1. Timothy Mastro Family Health International XVII International AIDS Conference Mexico City 7 August 2008

2. Rationale for ARV PrEP for HIV Prevention • Data suggesting that ARV PrEP may be effective • ARVs for PMTCT • Post-exposure prophylaxis for HIV • Monkey models for SHIV transmission • Available ARVs appear safe • Available ARVs can be used once daily • TDF: tenofovir disoproxil fumarate: Viread ® • FTC: emtricitibine: Emtriva ® • TDF/FTC: Truvada ®

3. Data from Monkey Studies at CDC:Prevention of Rectal SHIV Transmission by Chemoprophylaxis with ARVs Laboratory Branch, DHAP, CDC 100 FTC/Tenofovir (subcut, n = 6) 75 FTC/TDF (oral, n = 6) p = 0.0075, [HR = 7.8] % Uninfected animals 50 FTC (subcut, n = 6) p = 0.021, [HR = 3.9] 25 TDF (oral, n = 4)* p = 0.3 Control (n = 18) 0 0 2 4 6 8 10 12 14 Number of rectal exposures

4. One Completed Clinical Trial • West Africa Phase II PrEP Trial (FHI/BMGF) • RCT: daily TDF 300mg and placebo • Women (n=936) in Ghana, Cameroon, Nigeria • Conducted June 2004 - March 2006 • No evidence of increased clinical or laboratory adverse effects • No evidence of risk compensation • Inadequate power to assess efficacy • 8 HIV seroconversions: 2 TDF, 6 placebo • RR = 0.35, p=0.24

5. Ongoing PrEP Trials • Tenofovir Extended Safety Study (CDC) • Bangkok Tenofovir Study (CDC) • Botswana TDF2 (TDF/FTC) Trial (CDC) • iPrEX (UCSF/NIAID/BMGF) • Partners PrEP (UW/BMGF)

6. Planned PrEP Trials • FEM-PrEP (FHI/USAID/BMGF) • VOICE (MTN 003) (NIAID)

7. OnGOINGPrEP TRIALS

8. U.S. Extended Tenofovir Safety Trial • Sponsor CDC • Objective To assess clinical, laboratory and behavioral safety; and adherence and acceptability • Design Randomized double-blind placebo controlled phase II extended safety study with 1:1 TDF : placebo • Duration 24 months with DSMB review of data every 6 months

9. U.S. Extended Tenofovir Safety Trial • 400 HIV-neg MSM (Atlanta, San Francisco, Boston) • 9 month delay in enrollment of 200 men to assess behavioral changes once drug prophylaxis started • Close monitoring of seroconverters for resistance and clinical outcomes • Adverse events, and access to HIV care if infected, managed through physician referral • Started February 2005; fully enrolled July 2007; follow-up to end August 2009

10. Bangkok Tenofovir Study (BTS)BMA Drug Treatment Clinics Sponsor: CDC TUC Lab (Nonthaburi) BMA Lab Thailand Bangkok

11. Bangkok Tenofovir Study (BTS)

12. BTS Objectives

13. Botswana TDF-2 Study Sponsor: CDC

14. Botswana TDF-2 Study • Trial started in 2005 with TDF; halted enrollment (at N=71) in March 2006 to prepare for switch to Truvada (TDF/FTC). • New trial (TDF-2) started in February 2007 • Study population originally 1200 heterosexual men and women aged 18-29 • Now planning to expand age range to 18-39 and increase N to 1800-2000 through addition of new site

15. The iPrEx Study:Safety, Efficacy, Behavior, and Biology Sponsored by NIH/NIAID/DAIDS with co-funding by the Bill and Melinda Gates Foundation and drug donated by Gilead Sciences

16. The iPrEX Study • Plans to enroll 3000 high-risk MSM • Randomized 1:1 daily oral PrEP • FTC/TDF vs Placebo • Followed on drug for: • HIV seroconversion • Adverse events (especially renal & liver) • Metabolic effects (Bone, Fat, Lipids) • HBV flares among HBsAg+ • Risk behavior & STIs • Adherence • If infected • Drug resistance • Viral load • Immune responses & CD4 count

17. The iPrEX Study

18. After 3 Years of Preparation, iPrEx is Enrolling as Planned

19. Why MSM? • MSM bear a major burden of the epidemic • Throughout the Americas • In some parts of Asia • The burden in Africa is increasingly appreciated • Efficacy could be different after rectal exposure • Higher efficiency of transmission • Possibly different tissue penetration of virus and drug • iPrEx is the only efficacy trial of PrEP in MSM

