424 Adjusted difference (95% CI)b

VL <40 c/mL and TND + TND at baseline

336 (84) 341 (80) 3.1 (−2.2 to 8.3)

What does it all mean?

• DTG-based 2DR virologically non-inferior overall but some signals of concern

• 96 week GEMINI data crucial

• DTG/3TC switch data in RCTs crucial

• My view:

– We cannot say confidently yet that 2DR = 3DR

OTHER END-POINTS: DO 2DR=3DR?

Toxicity?

• Most (if any) benefit of 2DR has been due to absence of tenofovir-DF

• Additional benefits uncertain

• We must not forget concerns beyond NRTI – Protease inhibitors & long-term safety

– Integrase inhibitors & weight gain

– Dolutegravir & CNS toxicity

– Dolutegravir & safety in pregnancy

Immune activation & inflammation • GUSTA Study: DRV/r + MVC inferior to continued 3DR

– Immune sub-study in patients who remained suppressed: • Increased T-cell activation, inflammation & microbial translocation

unchanged

• NEAT-001: DRV/r + RAL vs DRV/r + TDF/FTC first line – No difference in inflammatory biomarkers

• Italian triple to DTG + 3TC switch cohort: – No increase in immune activation, most VL stayed <3

• TRILOBITHE: non-randomised switch cohort: – Inflammation/immune activation similar or improved on 2DR

Merlini E et al. EACS Conference, Milan, October 2017 PE8/7. Bernardino JI et al. CROI 2015, abstract 766. Maggiolo F et al. Poster 104, Glasgow 2018. Vallejo A et al. HIV Medicine 2019.

CD4:CD8 ratio…. • General population: low ratio marker for immunosenescence and

predicts of all-cause mortality

• PLHIV: low ratio assocd with immunosenescence/inflammation; data

conflicting as predictor of non-AIDS morbidity and mortality

Ratio continued to up to 15 yrs post-ART; Normalisation (>1) strongly related to baseline CD4 & only seen if baseline >200

CD4:CD8 ratio

• Icona – 1241 people on triple ART switched to

• Dual or monotherapy vs different triple regimen

– At 12 months, significant difference in CD8 count & CD4:CD8 ratio favouring 3DR

• STARTMRK – Faster time to CD4:CD8 normalisation on RAL vs EFV

• Implications of altered ratio + impact of non-ARV drugs & co-morbidities uncertain

Mussini C et al. BMC Medicine (2018) 16:79; Serrano-Villar S et al. J Antimicrob Chemother. 2017 Jan;72(1):235-239.

G.O.T

https://gameoftcells.medicine.wisc.edu/

Telomere length?!

• NEAT 001: TDF/FTC + DRV/r vs RAL + DRV/r

– 3DR led to significantly greater gain in telomere length than the 2DR

Stella-Ascariz N et al. J Infect Dis. 2018 Jul 3

Patient reported outcomes? SWORD High baseline treatment satisfaction, improved with switch

Patient reported outcomes? SWORD High baseline treatment satisfaction, improved with switch

HIV Drug Therapy Glasgow; October 28-31, 2018; Glasgow, UK

-4

-3

-2

-1

0

1

4 24 48 56 76 100

Mean

ch

an

ge f

rom

baseli

ne/l

ate

-sw

itch

ba

seli

ne

(95%

CI)

Weeks on treatment

ResultsStudy Disposition, Virologic Efficacy, and Safety and Tolerability

Demographics and baseline characteristics have been previously reported1

Through 100 weeks of treatment, DTG + RPV demonstrated continued efficacy in the early-switch group

Virologic efficacy (93%) in the late-switch DTG + RPV group at Week 100 was similar to that of the early-switch group at Week 48 (95%)1,7

The safety profile of the late-switch DTG + RPV group was similar to that of the early-switch DTG + RPV group 48 weeks after switching, and AEs were consistent with those of DTG and RPV individually7

HIV Treatment Satisfaction Questionnaire, status version

Mean treatment satisfaction score was high at baseline for both groups (early-switch group, 54.4; CAR group, 53.9)

Participants in the early-switch DTG + RPV group reported significant improvement from baseline in overall treatment satisfaction, which was maintained at each time point over 100 weeks (Figure 2)

There was minimal change from baseline in patient-reported treatment satisfaction among subjects who continued on CAR during the first 48 weeks

After switching from CAR to DTG + RPV at Week 52, participants in the late-switch group showed an improvement in overall treatment satisfaction, similar to that of the early-switch DTG + RPV group after 48 weeks (Figure 2)

