Overview of ARV-based prevention trials

Overview of ARV-based prevention trials Catherine Hankins BA MD MSc CCFP FRCPC Deputy Director, Science Amsterdam Institute for Global Health and Development; Department of Global Health, Academic Medical Centre, University of Amsterdam Honorary Professor Department of Infectious Disease Epidemiology London School of Hygiene and Tropical Medicine IAS-ILF Satellite at CROI 2013 Sex and Gender Differences in ARV-based Prevention Research, March 3, 2013, Atlanta

Overview of ARV-based prevention trials u Place of ARV-based prevention in combination prevention u Pre-exposure prophylaxis trials u Early treatment for prevention: HPTN 052 u Treatment as prevention: prevention benefits of scaling up treatment following national eligibility criteria

Hankins and De Zalduondo AIDS 2010 Combination Prevention: Basic Attributes Evidence-informed, human rights-based, and context-specific, tailored to local epidemics and needs Fully engages affected communities, promoting human rights and gender equality Operates synergistically on multiple levels individual, family and society Invests in decentralized and community responses Flexible adapts to changing epidemic patterns and rapidly deploys innovations Combines biomedical, behavioural and structural elements to address immediate risks, underlying vulnerabilities, and pathways that link them

Mellors 5.25.10 Antiretroviral Prevention Train

HIV prevention with ARVs (since 2010) HIV prevention (before 2010) Topical preexposure prophylaxis (microbicides) for women Abdool Karim Q, Science 2010 Oral pre-exposure prophylaxis Grant R, NEJM 2010 (MSM) Baeten J, NEJM 2012 (Couples) Thigpen M, NEJM 2012 (Heterosexuals) Treatment for prevention Cohen M, NEJM 2011 Note: PMTCT, Screening transfusions, Harm reduction, Universal precautions, Vaccines, etc. have not been included HIV PREVENTION Male circumcision Auvert B, PloS Med 2005 Gray R, Lancet 2007 Bailey R, Lancet 2007 Treatment of STIs Grosskurth H, Lancet 2000 Female Condoms Male Condoms HIV Counselling &Testing Coates T, Lancet 2000 Behavioural Intervention - Abstinence - Be Faithful

Antiretroviral Drugs for Preventing Sexual HIV Transmission Antiretroviral therapy for HIV+ persons Ø Reduces onward HIV transmission T4P: early treatment for prevention before CD4+ cells reach 350/uL TasP: treatment as prevention i.e. populationlevel benefits of lower community viral load with ART scale-up following national eligibility criteria Antiretroviral prophylaxis for HIV- persons Ø Reduces HIV acquisition Pre-exposure prophylaxis to prevent sexual transmission: è ; è ; è

HIV Prevention Options Timeline * ** AVAC, January 2013 2010 2011 2012 2013 2014 2015 2016 Oral TDF/FTC Oral TDF TFV gel Rectal TFV gel DPV Ring TMC 278 LA Inject. GSK1265744 LAP DNA/Ad5 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 2005 Bangkok Tenofovir Study/CDC 4370 TIMELINE LEGEND Oral TDF 2008 Partners PrEP Partners PrEP (no placebo) Positive efficacy result Oral TDF/FTC 2009 VOICE/MTN 003 2007 TDF2/CDC 4940 TDF2 Open-Label Extension 2007 iprex iprex Open-Label Extension (OLE) 2009 FEM-PrEP 2007 CAPRISA 004 2009 VOICE/MTN 003 2009 HVTN 505 FACTS 001 US FDA approval MTN 017 The Ring Study/IPM 027 ASPIRE/MTN 020 Additional demonstration projects & intermittent PrEP studies CAPRISA 008 Various phase I TMC278 LA injectable trials (SSAT 040 & MWRI-01) Arm stopped Regulatory submission/filing Planned Final results pending FACTS 002 and other adolescent studies TFV gel Rectal TFV gel DPV ring TMC278 LA Injectable DNA/Ad5 Pox-Protein GSK1265744 LAP Earliest regulatory submission Possible LA Injectable Efficacy Trial Earliest regulatory submission South Africa Licensure Study Pox-Protein RV 144 2004 Various Phase I/II preliminary and bridging studies * Trial end-dates are estimates; due to the nature of clinical trials the actual dates may change. For full trial details, see www.avac.org/pxrd. ** Not all trials included are effectiveness trials. Trials included on this list are mainly phase II/IIb, III/IIIb and IV trials. Southern Africa Research Study Thai Licensure Study

