1. Antiretroviral Pre-Exposure Prophylaxis for HIV-1 Prevention among Heterosexual African Men and Women: The Partners PrEP Study Jared Baeten, MD PhD & Connie Celum, MD MPH on behalf of The Partners PrEP Study Team IAS 2011 Study Funder: Bill & Melinda Gates Foundation

2. Background The Partners PrEP Study is a phase III, randomized, double-blind, placebo-controlled, three-arm trial of daily oral tenofovir (TDF) and emtricitabine/tenofovir (FTC/TDF) PrEP for the prevention of HIV acquisition by HIV seronegative partners in heterosexual HIV serodiscordant partnerships

3. Partners PrEP Study 4758 HIV serodiscordant couples (HIV+ partner not yet medically eligible for ART) TDF once dailyPlacebo once daily Randomize HIV- partners (normal liver, renal, hematologic function) 1° endpoint: HIV infection in HIV- partner Co- 1° endpoint: Safety Follow couples for up to 36 months FTC/TDF once daily All receiving comprehensive HIV prevention services

4. Jinja, Kabwohe, Kampala, Mbale, Tororo, Uganda Eldoret, Kisumu, Nairobi, Thika, Kenya Partners PrEP Study: Sites

5. HIV- participants - Monthly HIV & pregnancy testing - Monthly symptom & 3-monthly laboratory safety monitoring - Monthly provision of study medication and individualized adherence counseling, including not sharing study drug Study Procedures HIV+ participants - 3-monthly visits - 6-monthly CD4 counts - ongoing HIV primary care - active referral for ART, following national guidelines

6. HIV- participants - Monthly HIV & pregnancy testing - Monthly symptom & 3-monthly laboratory safety monitoring - Monthly provision of study medication and individualized adherence counseling, including not sharing study drug Study Procedures HIV+ participants - 3-monthly visits - 6-monthly CD4 counts - ongoing HIV primary care - active referral for ART following national guidelines All participants: comprehensive HIV prevention package - Risk reduction counseling (individual and couple) - Free condoms and condom counseling - Contraception counseling and provision - Screening and treatment for STIs - Counseling & referral for other HIV prevention interventions (e.g., male circumcision), per national policies -

7. Interim monitoring Independent Data and Safety Monitoring Board (DSMB) review every 6 months Interim reviews of efficacy conducted August 2010 & March 2011 Monitored with Lan-DeMets modification of O’Brien-Fleming interim monitoring Pre-specified conservative stopping criteria, against H 0 =0.7 During Closed Session in March 2011 meeting, DSMB observed strong trend for HIV protection on PrEP arms Determined ad hoc meeting may be required before scheduled interim review Meeting called for 10 July 2011; study team informed shortly before meeting DSMB meeting on 10 July 2011 reviewed data through 31 May 2011 DSMB recommended 1) study results be publicly reported & 2) the placebo arm be discontinued, because of clear demonstration of HIV protection from PrEP

8. Population characteristics Total (n=4747*) TDF (n=1584) FTC/TDF (n=1579) Placebo (n=1584) HIV- partner female / male38% / 62% 36% / 64%39% / 61% Age of HIV- partner, years (median/IQR) 33 (28,40) 33 (28,40) 33 (28,40) 33 (28,40) Couple married98%97%98% Duration of partnership, years (median/IQR) 7 (3,14) 7 (3,14) 7 (3,14) 7 (3,14) Duration known HIV serodiscordant, years (median/IQR) 0.4 (0.1,2.0) 0.5 (0.1,2.0) 0.4 (0.1,2.0) 0.4 (0.1,2.0) CD4 count, HIV+ partner, cells/mm 3 (median/IQR) 495 (375,662) 491 (370,661) 497 (380,664) 499 (375,663) Plasma viral load, HIV+ partner, log 10 copies/mL (median/IQR) 3.9 (3.2, 4.5) 3.9 (3.2,4.5) 3.9 (3.1,4.5) 3.9 (3.2,4.5) Started ART, HIV+ partner, during follow-up 19%20%18%20% * 11 couples found after randomization to be ineligible and exited from the study