1.41.8 1.5

1.4 1.6 1.5

0.1 0.2

0.41.1

1.3 1.4

-0.5

0.5

1.5

2.5

0 20 40 60 80 100513 503 509 509 509 509 509

507 499 506 505

471 475 475

BL 4 24 48 56 76 100

Mean

(95%

CI)

ch

an

ge i

n

tota

l sco

re f

rom

b

ase

lin

e/la

te-s

wit

ch

baseli

ne P<0.001 P<0.001 P=0.002

CAR group, n

Weeks on study

Early-switch group, n

Late-switch group, n

Late-switch group

Early-switch group

CAR group

Introduction

durable virologic suppression

Two-drug regimens may provide better treatment options for patients with virologic suppression who want to simplify their therapy or reduce the risk of long-term toxicities associated with using a 3- or 4-drug regimen over their lifetime

In the identically designed phase III studies, SWORD-1 and SWORD-2, the 2-drug regimen of dolutegravir + rilpivirine (DTG + RPV, as single entities) demonstrated high efficacy and was noninferior to the continuation of a 3- or 4-drug antiretroviral regimen in virologically suppressed HIV-1–infected adults at 48 weeks1

The pooled patient-reported outcome measures at Week 48 from the SWORD-1 and SWORD-2 studies demonstrated maintenance of high levels of treatment satisfaction and health status and low levels of symptom burden in patients who switched to DTG + RPV2

This analysis describes the pooled patient-reported outcome measures at Week 100 from the SWORD studies

MethodsSWORD-1 (NCT02429791) and SWORD-2 (NCT02422797) are phase III, randomized (1:1), multicenter, open-label, parallel-group, noninferiority studies

A full description of the study design, including eligibility criteria and endpoints, has been previously reported1

Study Populations

The early-switch group participants were randomized to DTG + RPV on Day 1 and received at least 1 dose of DTG + RPV

The late-switch group participants were randomized to continue their current antiretroviral regimen (CAR) and switched to DTG + RPV at Week 52 and received at least 1 dose upon switching

Baseline for the late-switch group for all measures is the last data point before the switch from CAR to DTG + RPV at Week 52 (late-switch baseline)

Health Outcomes Assessments

The HIV Treatment Satisfaction Questionnaire, status version (HIVTSQs), is a 10-item, self-reported instrument that measures treatment satisfaction overall (possible scores range from 0 [no satisfaction] to 60 [absolute satisfaction]) and by specific domains3

The Symptom Distress Module is a 20-item, self-reported measure that addresses the presence of and perceived distress linked to symptoms associated with HIV infection or its treatment4

The symptom bother score assesses the level of bother with a total score for all symptoms ranging from 0 (no symptoms present) to 80 (all symptoms present at worst level)

The European Quality of Life 5-Dimensional 5-Level instrument is a standardized global health state questionnaire assessing mobility, self-care, usual activities, pain/discomfort, and

5

Symptom Distress Module

Low levels of treatment burden were reported at baseline: mean (SD) symptom bother scores were 9.6 (10.0) in the early-switch DTG + RPV group, 11.0 (11.2) in the CAR treatment arm; late-switch baseline mean (SD) symptom bother score was 10.3 (11.0)

Participants in the early-switch DTG + RPV group reported initial improvement from baseline in symptom burden, which was reduced to a minor improvement from Week 24 to Week 100 (Figure 3)

After switching from CAR to DTG + RPV at Week 52, participants in the late-switch group showed a similar pattern of change in symptom burden compared with the early-switch DTG + RPV group, with initial improvement in symptom burden following switch and then attenuated improvement from Week 76 to Week 100 (Figure 3)

European Quality of Life 5-Dimensional 5-Level Instrument

Baseline health status was high in the early-switch and CAR groups (EQ-5D mean utility, 0.96 and 0.94, respectively) and at late-switch Baseline for the late-switch group (EQ-5D mean utility, 0.94); there was no change from baseline after 48 weeks in the CAR group or between weeks 48 and 100 in the late-switch group (mean change, 0.00 for both groups), and little change from Baseline at Weeks 48 and 100 in the early-

Patient-Reported Outcome Change From Baseline By Baseline Third-Agent Class

At Week 100, subgroup analysis by third-agent class suggests potential improvement of overall symptoms in participants in the early-switch DTG + RPV group who switched from NNRTI- or PI-based regimens (Figure 4A)

Overall treatment satisfaction improved from baseline regardless of baseline third agent in the early-switch DTG + RPV group at Week 100 and among those who switched from an NNRTI- or PI-based regimen after 48 weeks in the late-switch DTG + RPV group (Figure 4B)

Figure 3. Mean (95% CI) Change in Treatment Symptoms Assessed by Symptom Bother Score

P101

Alan Oglesby,1 Kostas Angelis,2 Yogesh Punekar,3 Sara Lopes,3 Antonio Antela,4 Michael Aboud,3

