Antiretrovirals for HIV prevention:

Transcription

1 Antiretrovirals for HIV prevention: Topical PrEP, Systemic PrEP and Treatment for Prevention Presentation at 6th International workshop on HIV treatment, pathogenesis and prevention research in resource-limited settings Mombasa, Kenya, 8 May 2012 Salim S Abdool Karim, MBChB, PhD Professor in Clinical Epidemiology, Columbia University President, Medical Research Council of South Africa Director: CAPRISA & Pro Vice-Chancellor (Research): University of KwaZulu-Natal Associate Member, Ragon Institute of MGH, MIT and Harvard Adjunct Professor of Medicine, Cornell University

2 Outline Why PrEP and TasP for HIV prevention? Brief history of PrEP trials Results of the PrEP and TasP trials Changing landscape of HIV prevention Challenges & some remaining questions

3 Global HIV epidemic 33.3 million living with HIV, 2.6 million new infections, 1.8 million deaths Source: UNAIDS 2010 South Africa: 0.7% of world s population 16.2% of global HIV burden (5.4m) Country with the most AIDS cases

4 HIV prevalence in pregnant women in rural Vulindlela, South Africa ( ) Age Group (Years) HIV Prevalence (N=1237) % % % % %

5 HIV prevalence among MSM in Africa HIV prevalence in MSM: Range: 6.2% in Egypt to 30.9% in Cape Town Source: Griensven et al. Current Opinion in HIV and AIDS 2009, 4:

6 Africa needs new HIV prevention approaches In South Africa the epidemic continues to grow despite increased prevention efforts Male condom distributed in 2002/3: 358 million Female condom distribution doubled from 1,3 million in 2003 to 2,6 million in 2004 Combating the HIV epidemic is not only about scaling proven prevention we also need new prevention technologies New HIV prevention technologies are urgently needed in Africa and the world, especially those that empower women

7 ART for prevention: Epidemiological basis for TasP

8 Extending ART for prevention: mathematical modeling impact

9 Why pre-exposure antiretroviral agents for HIV prevention? Biological plausibility (ARVs prevent viral replication) More than 50 animal challenge studies since 1995 show protection Success of post-exposure prophylaxis for needlestick exposure in observational data pmtct: Proof of concept in humans

10 Rationale for choice of ARV Why Tenofovir? Effective therapeutic agent Good safety profile Rapidly absorbed and long half-life Effective in suppressing viral load Protects against SIV in monkey studies

11 Outline Why PrEP and TasP for HIV prevention? Brief history of PrEP trials Results of the PrEP and TasP trials Changing landscape of HIV prevention Challenges & some remaining questions

12 First oral PrEP studies halted by activists At what cost? How many infections could have been prevented if these trials went ahead?

13 First 10 microbicide trials: No protection 1 st class: Surfactants 2 nd class: Polymers 3 rd class: ARVs eg. N9, SAVVY Kenya N-9 sponge trial eg. PRO2000, Carraguard, Cellulose Sulfate (CS) CONRAD CS trial FHI CS Trial eg. Tenofovir gel CAPRISA 004 Tenofovir gel trial MTN003 VOICE Tenofovir gel & tablet trial Zena Stein publishes seminal article HIV prevention: the need for methods women can use FHI N-9 film trial UNAIDS COL-1492 trial FHI SAVVY trial PopCouncil Carraguard trial HPTN PRO2000 & BufferGel trial MDP 0.5% PRO2000 2% PRO2000 trial VOICE Truvada tablets FACTS 001 Tenofovir gel trial CAPRISA 008 Tenofovir gel implementation trial IPM dapivarine ring MTN dapivarine ring Safe but not effective Increased HIV infection Stopped for futility Effective Planned

14 Outline Why PrEP and TasP for HIV prevention? Brief history of PrEP trials Results of the PrEP and TasP trials Changing landscape of HIV prevention Challenges & some remaining questions

15 July 2010: Proof of Concept for microbicides

16 November 2010: Oral PrEP prevents HIV in MSM iprex trial 131 infections after randomization 48 in FTC/TDF 83 in placebo 2499 Men who have sex with Men Effect of daily TDF-FTC on HIV: 42% (CI: 15% - 63%)

17 May 2011: ART prevents HIV transmission from infected partners in discordant couples (HPTN 052) 1763 discordant couples in Africa & America Effect on ART (HIV +ve) on HIV: 96% (CI: 73% - 99%)

