Will Resistance Ruin the Rollout?

John Mellors & Many ColleaguesInternational HIV Drug Resistance Workshop

Johannesburg, SAOctober 22-23, 2018

Stopping HIV Transmission

• Reduce infectivity of infected individuals– Antiretroviral therapy!– Cohort studies, HPTN 052 (>90% reduction)1

• Eliminate contact with HIV– Possible for blood supply– Difficult for sexual transmission

• Reduce susceptibility of uninfected individuals– Male circumcision! (50-60% reduction)2,3

– Chemo prophylaxis = PrEP! (Pre-exposure Prophylaxis)4

– Vaccine prophylaxis…some day?

1Cohen MS, et al. N Engl J Med 2011; 2Bailey RC, et al. Lancet 2007; 3Gray, et al. Lancet 2007; 4Grant RM, et al. N Engl J Med 2010

Topics I’ll Cover

• Good News about ART• Concerns about ART• Good News about PrEP• Concerns about PrEP• Doomsday Scenario!• Planning for Better Outcomes

Good News About ART

• Has saved 7-8 million lives• ~21 million are on it; about 50% of all PLWH• HIV-1 incidence declining in several LMIC• Major reductions in MTCT

Good News About ART

• NRTIs have residual drug activity despite signature mutations– Still inhibit wild-type virus– Resistance is relative not absolute– Complex resistance interactions, e.g. 184V hypersusceptibility to TNVSurprisingly good efficacy of PI-based 2nd line-ART with recycled NRTI

• New ART regimens‒ Tenofovir/Lamivudine/Dolutegravir (TLD)‒ Better tolerated and higher efficacy than EFV-based regimens (TLE)‒ Encouraging activity in 2nd line with recycled NRTI (Dawning Study)

Wang R, et al. IAS 2018

DAWNING TRIAL: Week 48 <50 copies/ml

Concerns About ART

• Long-term (4-5 year) suppression rates of 60-85%– Worse in children, adolescents, MSM, and post-partum women– 80% not suppressed have resistance15-40% on ART could transmit resistance

• Spotty viral load (HIV RNA) monitoring– Only 50% of programs offer HIV RNA testing– Late switches from failing ART

• Resistance testing is limited– Surveillance systems are in arrears

• ARV stock-outs and gray-black market ARVs– Makes new ART regimens vulnerable

52%

31%

10%

29%

46%

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Zero ARV stock-out ≥85% Retention on ART ≥90% Viral load testing coverage

≥90% Viral load suppression

≥5% of patients on second line ART

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Program quality indicator targets

Suboptimal progress in HIVDR prevention across the 45 HIV focus countries

UNAIDS/WHO/UNICEF Global AIDS Monitoring 2018; WHO/AIDS medicine and laboratory diagnostic survey

Proportion of missing data ranges from 16% to 40%, depending on the indicator

Baseline data: cohort 2016-2017

Courtesy Silvia Bertagnolio

Increasing NNRTI PDR

WHO HIV Drug Resistance Report 2017

Tenofovir/Lamivudine/Dolutegravir (TLD)

• Some Concerns– TL components overlap with TLE and TNV/FTC for PrEP– Double dosing of DTG required with rifampin (Tb)Can select resistance as monotherapy or with recycled NRTI

Wang R, et al. IAS 2018

DTG Mutation Emergence: DAWNING Trial

DTG Resistance Emergence: DAWNING Trial

Zash, Mahema, Shapiro. N Engl J Med July 24, 2018

Updated data since 1 May: 4/596 (0.67%)

95%CI still does not overlap with other groups

Future of TLD Rollout?

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% of Adult ART Patients per Country on ARV Regimens, at the end of the COP18 TLD Transition (pre June, 2018 WHO/PEPFAR Revised Guidance)

% on TLD % on TLE or TEE % on LNZ % on All other Regimens

• Based on submission of original TLD supply plans for PEPFAR work planning in February, 2018. Table does not include Ethiopia, Vietnam, or Uganda NMS, as supply plans for these programs were not submitted. Botswana was also excluded, given that their supply plan only includes current and future patients on DTG-based regimens.

Slides Courtesy Elliott Raizes

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% of Adult ARV Patients per Country on ARV Regimen at the end of the COP 18 TLD Transition (per revised TLD Supply Plans, submitted in June/July 2018 Post DTG Safety Alert

% on TLD % on TLE or TEE % on LNZ % on All other Regimens

Slides Courtesy Elliott Raizes

What about PrEP?

ART NOT PrEP Drives Spread of HIV Drug Resistance

Abbas, Mellors JID 2013

Good News About PrEP

• PrEP works, if taken– IPrEx and multiple other studies– “On Demand” PrEP makes sense & works (IPERGAY)1

• More people are taking PrEP but still limited– Especially in the US; national rollouts starting: Kenya

• Resistance from PrEP is infrequent2

– Mostly when started in acute HIV infection– Rare breakthroughs are being reported3

• Better PrEP is coming and needed for population bulge!– Topical, longer acting oral, injectable, implantable

1Molina JM, et al. Lancet 2017; 2Parikh UM and Mellors JW COHA 2016; 3Ruone, et al. JAIDS 2016

Pipeline of New PrEP

• Dapivirine Intravaginal Ring (DPV IVR)– Under EMA review

• FTC/Tenofovir alafenamide (F/TAF)– In Phase III

• Rilpivirine LA (RPV LA)– Development stopped: cross-resistance, cold chain

• Cabotegravir LA (CBV LA)– In Phase III

• EFdA (MK-8591)– Once pill monthly; year long implant?