Rodica van Solingen,5 Elizabeth Blair,1 Lesley Kahl,3 Martin Gartland,1 Brian Wynne,1 Miranda Murray3

1ViiV Healthcare, Research Triangle Park, NC, USA; 2GlaxoSmithKline, Uxbridge, UK; 3ViiV Healthcare, Brentford, UK; 4Infectious Diseases Unit, Hospital Clinico de Santiago, La Coruna, Spain; 5Janssen Pharmaceutica NV, Beerse, Belgium

Patient-Reported Outcomes After Switching to a 2-Drug Regimen of Dolutegravir + Rilpivirine: Week 100 Results From the SWORD-1 and SWORD-2 Studies

Acknowledgments: This study was funded by ViiV Healthcare. Rilpivirine was supplied by Janssen Pharmaceutica NV. Editorial assistance and graphic design support for this poster were provided under the direction of the authors by MedThink SciCom and funded

by ViiV Healthcare.

References: 1. Llibre et al. Lancet. 2018;391:839-849. 2. Oglesby et al. Presented at: 16th European AIDS Conference; October 25-27, 2017; Milan, Italy. 3. Woodcock and Bradley. Value Health. 2006;9:320-333. 4. Justice et al. J Clin Epidemiol. 2001;54(suppl 1):S77-S90.

5. Herdman et al. Qual Life Res. 2011;20:1727-1736. 6. Devlin et al. Health Econ. 2018;27:7-22. 7. Aboud et al. Presented at: 22nd International AIDS Conference; July 23-27, 2018; Amsterdam, the Netherlands.

Conclusions

High levels of treatment satisfaction and health status and a low level of symptom burden

were reported by participants entering the study and were slightly improved and maintained

100 weeks after switching to DTG + RPV

These results are consistent with previously reported tolerance and toxicity data

Results after 48 weeks of exposure to DTG + RPV in the late-switch group (Weeks 52-100)

were similar to the results from the first 48 weeks in the early-switch group

These results provide long-term evidence that the 2-drug regimen of DTG + RPV is a

well-tolerated, alternative treatment option for virologically suppressed patients who are on

a 3- or 4-drug regimen and have not experienced previous virologic failure

Figure 2. Mean (95% CI) Change From Baseline/Late-Switch Baseline of Treatment Satisfaction Total Score Assessed by HIVTSQs: LOCF Dataset

Figure 1. Study Design of the Identical SWORD-1 and SWORD-2 Studies

DTG + RPV (n=513)

Day 1

Screening

Week 148

CAR (n=511)DTG + RPV

VL <50 c/mL on INSTI, NNRTI,or PI + 2 NRTIs

1:1

DTG + RPV

Week 52

Early-switch phase Late-switch phase Continuation phase

Week 100

BL, baseline; CAR, current antiretroviral regimen; HIVTSQs, HIV Treatment Satisfaction Questionnaire, status version; LOCF, last observation carried forward. P values of early-switch group versus CAR are based on a Wilcoxon rank-sum test.

Early-switch group, n 436 442 442 442 442 442

CAR group, n 426 433 432

Late-switch group

Late-switch group, n 402 408 408

Early-switch group CAR group

P<0.001 P=0.088 P=0.014

CAR, current antiretroviral regimen. P values for treatment difference are calculated from an ANCOVA model adjusting for age, baseline third-agent class, sex, race, and baseline symptom bother score.

Figure 4. Mean (95% CI) Change From Baseline/Late-Switch Baseline at Week 100 by Baseline Third-Agent Class in (A) Symptom Bother Score and (B) HIVTSQs Score in the Early-Switch and Late-Switch Groups

DTG, dolutegravir; HIVTSQs, HIV Treatment Satisfaction Questionnaire, status version; INI, integrase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; RPV, rilpivirine.

-4

-3

-2

-1

0

1

2

3

Mean

ch

an

ge f

rom

baseli

ne

(9

5%

CI)

Baseline third-agent class

Symptom bother score at week 100

Early-switch group Late-switch group

A

n 233 239 102 83 107 86

NNRTI INI PI -2

-1

0

1

2

3

4

5

Me

an

ch

an

ge f

rom

ba

selin

e(9

5%

CI)

Baseline third-agent class

HIVTSQs score at week 100

Early-switch group Late-switch group

B

NNRTI INI PI

n 274 267 104 88 131 120

Mean (95% CI) Change From Baseline/Late-Switch Baseline of Treatment Satisfaction Total Score Assessed by HIVTSQs: LOCF Dataset

Oglesby A et al. Poster 101, Glasgow 2018

BIKTARVY SHOWS PRO

BENEFITS VS TRIUMEQ

Cost?

