1. Session: Treatment is Prevention? 16 th International Conference on AIDS and Sexually Transmitted Infections in Africa, Addis Ababa, Ethiopia Catherine Hankins BA (Hons) MD MSc CCFP FRCPC Science Adviser to UNAIDS Zero new HIV infections Zero discrimination Zero AIDS-related deaths Efficacy of antiretroviral drugs for prevention of new HIV infections

2. Antiretroviral-based HIV Prevention Strategies Antiretroviral therapy for HIV+ persons: Reduce onward transmission –Prevent horizontal transmission: T4P (early treatment for prevention) and TasP (population-level effects with current treatment eligibility of 350 CD4+ cells) –Prevent vertical transmission (through maternal treatment) Antiretroviral prevention for HIV- persons: Reduce HIV acquisition –Prevent horizontal transmission (M  F; M  M; F  M) –Prevent vertical transmission (infant during breastfeeding)

3. Efficacy of antiretroviral drugs for prevention of new sexually transmitted HIV infections Post-exposure prophylaxis (PEP) [Occupational] Non-occupational (N-PEP) Pre-exposure prophylaxis (PrEP) Topical (microbicides) Oral (tablet) Injectable Treatment as Prevention (TasP) Treatment for Prevention (T4P)

6. Experimental antiretroviral-based pre-exposure prophylaxis strategies Injectable PrEP: subcutaneous or intramuscular (Phase 1 trials)) Tenofovir (TDF) Tenofovir/emtricitabine TDF/FTC

7. Goals of topical and oral antiretroviral-based HIV prevention Right drug safe, effective, minimal resistance Right place sufficient concentrations at site of exposure Right time short onset of activity and long half-life to optimise efficacy with variable adherence

8. CAPRISA 004 1% tenofovir gel women 18-40 years annual HIV incidence 9.1% vs. 5.6% (controls vs. gel users) adherence (‘dose’/response relationship) overall effectiveness 39% (54% in women who used gel in 80% or more of sex acts) Confirmatory trials: FACTS 001: dosing before & after sex VOICE: once daily whether or not sex is anticipated or has occurred.

9. Five study groups and 2 sequential randomisations Women use product for average of 21 months TOTAL SAMPLE (5000) Oral Pill (3000) Vaginal Gel (2000) Truvada (1000) Tenofovir (1000) Oral Placebo (1000) Tenofovir Gel (1000) Placebo Gel (1000) Funded by NIH and BMGF

10. What’s different in FACTS 001? Focus on young women aged 18-30 years VOICE enrolled 18-45 years, CAPRISA 004 enrolled 18-40 years Before and after sex dosing of 1% tenofovir gel like CAPRISA 004 but not like daily dosing of VOICE More women: 2,600 women to be enrolled at 9 sites CAPRISA 004 (899 at 2 sites) or VOICE (2000 at 15 sites) Breastfeeding women can enroll Closer examination of HSV-2 prevention CAPRISA 004 51% protection; VOICE did not look Actively implementing UNAIDS/AVAC Good Participatory Practice Guidelines FACTS 002: 60 adolescent girls 16-17 years, safety, feasibility, and acceptability of daily use for 6 months

11. PrEP Trial Risk Reduction Results 2010-2011 CAPRISA 004iPrExPartners PrEPTDF2 Study participantsHeterosexual women Men who have sex with men (MSM) and trans women Serodiscordant heterosexual couples Heterosexual men and women Type of PrEPCoital tenofovir gel (vaginal) Daily TDF/FTC pill Daily TDF pill Daily TDF/FTC pill Reduced risk of HIV infection Overall 39%44%62% (TDF) 73% (TDF/ FTC) 63% Consistent users 54%73%-78% Safety concerns Diarrhea Nausea Headache Decrease in kidney function and bone density Drug resistance Nausea Diarrhea Nausea Vomiting Dizziness

12. Pre-exposure prophylaxis for women as of December 2011 TrialCountry 1% Tenofovir vaginal gel Oral Tenofovir daily tablets Oral Tenofovir/F TC daily tablets CAPRISA 008South Africa ✔ -- VOICE gelUganda, South Africa, Zimbabwe X-- FACTS 001South Africa ?-- Fem PrEPKen, SA, Tanz --X VOICE oralUga, SA, Zim -X? Partners PrEP Kenya, Uganda - ✔✔ TDF-2Botswana -- ✔

13. Systemic versus topical administration in women

14. Male and female condoms Male condom effectiveness –Meta-analyses: Greater than 90% when used correctly and consistently (Condoms for HIV prevention in developing countries: a review of the scientific literature. UNAIDS 2003) –Cochrane Review: always vs. never: 80% reduction in incidence Female condoms: (Peters et al 2010) –minimal investment in R&D by global public policy makers; resultant price monopolies: 25 times price of male condom –WHO ambivalence to recommend washing and reuse –lack of active promotion by UNAIDS contributing to low demand –stock-outs –underproduction with no economies of scale –good acceptability with frustrated demand

15. HIV Incidence: Annual number of people newly infected with HIV decreased by 21% below the number of new infections at the peak of the epidemic in 1997 to 2.7 million [2.4–2.9 million] in 2010 20052006200720082009200020012002200320041995199619971998199919901991199219931994 M I L L I O N S 4.0 3.5 3.0 2.5 1.0 1.5 2.0 0.5 0.0 Dotted lines represent ranges, solid lines represent the best estimate.  What has been the contribution of TasP?

