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Microbicides: A new hope for HIV prevention 1 Salim S. Abdool Karim, MBChB, PhD Professor of Clinical Epidemiology, Columbia University Adjunct Professor of Medicine, Cornell University Pro Vice-Chancellor (Research), University of KwaZulu-Natal HIV Center, Columbia University, New York - 24 March 2011

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Outline Brief review of the main CAPRISA 004 trial results A new hope Three key lessons from CAPRISA 004 1.Adherence 2.Breakthrough infection clues 3.HSV-2 impact Conclusions

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Age Group (Years) HIV Prevalence (N=1237) 1610.6% 17-1821.3% 19-2033.0% 21-2244.3% 23-2451.1% HIV prevalence in pregnant women in rural Vulindlela, South Africa (2005-2008)

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Source: Abdool Karim Q, Abdool Karim SS, Singh B, Short R, Ngxongo S. AIDS 1992; 6: 1535-9 The urgent need for new prevention: Age & gender profile of HIV infection: South Africa 0 49

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Abdool Karim Q, et al. Clinical Infectious Diseases 2010; 50(S3):S122S129 5

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Preventing sexual spread of HIV: Existing accepted proven HIV prevention strategies - ABCCC: A bstinence B ehaviour (Be faithful) C ondoms (Male & Female) C ounselling and Testing C ircumcision (Medical Male) Which of these are prevention tools for young women in Africa?

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Africa needs new HIV prevention technologies 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, especially those that empower women

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Stopped for futility Safe but not effective Increased HIV infection Zena Stein publishes seminal article HIV prevention: the need for methods women can use Kenya N-9 sponge trial FHI N-9 film trial UNAIDS COL-1492 trial CONRAD CS trial FHI SAVVY trial PopCouncil Carraguard trial HPTN PRO2000 & BufferGel trial 1 st class: Surfactants eg. N9, SAVVY 2 nd class: Polymers eg. PRO2000, Carraguard, Cellulose Sulfate (CS) 3 rd class: ARVs eg. Tenofovir gel CAPRISA 004 Tenofovir gel trial MDP 0.5% PRO2000 trial 90 92 98 00 03 04 04 05 05 07 09 11 FHI CS Trial 2% PRO2000 Planned MTN003 VOICE Tenofovir gel & tablet trial FACTS 001 Tenofovir gel trial CAPRISA 008 Tenofovir gel implementation trial Effective Past and current microbicide trials IPM dapivarine ring

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10 BAT 24 coitally-related gel use Insert 1 gel up to 12 hours Before sex, insert 1 gel as soon as possible within 12 hours After sex, no more than Two doses in 24 hours HIVNET 012 nevirapine regimen CAPRISA 004 tenofovir gel regimen asap 72 hrs 12 hrs Onset of labour Delivery CAPRISA 004 assessed the safety and effectiveness of 1% tenofovir gel

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Methods Proof of concept double-blinded, randomized, placebo- controlled trial Enrolled high risk HIV uninfected women reporting two coital acts in past 30 days known high risk populations from pre-trial feasibility studies Endpoint driven trial (92 HIV endpoints) HIV infection is primary safety & effectiveness endpoint: HIV negative:2 negative rapid HIV tests HIV endpoint:PCR+ in 2 separate blood specimens Positive Western blot Intent-to-treat analysis except for adherence analysis Intent-to-treat analysis

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CAPRISA Vulindlela Clinic KwaZulu-Natal Midlands CAPRISA eThekwini Clinic Durban City Centre CAPRISA 004: Urban and Rural sites

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Screening and Enrollment 196 excluded: 135 co-enrolled 50 in other study

Impact of adherence on effectiveness of tenofovir gel 19 # HIVN HIV incidence Effect p-value TFVPlacebo High adherers (>80% gel adherence) 363364.29.3 54% 0.03 Intermediate adherers (50-80% adherence) 201816.310.0 38% 0.29 Low adherers (