1. Looking back, looking forward: what we know and don’t know about oral PrEP and tenofovir gel for preventing HIV in women Jared Baeten MD PhD Departments of Global Health and Medicine University of Washington Satellite: CHOICE MATTERS: expanding the method mix of ARV-based prevention for women in 2012 and beyond

2. Starting point… IDU MSM Serodiscordant Couples High-risk Women Image: AVAC Multiple clinical trials (eight) in key populations, evaluating oral TDF, oral FTC/TDF, and TFV vaginal gel. Together, providing a comprehensive and coordinated picture of PrEP for HIV prevention.

3. Oral and topical tenofovir trials: 2012 StudyPopulationNPrEP agent CAPRISA 004 South Africa Women889TFV gel iPrEx Brazil, Ecuador, Peru, South Africa, Thailand, US MSM2499Oral FTC/TDF Partners PrEP Study Kenya, Uganda Heterosexual couples 4758 Oral TDF, Oral FTC/TDF TDF2 Study Botswana Heterosexual men and women 1219Oral FTC/TDF FEM-PrEP Kenya, S Africa, Tanzania Women1950Oral FTC/TDF VOICE South Africa, Uganda, Zimbabwe Women5029 Oral TDF, Oral FTC/TDF, TFV gel Bangkok Tenofovir Study Thailand IDUs2400Oral TDF FACTS 001 South Africa Women2200TFV gel

4. Outline What we know What we’ve learned from clinical trials of oral and topical tenofovir for HIV prevention in women What we don’t (yet) know What can we answer in the short- and medium-term What awaits us What are the next steps in the field

5. What we know

6. Oral and topical tenofovir work for preventing HIV acquisition

7. Efficacy in PrEP trials StudyPopulationNResults CAPRISA 004 South Africa Women88939% efficacy vaginal TFV gel iPrEx Brazil, Ecuador, Peru, South Africa, Thailand, US MSM249944% efficacy FTC/TDF TDF2 Study Botswana Young men and women 120062% efficacy FTC/TDF Partners PrEP Study Kenya, Uganda Heterosexual couples 4758 67% efficacy TDF 75% efficacy FTC/TDF

8. FDA review of Truvada® PrEP for HIV prevention Deborah Birnkrant, director of the Division of Antiviral Products, US FDA, 16 July 2012

9. What we know Oral and topical tenofovir work for preventing HIV acquisition Adherence to oral/topical PrEP is key to HIV protection

10. CAPRISA 004: Adherence  Efficacy High (>80% gel adherence) n=336 (38%) 54% effective Intermediate (50-80% adherence) n=181 (20%) 38% effective Low (<50% gel adherence) n=367 (42%) 28% effective Abdool Karim et al, Science 2010

11. Adherence and HIV protection in oral PrEP trials % of blood samples with tenofovir detected HIV protection efficacy in randomized comparison Partners PrEP FTC/TDF arm 81%75% TDF279%62% iPrEx51%44% FEM-PrEP26%6% There is a clear dose-response between evidence of PrEP use & efficacy Baeten et al N Engl J Med 2012 Grant et al N Engl J Med 2010 Van Damme et al N Engl J Med 2012 Thigpen et al N Engl J Med 2012

12. Tenofovir levels and HIV protection And when PrEP was taken (=detected in blood), protection was very high % of non- seroconverters with tenofovir detected in blood HIV-1 relative risk reduction: detection versus no detection of tenofovir Protectionp-value iPrEx51%92%<0.001 Partners PrEP FTC/TDF arm 81%90%0.002 Baeten et al N Engl J Med 2012 Grant et al N Engl J Med 2010

13. What we know Oral and topical tenofovir work for preventing HIV acquisition Adherence to oral/topical PrEP is key to HIV protection PrEP is not for everyone

14. CAPRISA 004 adherence High (>80% gel adherence) n=336 (38%) 54% effective Intermediate (50-80% adherence) n=181 (20%) 38% effective Low (<50% gel adherence) n=367 (42%) 28% effective Abdool Karim et al, Science 2010

15. Tenofovir levels in trials In the clinical trials, not everyone took PrEP % of non- seroconverters with tenofovir detected in blood HIV-1 relative risk reduction: detection versus no detection of tenofovir Protectionp-value iPrEx51%92%<0.001 Partners PrEP FTC/TDF arm 81%90%0.002 Baeten et al N Engl J Med 2012 Grant et al N Engl J Med 2010