16. Partners for the Prevention of HSV/HIV Transmission Study: Discordant Couples HIV Incidence (per 100-person-years) 2.24 (1.84-2.72) 0.37 (0.09-2.04) HIV Partner Had Initiated ART NoYes 92% Reduction Donnell D, et al. Lancet. 2010;375:2092-2098.

17. Efficacy of HIV Prevention Strategies From Randomised Clinical Trials Abdool Karim SS, et al. Lancet. 2011;[Epub ahead of print]. 100020406080 Efficacy (%) StudyEffect Size, % (95% CI) ART for prevention; HPTN 052, Africa, Asia, Americas PrEP for discordant couples; Partners PrEP, Uganda, Kenya PrEP for heterosexual men and women; TDF2, Botswana Medical male circumcision; Orange Farm, Rakai, Kisumu PrEP for MSMs; iPrEX, Americas, Thailand, South Africa Treatment sexually transmitted infections; Mwanza, Tanzania Microbicide gel/topical PrEP; CAPRISA 004, South Africa HIV vaccine; RV144, Thailand 96 (73-99) 73 (49-85) 63 (21-84) 57 (38-66) 44 (15-63) 42 (21-58) 39 (6-60) 31 (1-51)

18. HPTN 052 Enrollment (Total Enrollment: 1763 couples) U.S. Brazil South Africa Botswana Kenya Thailand India Americas 278 Africa 954 Asia 531 Zimbabwe Malawi

19. 1763 stable, healthy, serodiscordant couples, sexually active in 9 countries CD4 count: 350 to 550 cells/mm 3 Primary Transmission Endpoint Virally linked transmission events Primary Clinical Endpoint WHO stage 4 clinical events, pulmonary tuberculosis, severe bacterial infection and/or death HPTN 052 study design: Prevention of HIV Infection with Early Antiretroviral Treatment Immediate ART CD4 350-550 Delayed ART CD4 <250 Randomization Cohen et al NEJM 2011. (See HIV This Week Issue 93)

20. Total HIV-1 Transmission Events: 39 HPTN 052: HIV-1 Transmission Linked Transmissions: 28 Unlinked Transmissions: 11 p < 0.001 Immediate Arm: 1 Delayed Arm: 27 18/28 (64%) transmissions from infected participants with CD4 >350 cells/mm 3 23/28 (82%) transmissions in sub-Saharan Africa (54% of 1763 couples were in SSA) 50% of initial HIV infections were in men but 18/28 (64%) transmissions were from female to male partners 96% reduction

21. 96% Results of the HPTN052 trial announced on 12 May 2011 show that if an HIV-positive person adheres to an effective antiretroviral therapy regimen, the risk of transmitting the virus to their uninfected sexual partner can be reduced by 96% UNAIDS 2011 AIDS at 30 Treatment for prevention is a game changer. Michel Sidibe Executive Director of UNAIDS

22. Coverage of antiretroviral therapy at the end of 2010 (WHO 2010 Guidelines, CD4<350) New infections are outstripping expansion of treatment availability - for every 1 person who starts taking antiretroviral treatment, another 2 are newly infected

23. HPTN 071: PopART Trial PopART: Universal voluntary HIV testing delivered through a house-to-house campaign Male circumcision offered to men who test HIV-negative Immediate ART offered to all who test HIV-positive Counselling and condom provision Strengthening of PMTCT services Syndromic STI treatment at clinic Community HIV providers (CHiPs) to deliver testing, counselling, linkage to care and treatment support PopART Trial 24 community clusters (30-60,000) in Zambia and South Africa randomised to full PopART, PopART but Rx at 350, or (enhanced) standard of care Richard Hayes LSHTM

24.  50%  in sexual transmission of HIV  50%  of HIV transmission among people who inject drugs  50%  TB deaths in people living with HIV  Ensure no children are born with HIV and reduction of AIDS-related maternal deaths  15 million on antiretroviral treatment Bold new targets for 2015

25. Acknowledgements Paul De Lay Connie Celem Myron Cohen Linda Gail Bekker Salim Abdool Karim Quarraisha Abdool Karim Jared Beaten Sharon Hillier Helen Rees Deborah Baron Pedro Cahn Kevin O ’ Reilly Richard Hayes Thank you for your attention Zero new HIV infections Zero discrimination Zero HIV-related deaths Sign up at: http://hivthisweek.unaids.org http://hivthisweek.unaids.org

26. AIDS at 30 Nations at the crossroads VISION ZERO NEW HIV INFECTIONS. ZERO DISCRIMINATION. ZERO AIDS-RELATED DEATHS.