18 July 2011: Oral PrEP prevents HIV transmission in discordant couples (PartnersPrEP) 4,758 HIV discordant couples in Kenya & Uganda Effect of TDF on HIV: 67% (CI: 44% - 81%) Effect of FTC/TDF on HIV: 75% (CI: 55% - 87%)

19 July 2011: Oral PrEP prevents HIV in heterosexual men & women (Botswana TDF2) 1219 heterosexual men & women in Botswana Effect of TDF-FTC on HIV: 63%

20 April 2011: FEM-PrEP trial stops: Truvada Tenofovir + FTC not effective in women September & November 2011: VOICE stops tenofovir tablet and tenofovir gel arms: not effective TOTAL SAMPLE (5000) ORAL (3000) TOPICAL (2000) Truvada (1000) Tenofovir tablet (1000) Placebo tablet (1000) Tenofovir Gel Placebo Gel (1000) (1000) DSBM recommends halting tenofovir tablet and tenofovir gel arms: No protection against HIV

21 False impression of oral & topical PrEP following VOICE & FEM-PrEP results

22 Actual situation with oral & topical PrEP following VOICE & FEM-PrEP results

23 Likely reasons for the discordant trial outcomes: High vaginal tenofovir concentrations needed at exposure Probability of HIV infection Placebo gel Tenofovir gel TFV 1000ng/ml Tenofovir gel TFV >1000ng/ml p=0.01* *comparing women with tenofovir concentration >1000ng/ml vs placebo. Adjusted p= Years on study

24 Likely reasons for the discordant trial outcomes: Adherence is essential # HIV N HIV incidence TFV Placebo Effect p-value High adherers (>80% gel adherence) Intermediate adherers (50-80% adherence) Low adherers (<50% gel adherence) % % % 0.30 CAPRISA 004 was developed after extensive consultation with international scientific experts and review of monkey challenge data. Just as importantly, it followed detailed consultation with the communities involved. Source: Abdool Karim S, Abdool Karim Q, Nature, 446; 2007 Source of data in table: Abdool Karim Q, Abdool Karim SS, Frolich J, et al. Science 2010

25 Evidence: Tenofovir PrEP prevents HIV 1. Tenofovir-based PrEP: HIV incidence in 4 trials 2. In FEM-PrEP, drug only detected in ± 26% women Adherence too low to assess Truvada efficacy (?VOICE) 3. Clear dose-response: - adherence = HIV (within & across studies) 4. Drug levels correlate with HIV protection: - presence of drug = HIV protection 5. Repeatedly highly effective in cell culture, explant tissues, mice & monkeys 6. The FDA yesterday pronounced that TDF-FTC is safe and effective in preventing HIV

26 Why bother with PrEP now that we have Treatment for Prevention? Age & gender HIV prevalence in South Africa 10 8 Male Female Prevalence (%) < >49 Source: Abdool Karim Q, Abdool Karim SS, Singh B, Short R, Ngxongo S. AIDS 1992; 6:

27 High HIV prevalence in young women in Africa 15 Kenya Men Women Malawi Men Women HIV prevalence (%) 10 5 HIV prevalence (%) Cameroon Men Women Lesotho Men Women HIV prevalence (%) 10 5 HIV prevalence (%)

28 Preventing sexual spread of HIV: Existing accepted proven HIV prevention strategies - ABCCC: Abstinence Behaviour (Be faithful) Condoms (Male & Female) Circumcision (Medical Male) Decrease Viral Load with ART: TasP Which of these are prevention tools for young women in Africa?

29 Unique strength of oral & topical PrEP empowerment of women to address HIV risk in young women HIV prevalence in Vulindlela schools (grades 9 & 10) Age Group Boys HIV Prevalence Girls % 2.2% % 3.7% % 7.3% % 14.2%

30 Outline Why PrEP and TasP for HIV prevention? Brief history of PrEP trials Results of the PrEP and TasP trials Changing landscape of HIV prevention Challenges & some remaining questions

31 Clinical trial evidence for preventing sexual HIV transmission June 2010 Study Effect size (CI) Medical male circumcision (Orange Farm, Rakai, Kisumu) 54% (38; 66) STD treatment (Mwanza) 42% (21; 58) HIV Vaccine (Thai RV144) 31% (1; 51) 0% % Efficacy