• Capsid Inhibitor (GS-6207)– Low pMolar potency, long-term depot delivery possible

PrEP PRODUCTS: APPROVED or in DEVELOPMENT

Oral PrEPTruvada

(TDF-FTC)

Vaginal RingDapivirine

(DPV)

Being Rolled Out

In Regulatory Review

InjectableCabotegravir

(CAB)

In Phase III Trials

RISK OF RESISTANCE WITH TDF/FTC PREP

Continuing PrEP after

breakthrough infection

Starting PrEP during

undetected acute infection

Failing PrEP due to

transmitted resistance

RCT and Follow-up Studies

FEM-PrEP

iPrEX

TDF2

Partners PrEP

VOICE

HPTN-067

PROUD

IPERGAY

USA DEMO

iPrEX OLE

Randomized Clinical Trials Open-Label and Demo Projects

10 CASES OF TDF/FTC RESISTANCE DURING F/U

Case Study Genotype Notes1 FEM-PrEP M184I High drug levels

2 FEM-PrEP M184V No FTC detected

3 FEM-PrEP M184I Could not rule out acute infection at enrollment

4 FEM-PrEP K103N, M184V Seroconverted 48 weeks after discontinuing study product

5 VOICE M184M/V 309 days on oral TDF/FTC

6 HPTN-067 3.9% K65R, 62.3% M184ITime-driven arm

(1 tablet 2X/week + post-coitalboost)

7 iPrEX OLE M184V

8 Partners PrEP 0.5% K65R, 16.4% M184V 454 Sequencing

9 Partners PrEP 1.2% K65R, 5.5% M184I, 7.7% M184V

454 Sequencing

10 Partners PrEP 1.9% M184V 454 Sequencing

12 CASES OF TDF/FTC RESISTANCE IN ACUTE INFECTION

Case StudyApproximate Time on

PrEP beforeSeroconversion

Genotype

1 iPrEX 4 weeks M184I

2 iPrEX 4 weeks M184V

3 TDF2 7 months A62V, K65R, M184V

4 Partners PrEP 4 weeks M184V

5 Partners PrEP 4 weeks M184I/V

6 VOICE 26 days M184M/V

7 VOICE 29 days M184M/I/V

8 PROUD 4 weeks M184M/I/V

9 PROUD 4 weeks M184I/M

10 HPTN-067 4 weeks K65R (24.7%)

11 HPTN-067 4 weeks M184I (3.4%)

12 USA DEMO 1 week M184M/I

SUMMARY OF RESISTANCE IN TDF/FTC PREP STUDIES*

Study# in

TDF/FTCArm

HIV Infectedat Follow Up

Resistant at Follow Up

HIV Infected at Enrollment

Resistant at Enrollment

FEM-PrEP 1062 33 4 1 0

iPrEX 1226 48 0 2 2

TDF2 601 9 0 1 1

Partners PrEP 1583 21 3 4 2

VOICE 1003 61 1 9 2

IPERGAY 199 2 0 3* NR

PROUD 275 3 0 3 2

HPTN-067 622 9 1 3 2

USA DEMO 557 2 0 3 1

IPrEX OLE 1225 28 1 0 0

TOTAL 8353 216 10 (4.6%) 26 12 (46%)

*Parikh and Mellors, Current Opinions in HIV/AIDS, 2016

*Excluded due to no data reported*Excluded mutations found at <1%

5 REPORTED TNV/FTC BREAKTHROUGH HIVDR CASES

Case Patient PrEP Duration

Adherence Resistance Ref

1 Toronto Case43yo MSM

>21 months Pharmacy RecordsTFV levels high

High: 3TC, FTC, NVP, EVGIntermediate: ABC, EFV, ETR, RTGLow: TFV, DTG

Knox et al. NEJM 2017

2 NewYork Case26yo MSM

4 months TFV and TFV-DP levels in hair and DBS consistent with daily use

K65R+M184V, K103S, E138Q, Y188L

Markowitz et al. JAIDS 2017

3 North CarolinaCase34yo MSM

~11 months Adequate K65R, M184V, K103N Thaden CROI 2018

4 King Country CaseMSM

Unknown Self-reported high reported resistance to both drugs in Truvada

Mathew Golden, unpublished

5 San Francisco Case21yo MSM

13 months Consistent with ≥4 doses/week

L74V, L100I, M184V, K103N Cohen IDWeek 2018

PrEP breakthrough cases rare but increasing?

Amsterdam Case (CROI 2017): No resistance

TDF/FTC Resistance Summary

• Resistance is infrequent (3%) from use of oral TDF/FTC PrEP if HIV-1 infection is not present at the time PrEP is started

• Resistance is more common (46%) if TDF/FTC PrEP is started during undiagnosed acute HIV-1 infection

• Acute HIV-1 infections should be excluded before starting PrEP!