20. Partners PrEP • Multisite trial of pre-exposure prophylaxis against HIV in HIV discordant couples • Parallel comparison of TDF and TDF/FTC PrEP to prevent HIV-1 acquisition within HIV-1 discordant couples Jared Baeten, MD, PhD Connie Celum, MD, MPH University of Washington

21. Where Partners PrEP Study Fits into the PrEP Research Landscape • When considering possible wide-spread implementation, HIV discordant couples would be a priority target • More than half of new HIV transmissions occur in stable couples • 3 Arm Trial: side-by-side evaluation of TDF and FTC/TDF • Will enroll and follow HIV+ partners • Assess PrEP efficacy vs. HIV+ partner characteristics (e.g., high viral load) • Drug levels to test for drug sharing (in context of counseling re: sharing) • Assess baseline and longitudinal resistance in HIV+ partners • marker / impact of sharing • transmitted vs. acquired resistance in seroconverters

22. Partners PreP: Design

23. Partners PrEP: Statistical Power • Sample size = 3900 HIV discordant couples • 1:1:1 randomization (common placebo arm) • estimated HIV incidence in placebo arm of 3.25%  With 191 endpoints, >80% power to detect 60% efficacy of each arm against placebo and ‘rule out’ <30% efficacy

24. Partners PrEP: Timeline • Funding awarded from BMGF: mid-2007 • Protocol development and pre-IND: May 2007 • IND approved: September 2007 • Site preparedness, stakeholder sessions, IRB & national drug authority approvals: October 2007-present • First 2 sites activated: May & June 2008 • Additional 6 sites to be activated: Q3-Q4 2008 • Target enrollment period: 2 years • Completion of follow-up and results: 2011

25. Planned PREP TRIALS

26. FHI FEM-PrEP: Trial Overview

27. FHI FEM-PrEP: Trial Objectives

28. FEM PrEP: Timeline • Jun 2007 Initiation of non-research community activities (i.e., CABs) • Aug 2007 Initiation of site preparedness activities • Oct 2007 Investigators’ meeting (Nairobi) • Mar 2008 FHI PHSC approval • May 2008 IND submission • Jul 2008 1st training (Kenya) • Q4 2008 1st screening • Q3 2011 Trial completion (primary objective) • Q3 2012 Trial completion (seroconverter objectives)

29. VOICE Vaginal and Oral Interventions to Control the Epidemic Sponsor: NIAID/NIH

30. VOICE Study Objectives

31. The VOICE Study • Safety and effectiveness study of tenofovir gel, tenofovir tablet and Truvada tablet for prevention of HIV infection in 4,200 women • Randomized trial with 5 study groups. Two sequential randomizations. Women will use product for average of 21 months

32. VOICE Study Hypothesis • >25% difference in effectiveness • Between tenofovir 1% gel and placebo gel • Between TDF and oral placebo • Between FTC/TDF and oral placebo • No difference in safety • Between daily regimens of tenofovir 1% gel and placebo gel • Between daily regimens of TDF and oral placebo • Between daily regimens of FTC/TDF and oral placebo

33. VOICE Study Sites South Africa Malawi Uganda Zambia Zimbabwe

34. VOICE Study Timeline *Strategic Working Group, Division of AIDS, National Institute of Allergy and Infectious Diseases (NIAID) ** Prevention Sciences Review Committee, NIAID ***Division of AIDS, NIAID

35. Summary of Ongoing PrEP Studies - I

36. Summary of Ongoing PrEP Studies - II

37. Summary of Planned PrEP Studies

38. Total Participants in 7 Trials

39. Next Steps • Intermittent vs. daily PrEP • New ARVs and combinations • Formulations: oral, injectable, gel, vaginal ring • Adolescents • Program implementation

40. Acknowledgements • Lynn Paxton CDC • J Gerardo Garcia-Lerma CDC • Walid Heneine CDC • Bob Grant University of California, San Francisco • Connie Celum University of Washington • Lut Van Damme Family Health International • Amy Corneli Family Health International • Sharon Hillier Magee Hospital, University of Pittsburgh • Ward Cates Family Health International • Mitchell Warren AIDS Vaccine Advocacy Coalition