32 Clinical trial evidence for preventing sexual HIV transmission Today Study Treatment for prevention (Africa, Asia, America s) PrEP for discordant couples (Partners PrEP) PrEP for heterosexuals (Botswana TDF2) Medical male circumcision (Orange Farm, Rakai, Kisumu) PrEP for MSMs (America s, Thailand, South Africa) STD treatment (Mwanza) Microbicide (CAPRISA 004 tenofovir gel) HIV Vaccine (Thai RV144) 0% % Efficacy Effect size (CI) 96% (73; 99) 73% (49; 85) 63% (21; 48) 54% (38; 66) 44% (15; 63) 42% (21; 58) 39% (6; 60) 31% (1; 51)

33 ARV prophylaxis Microbicides for women Abdool Karim Q, Science 2010 Male circumcision Auvert B, PloS Med 2005 Gray R, Lancet 2007 Bailey R, Lancet 2007 Treatment of STIs Grosskurth H, Lancet 2000 Female Condoms Oral pre-exposure prophylaxis Grant R, NEJM 2010 (MSM) Baeten J, 2011 (Couples) Paxton L, 2011 (Heterosexuals) Post Exposure prophylaxis (PEP) Scheckter M, 2002 HIV PREVENTION Treatment for prevention Cohen M, NEJM 2011 Donnell D, Lancet 2010 Male Condoms HIV Counselling and Testing Coates T, Lancet 2000 Behavioural Intervention - Abstinence - Be Faithful Note: PMTCT, Screening transfusions, Harm reduction, Universal precautions, etc. have not been included this is focused on reducing sexual transmission

34 A change in the discourse.. zero new HIV infections zero discrimination zero AIDS-related deaths

35 Outline Why PrEP and TasP for HIV prevention? Brief history of PrEP trials Results of the PrEP and TasP trials Changing landscape of HIV prevention Challenges & some remaining questions

36 5 key challenges in PrEP & TasP: 1. Adherence: Will healthy people be willing to take medication everyday for decades? 2. Safety: Are ARVs safe in long-term? 3. Resistance: Will HIV infection on PrEP cause ARV resistance & will TasP lead to widespread resistance with poor adherence in well people? 4. Displacing condoms: Will there be behavioural disinhibition / risk compensation? 5. Cost and Health service burden: Can we afford large populations on ARVs as PrEP or TasP?

37 Hormonal contraception and increased HIV acquisition women living with HIV or at high risk of HIV can safely continue to use hormonal contraceptives to prevent pregnancy.

38 Some remaining questions in PrEP... Which drugs & formulations are most efficacious & safe? Which dosing (daily vs. intermittent vs. coitally related) achieves highest adherence, efficacy and safety? Do long-acting rings or injectables increase adherence and/or risk of drug resistance? Will resistance to PrEP affect later ARV treatment? Combination ARVs: are they better for efficacy, safety & resistance? PrEP rollout is it feasible, affordable and practical? A specific ARV or ARV class be set aside for PrEP?

39 Conclusions There is new hope in HIV prevention More positive trials since July 2010 than in previous 29 years Treatment for prevention in particular provides huge hope Microbicides and oral PrEP: Promising new HIV prevention technologies for women Gender dynamic is key to controlling HIV in Africa Hillary Rodham Clinton s NIH speech, Nov 8, 2011: a historic opportunity, one that the world has today: to change the course of this pandemic and usher in an AIDS-free generation. President Barak Obama s 2011 World AIDS Day speech:.few could have imagined that we d be talking about the real possibility of an AIDS-free generation. But that s what we re talking about.

40 Acknowledgements CAPRISA was established as part of the Comprehensive International Program of Research on AIDS (CIPRA) of the National Institutes of Health (NIH) (grant# AI51794) CAPRISA is funded by: DAIDS, NIAID, National Institutes of Health US Agency for International Development (USAID) via FHI and CONRAD President s Emergency fund for AIDS Relief (PEPFAR) US Centers for Disease Control and Prevention (CDC) South African Department of Science and Technology (DST) Fogarty International Center, NIH Howard Hughes Medical Institute (HHMI) Gilead Sciences (Tenofovir API) Royal Netherlands Embassy and MIET MACAIDS Fund (via Tides Foundation) Technology Innovation Agency (LIFELab) Past Funders: National Research Foundation, South Africa (NRF), CHAVI, SAAVI, European Commission EDCTP, Johap Oxfam, Doris Duke Charitable Foundation (DDCF), Global Fund against AIDS, TB & Malaria (GFATM)