9. Retention Study month (# expected) TotalTDFFTC/TDFPlacebo Month 6 (n=4738) 98% Month 12 (n=4052) 96% 97%96% Month 18 (n=3055) 95% Month 24 (n=2027) 95%94%95% Month 30 (n=605) 95%94% 98% Month 36 (n=17) 100% Person-years of follow-up7,3372,4412,4522,444

10. Adherence TotalTDFFTC/TDFPlacebo Dispensed doses taken97% Pill bottles returned98% Primary measure of adherence = monthly pill count of unused study product

11. Pregnancy TotalTDFFTC/TDFPlacebo Number of pregnancies2721077689 Pregnancy incidence, per 100 woman-years 10.312.18.99.9 P-value vs. placebop=0.12p=0.50 Time off study drug due to pregnancy 1.8%2.6%1.4%1.6% Among HIV- women (n=1785): Hormonal contraceptive use at most recent study visit: 10% OCP, 26% injectable, 8% implant

12. HIV seroconversion endpoints 12 HIV infected at enrollment 78 HIV acquisition events in primary study (mITT) analysis 90 HIV acquisition events for ITT analysis (as of 31 May 2011)

13. Primary efficacy results TDFFTC/TDFPlacebo Number of HIV infections181347 HIV incidence, per 100 person-years 0.740.531.92 HIV protection efficacy, vs placebo62%73% 95% CI(34-78%)(49-85%) p-value0.0003<0.0001 Z-score, vs. H 0 =0.7-2.17-2.99 Primary analysis: modified intention-to-treat (mITT) excluding infections present at randomization (3 TDF, 3 FTC/TDF, 6 placebo) ITT analysis results similar

14. Primary efficacy results TDFFTC/TDFPlacebo Number of HIV infections181347 HIV incidence, per 100 person-years 0.740.531.92 HIV protection efficacy, vs placebo62%73% 95% CI(34-78%)(49-85%) p-value0.0003<0.0001 Z-score, vs. H 0 =0.7-2.17-2.99 Primary analysis: modified intention-to-treat (mITT) excluding infections present at randomization (3 TDF, 3 FTC/TDF, 6 placebo) ITT analysis results similar Effect of TDF and FTC/TDF statistically similar (p=0.18)

15. Primary efficacy results TDF FTC/TDF Placebo

16. Subgroup analysis - gender Efficacy95% CIP-valueInteraction p-value TDF Women Men 68% 55% 29-85% 4-79% p=0.01 p=0.04 p=0.54 FTC/TDF Women Men 62% 83% 19-82% 49-94% p=0.01 p=0.001 p=0.24 Both TDF and FTC/TDF significantly reduced HIV risk in both men and women Women: 42 total infections: 8 TDF, 9 FTC/TDF, 25 placebo Men: 36 infections: 10 TDF, 4 FTC/TDF, 22 placebo

17. Safety No statistically significant difference in deaths, SAEs, key laboratory AEs Number of participants with each safety event TotalTDFFTC/TDFPlacebo Death24 (<1%) 879 SAE320 (7%) 108107105 Confirmed creatinine AE49 (1%) 172012 Confirmed phosphorus AE403 (9%) 138133132

18. Tolerability % of participants reporting symptom TDFFTC/TDFPlaceboP-value TDF vs. Placebo P-value FTC/TDF vs. Placebo Nausea All visits Month 1 1.6% 6.3% 1.7% 5.9% 1.5% 4.5% p=0.23 p=0.03 p=0.18 p=0.07 Diarrhea All visits Month 1 1.6% 4.1% 1.8% 4.5% 1.4% 2.8% p=0.18 p=0.06 p=0.02 Monthly 19-item symptom questionnaire

19. Sexual behavior At enrollment, 27% of couples reported unprotected sex in the past month.

20. Sexual behavior At enrollment, 27% of couples reported unprotected sex in the past month. This declined during follow-up and was similar across the study arms.

21. Sexual behavior One-third reported an outside partner during the study: 34% TDF, 33% FTC/TDF, 33% placebo At enrollment, 27% of couples reported unprotected sex in the past month. This declined during follow-up and was similar across the study arms.