16. Sustained use (and non-use) of PrEP: Partners PrEP Study At Month 1, ~80% had tenofovir detected Donnell et al CROI 2012

17. Sustained use (and non-use) of PrEP : Partners PrEP Study Those who had no tenofovir at Month 1 tended to have no tenofovir throughout Donnell et al CROI 2012

18. Sustained use (and non-use) of PrEP : Partners PrEP Study Exception: pregnancies Those who had tenofovir at Month 1 tended to have tenofovir throughout Donnell et al CROI 2012

19. What we don’t know (yet)

20. What motivates PrEP adherence (and how to motivate when not present)

21. What motivates PrEP use? Risk perception is a potentially powerful driver of adherence FEM-PrEP = young women 70% perceived themselves to be at little or no HIV risk, very low adherence Understanding interface of risk perception & HIV prevention is key for any strategy

22. What we don’t know (yet) What motivates PrEP adherence (and how to motivate when not present) The potential interface of biology, adherence, and effectiveness

23. PrEP efficacy trial results in women StudyTFV gelTDFFTC/TDF CAPRISA 004 South Africa 39% efficacy TDF2 Study Botswana 49% efficacy / 75% as-treated Partners PrEP Study Kenya, Uganda 71% efficacy66% efficacy FEM-PrEP Kenya, S Africa, Tanzania 6% efficacy VOICE South Africa, Uganda, Zimbabwe Futility Ongoing FACTS 001 South Africa Ongoing

24. Pharmacokinetics and PrEP adherence PK studies offered one possible mechanism for lower HIV protection in women: oral tenofovir results in >10x higher concentrations in rectal tissue than cervical and vaginal tissue. Patterson et al. Sci Transl Med 2012 Tissue tenofovir concentrations at 24 hours after a single dose of oral FTC/TDF

25. Divergent PrEP trials: adherence + biology Adherence PrEP Efficacy Biology marginal vaginal concentrations, inflammation, acute HIV in partner, etc. could make PrEP more sensitive to imperfect adherence, particularly in women, which could have influenced some PrEP trial results

26. Tenofovir gel – does dosing matter? Two trials of tenofovir gel have conflicting results. Is there a benefit/toxicity balance to strike here, with daily use (VOICE) being “too much” and coital use (CAPRISA 004) favoring HIV-1 protection over toxicity? StudyCAPRISA 004VOICE Sample size889~2000 Number of HIV events 98Estimate ~90 Efficacy (95% CI) 39% (6-60%) ~0% Intervention Gel with coitus Daily gel

27. What we don’t know (yet) What motivates PrEP adherence (and how to motivate when not present) The potential interface of biology, adherence, and effectiveness Intermittent use

28. Adherence and perfection Imperfect, but still regular adherence, might still provide substantial HIV protection, although PrEP is still as a daily medication Estimated HIV risk reduction (95% CI) 2 doses/week 76% (56-96%) 4 doses/week 96% (90->99%) 7 doses/week 99% (96->99%) Anderson et al. CROI 2012

29. What awaits us

30. Trial completion and analysis

31. Ongoing trials: 2012 StudyPopulationOngoing Partners PrEP Study Kenya, Uganda Heterosexual couples Oral TDF vs. Oral FTC/TDF VOICE South Africa, Uganda, Zimbabwe Women Oral FTC/TDF vs. placebo Bangkok Tenofovir Study Thailand IDUs Oral TDF vs. placebo FACTS 001 South Africa Women TFV gel vs. placebo

32. What awaits us Trial completion and analysis Implementation science, demonstration projects

33. PrEP demonstration questions, 2012 TopicQuestion Targeting Who to prioritize for PrEP? How to deliver? Uptake Do those who might benefit most from PrEP want it? Adherence Who takes PrEP? Do they take it often enough? Sexual behaviorPrEP use as relates to behavior? ImpactHIV incidence? Resistance? Costs?

34. What awaits us Trial completion and analysis Implementation science, demonstration projects More options, opportunities for choice

35. GelVaginal ring Tenofovir is the first-generation prevention agent Vaginal filmInjectablePill Landmark health research is a process of continued development.

36. Thank you