Cost? Relative prices in London

gABC/3TC +gEFV

gABC/3TC +RAL

DRV/r + 3TC Triumeq DRV/r + RAL Genvoya

Laura Waters, personal communication, based on London ARV prices September 2018

Globally

• DTG + 3TC has the potential to be cheap and therefore highly accessible

• Challenges:

– Hepatitis B co-infection

– TB treatment

– Pregnancy

– Resistance

BASELINE RESISTANCE

Question!

Can you extrapolate 1st line results to stable switch? I used to think yes….

….but now I’m not sure!

• Proviral DNA may reveal unexpected resistance – 14% had M184V/I (GS-1878)

• Proviral DNA may miss pre-existing resistance – Only 50% with known M184V/I had it in DNA (GS-1824)

Most DNA is hyper-mutated nonsense &

not viable!

We have no good studies of DTG/3TC

with M184V/I

What about patients with no transfer

information?!

INJECTABLES

The challenges* *from a pessimistic Brit

Landowitz R et al. 9th IAS, Paris 2017. Abstract TUAC0106LB; ViiV: data on file; Personal communication, Prof Anton Pozniak, October 2018

RPV: 2-8oC

No light

The Pozniak Paradox

1000 ‘stable’ patients 30-minute clinic visits

ORAL: 2 visits/year = 1000 clinic hours

INJECTABLE: 6 visits/year = 3000 clinic hours

Staff

Booking Prescribing

Administering Chasing DNA

Patients

Time Convenience

Confidentiality Tolerability

GUIDELINES

https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/11/what-to-start accessed 12th November 2018

Recommended Initial Regimens for Most People with HIV

INSTI + 2 NRTI

TAF/FTC/BIC (AI)

ABC/3TC/DTG (AI) If HLA B*5701 negative

TDF/3TC or TAF/FTC + DTG (AI)

TDF/3TC (BI) or TAF/FTC + DTG (BII)

DHHS guidelines: October 2018

DHHS guidelines: October 2018 Recommended in certain clinical situations

https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/11/what-to-start accessed 12th November 2018

INSTI + 2 NRTI

TAF/FTC/EVG/c or TDF/FTC/EVG/c (BI)

ABC/3TC + RAL (CII) If VL <100k

PI/b + 2 NRTI

ATV/r or /c + TAF/FTC or TDF/FTC (BI) In general DRV preferred to ATV

DRV/r or /c + TAF/FTC or TDF/FTC (AI) or ABC/3TC (BII)

NNRTI + 2 NRTI

DOR/TDF/3TC (BI) or DOR + TAF/FTC (BIII)

EFV/TDF/FTC (BI) or EFV/TDF/3TC (BI) or EFV + TDF/FTC (BII) EFV 600mg

RPV/TAF/FTC or RPV TDF/FTC VL <100k and CD4 >200

Consider when ABC, TAF, and TDF Cannot be Used or Are Not Optimal

DTG + 3TC (BI) or DRV/r + 3TC (CI)

DRV/r OD + RAL BD If VL <100k and CD4 >200

EACS guidelines: October 2018

http://www.eacsociety.org/files/2018_guidelines-9.1-english.pdf accessed 12th November 2018

Alternative regimens (when none of the preferred regimens are feasible or available, whatever the reason)

INSTI + 2 NRTI

ABC/3TC + RAL Caution CATIONS

TAF/FTC/EVG/c or TDF/FTC/EVG/c

NNRTI + 2 NRTI

ABC/3TC + EFV or TDF/FTC/EFV Bedtime or 2 h before dinner

PI/r or PI/c + 2 NRTI

ABC/3TC or TDF/FTC + DRV/r or /c With FOOD

ABC/3TC or TAF/FTC or TDF/FTC + ATV/r or /c

Others

DTG + 3TC VL <500k, Caution CATIONS

RAL + DRV/r or /c VL <100k, CD4 >200 Caution CATIONS

The million dollar question

• Should a new paradigm show benefit over an old one?

• Or is ‘no worse’ enough?

Unmet needs

• Undiagnosed & late diagnosed HIV • Quality of life • Stigma • Long-term adherence • Co-morbidities & drug toxicities • Polypharmacy • Ageing • ART for people with limited options

The history of ART

1987 2019 1999 2009

Triple cART

48W GEMINI

3 YEAR SWORD

TAF ABC TDF

Conclusion

• 3DR works

• 2DR works

• 2DR remains non-routine, for now

Question 1: is dual therapy….

Not as good as triple therapy?

The same as as triple therapy?

Better than triple therapy?

Thank you!

? lwaters@nhs.net @drlaurajwaters