22. Ongoing testing Testing ongoing for the following, not yet available: HIV resistance in seroconverters HIV plasma viral load in seroconverters Plasma / intracellular drug levels in seroconverters and subset of non-seroconverters

23. Summary TDF and FTC/TDF PrEP definitively reduced risk of HIV acquisition, by 62% & 73%, respectively, in African men and women Similar efficacy between TDF & FTC/TDF HIV protection effect was robust in both women and men Study announcing findings 1.5 years earlier than expected TDF and FTC/TDF PrEP were safe & well- tolerated Mild gastrointestinal side effects, predominantly in Month 1 No evidence of risk compensation

24. Next steps Partners PrEP Study is continuing: DSMB strongly recommended blinded continuation of the active PrEP arms, to continue to gather comparative information on the efficacy, safety, tolerability and resistance with TDF vs. FTC/TDF PrEP Placebo arm participants currently stopping study medication. Thereafter, placebo arm will be offered active PrEP at the research clinics. Demonstration projects for PrEP are needed, including as part of evaluations of evidence-based combination HIV prevention

25. Partners PrEP Study Team University of Washington Coordinating Center Connie Celum (PI), Jared Baeten (Co-Chair and Medical Director), Deborah Donnell (Statistician), Justin Brantley, Tami Cloutier, Robert Coombs, Amy Dao, Shauna Durbin, Mira Emmanuel-Ogier, Lisa Frenkel, Carlos Flores, Harald Haugen, Renee Heffron, Ting Hong, Jim Hughes, Erin Kahle, Johanna Karas, Becky Karschney, Lara Kidoguchi, Meighan Krows, Matt Leidholm, Jai Lingappa, Toni Maddox, Angela McKay, Julie McElrath, Allison Mobley, Susan Morrison, Nelly Mugo, Andrew Mujugira, Vikram Nayani, Patrick Ndase, Apollo Odika, Hilda O’Hara, Dana Panteleeff, Jennifer Revall, Marothodi Semenya, John Sparkman, Kathy Thomas, Ellen Wilcox Sites –Eldoret, Kenya (Moi U, Indiana U): Edwin Were (PI), Ken Fife (PI), Cosmas Apaka –Jinja, Uganda (Makarere U, UW); Patrick Ndase (PI), Elly Katabira (PI), Fridah Gabona –Kabwohe, Uganda (KCRC): Elioda Tumwesigye (PI), Rogers Twesigye –Kampala, Uganda (Makarere U): Elly Katabira (PI), Allan Ronald (PI), Edith Nakku-Joloba –Kisumu, Kenya (KEMRI, UCSF): Elizabeth Bukusi (PI), Craig Cohen (PI), Josephine Odoyo –Mbale, Uganda (TASO, CDC): Jonathan Wangisi (PI), Jim Campbell (PI), Jordan Tappero (PI), Akasiima Mucunguzi –Nairobi, Kenya (KNH/U Nairobi, UW): James Kiarie (PI), Carey Farquhar (PI), Grace John-Stewart (PI), Harrison Tamooh, Freda Kinoti –Thika, Kenya (KNH/U Nairobi, UW): Nelly Mugo (PI), Kenneth Ngure –Tororo, Uganda (CDC, TASO): Jim Campbell (PI), Jonathan Wangisi (PI), Jordan Tappero (PI), Aloysious Kakia DF/Net (data center) : Lisa Ondrejcek, Darryl Pahl, Jae Chong CLS (laboratory oversight) : Wendy Stevens, Charlotte Ingram, Ute Jentsch, Mukthar Kader, Nombulelo Gqomane, Feroza Bulbulia, Jan van den Heuvel ClinPhone/Perceptive Informatics (randomization) Gilead (study drug) : Jim Rooney, Raj Sangha, Abboud Habr, Farideh Said Bill & Melinda Gates Foundation (study funder) : Stephen Becker HIV serodiscordant couples who test, screen, & participate

26. Partners PrEP Study Team