Key requirements for effective PrEP People Right drug (safe, effective, minimal resistance) Right place (sufficient concentrations at site of HIV exposure) Right time (short onset of activity and long half-life to optimize efficacy with variable adherence) Right population (at risk, motivated to use) Right timing (during periods of highest risk) Right delivery (cost-effective and efficient) Right decision-making (equity issues: prioritising key populations at highest risk of exposure MSM, SW, PWID, young women while fully scaling up ART)

Pre-exposure prophylaxis strategies Tenofovir (TDF) Tenofovir/emtricitabine TDF/FTC ü Partners PrEP Topical PrEP: 1% tenofovir gel ü iprex ü Partners PrEP ü TDF2 ü CAPRISA 004 Injectable PrEP: subcutaneous or intramuscular (Phase 1 trials)) Intermittent PrEP trials ASPIRE and IPM trials

Tenofovir-based px results, as of Feb 2013 Study Popula,on N Results CAPRISA 004 South Africa iprex Brazil, Ecuador, Peru, South Africa, Thailand, US TDF2 Study Botswana Women 889 Gay men, other MSM, transgender women 39% [CI = 6-60] efficacy coitally- dependent vaginal TFV gel 2499 42% [CI = 18-60] efficacy daily oral FTC/TDF Men and women 1200 62% [CI = 22-83] efficacy daily oral FTC/TDF Partners PrEP Study Kenya, Uganda FEM- PrEP Kenya, S Africa, Tanzania VOICE South Africa, Uganda, Zimbabwe Bangkok Tenofovir Study Thailand FACTS 001 South Africa Serodiscordant couples 4758 Women 1950 Women 5029 IDUs 2400 Women 2900 67% [CI = 44-81] efficacy daily oral TDF 75% [CI = 55-87] efficacy daily oral FTC/TDF FuQlity of daily oral FTC/TDF 6% [CI = - 52-41] FuQlity of daily oral TDF FuQlity of daily vaginal TFV gel Daily oral FTC/TDF ongoing Results expected at CROI, March 2013 Daily oral TDF ongoing Results expected by June 2013 Coitally- dependent vaginal TFV gel enrolling Results expected in 2015

Pre-Exposure Prophylaxis for Women as of March 3 2013 Trial CAPRISA 004 VOICE gel [daily] Country 1% Tenofovir vaginal gel Oral TDF (tenofovir) daily tablets Oral TDF/FTC (emtricitabine) daily tablets South Africa - - Uganda, South Africa, Zimbabwe X - - FACTS 001 South Africa? - - Fem PrEP Ken, SA, Tanz - - X VOICE oral Uga, SA, Zim - X? Partners PrEP Kenya, Uganda - TDF-2 Botswana - - Hankins

Research and Development Pipeline: New Trials MSM populations: Intermittent PrEP (IPERGAY, France): TDF/FTC versus placebo [controversy post FDA announcement] ADAPT (HPTN 067): daily versus intermittent TDF/FTC [no point in testing unpopular regimens] NEXT-PREP (HPTN 069): TDF/FTC +/- maraviroc [CCR5 blocker not used much in treatment] PROUD: UK immediate vs deferred TDF/FTC Women: Ring study (IPM) & ASPIRE (MTN) phase III dapivirine ring Safety and acceptability Follow-up to Phase I trials of long-acting injectables NNRTI rilpivirine (TMC 278) and integrase inhibitor S/GSK1265744

HPTN 052: HIV-1 Transmission (Cohen et all NEJM 2011) Total HIV-1 Transmission Events: 39 Linked Transmissions: 28 96% reduction Unlinked or TBD Transmissions: 11 Immediate Arm: 1 p < 0.001 Delayed Arm: 27 1763 stable, healthy, serodiscordant, sexually active couples in 9 countries [CD4 count: 350 to 550 cells/mm 3 ] randomised for the HIV+ partner to: start ART immediately or wait until CD4 250

ART coverage 2004-2011 Hlabisa, KwaZulu Natal HIV-infected: Individual, geo-located, HIV + adults identified through population-based HIV surveillance (2004-2011) Patients on ART: Individual, geo-located adult patients actively on ART in June (2004-2011) ART coverage: % all HIV-infected population receiving ART At 30-40% ART coverage, HIV acquisition hazard reduced by 38% (1.4% for 1% ART increase) Tanser et al CROI 2012 and Science 2013

With thanks for ideas and slides to: Helen Weiss Frank Tanser Salim Abdool Karim Mitchell Warren Myron Cohen John Mellors Bob Grant Jared Beaton Connie Celum Quarraisha Abdool Kevin O Reilly Karim Brazey De Zalduondo Thank you for your attention!