• Important to monitor resistance with PrEP rollout – rates of resistance outside of trial setting unknown.

Dapivirine Intravaginal Ring

Vaginal RingDapivirine

(DPV)

In Regulatory Review

WARNING!

We’re Using The Same Drugs and Drug Classes for ART and PrEP!

TDF/TAF and 3TC/FTC

EFV and DPV?

DTG and CBT?

Doomsday Scenario (To Provoke Discussion)

• More NTDs → TLD rollout is slow, sporadic or doesn’t occur– No other InSTIs are rolled out

• Or, TLD is rolled out but failure is > than expected– TL and other NRTI resistance = “functional monotherapy”– InSTI resistance and cross-resistance spreads

• TLE/TLD & TDF/FTC PrEP failures promote TL resistance– Have to abandon TL

• Alternative single-tablet regimens are not forthcoming– DRV, capsid and attachment inhibitors not affordable

Avoiding Doomsday

• Intensify HIV-1 RNA monitoring on ART– Assess and improve the “viral load” cascade Increase the % suppressed after 1, 3, 5 years on ART Suppression target = HIV RNA <50 copies/ml?

• More aggressive, timely & comprehensive surveillance for DR– ART starts– PrEP and ART failures Centralized NGS vs. simplified POC testing?

WHO/HIV ResNet: Global Action Plan on HIVDR 2018 Progress Report

RESISTANCE ASSESSMENT FROM PREP ROLL-OUT

Partner with roll-out projects and programs

Collect and test DBS from PrEP seroconverters

Determine frequency of resistance

selection in seroconverters

SUMMARY OF CONFIRMED GEMS COUNTRY PARTNERS

Country Partners Target # PrEP Users

(2017 – 2020)

Current # of PrEP

Initiators

KenyaPOWER; Partners Scale-Up; PrIMA; PrIYA; Jilinde; LVCT Health; CHAK;

SWOP; PATH; National Rollout87,000 26,000

South AfricaPOWER; CHARISMA; Anova Health Institute; Wit RHI; OUT Wellbeing 5,500 1,000

ZimbabwePZAT; PSI; CeSSHAR; I-TECH;

National Rollout 31,500 3,000

Uganda

University of Washington 1,200 TBD

TOTAL 125,200 30,000

Avoiding Doomsday

• Plan for future ART regimens now – oral STRs, SQ? Implant?– NRTI: MK-8951, GS-9131 – NNRTI: Etravirine? Doravirine?– PIs: DRV/c, ATV/c– INSTI: BIC?– Attach Inh: Fostemsavir– Mat Inh: GSK-2838232– Capsid Inh: GS-6207?– bnAbs?

Avoiding Doomsday

• Reduce infectivity of infected individuals– Long-term Effective Antiretroviral Therapy

• Eliminate contact with HIV– Blood supply

• Reduce susceptibility of uninfected individuals– Male circumcision– Long-term Effective PrEP

The Stakes Are High: Let’s Get On With It!

And Have A Great Workshop!

Modeling TeamAndrew Phillips, PhD, Lead ModelerFumiyo Nakagawa, PhD, Post-Doc. AssociateValentina Cambiano, PhD, Modeling Scientist

Policy and Rollout TeamLisa Levy, Policy Team LeadKristine Torjesen, MD/MPH, Policy and Evaluation Advisor, OPTIONS DirectorIrina Yacobson, MD, Policy SpecialistRick Homan, PhD, Health EconomistMaria Fawzy, MHA, Clinical Research Manager

Science TeamKevin McCormick, PhD, Post-Doc. AssociateKerri Penrose, MS, Research ScientistAmy Heaps, MS, Research ScientistBarbra Richardson, PhD, StatisticianUma Chandran, PhD, BioinformaticsRahil Sethi, BioinformaticsJacob Waldman, Bioinformatics

USAIDDelivette Castor, PhD, GEMS AORSarah Wiant, MPH GEMS Program Asst.

SOUTH AFRICA TeamCarole Wallis, PhD, Sr. Technical AdvisorZowie Bagley, Laboratory CoordinatorKeven Rebe, PhD, ANOVALubbe Wiesner, UCT, Pharmacokinetcs

KENYA TeamBhavna Chohan, PhD, Sr. Country Coord.Everline Bosek, Country Coordinator

Monitoring and EvaluationJill Peterson, MPP, M&E Director

ZIMBABWE TeamMegan Dunbar, PhD, Sr. Country CoordinatorImelda Mahaka, PZATNonhlahla Ndlovu, Country Coordinator

John W. Mellors, MD, Project DirectorUrvi M. Parikh, PhD, Project Co-Director

Lauren Berner, MA, Project AdministratorGEMS TEAM

GEMS PARTNERS

This program is made possible by the generous support of the American people through the United States Agency for International Development (USAID), in partnership with PEPFAR, under the terms of Cooperative Agreement Number AID-OAA-A-15-00031. The contents are the responsibility of University of Pittsburgh and do not necessarily reflect the views of

USAID or the United States Government.

Questions?