Pre-Exposure Prophylaxis (PrEP) 1 Prevention of HIV in At-Risk Women:

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1 Pre-Exposure Prophylaxis (PrEP) 1 Prevention of HIV in At-Risk Women: Coming of Age Aaron Kofman, BA, MD 14 Eli Y. Adashi, MD, MS, CPE, FACOG BRIGHT Series June 12, 2012

2 Women and the HIV Epidemic Global Indicators 2010

3 Global Indicator 1 Datum 2 New HIV Infections a Year 1,100,000 (41% of Total) Annual HIV-related Deaths 730,000 (41% of Total) HIV(+) Women Receiving ARVs (% in Need) 53% 1 LMICs 2 WHO/UNAIDS/UNICEF: GLOBAL HIV/AIDS RESPONSE, 2011

4 Global Indicator 1 Datum 2 Women Living with HIV 17,000,000 Women Living with HIV (% of Total Global Cohort) 50% Women Living with HIV (% of Total SSA Cohort) 3 59% 1 LMICs 2 WHO/UNAIDS/UNICEF: GLOBAL HIV/AIDS RESPONSE, SSA=Sub-Saharan Africa

5 Global Indicator 1 Datum 2 Young Women Living with HIV 3 3,200,000 Young Women Living with HIV (% of Young Global Cohort) 64% Young Women Living with HIV (% of Young SSA Cohort) 4 71% 1 LMICs 2 WHO/UNAIDS/UNICEF: GLOBAL HIV/AIDS RESPONSE, Young Women=15-24 Years Old 4 SSA=Sub-Saharan Africa

6 Trends: Women & HIV New HIV infections are on the decline Dying of HIV-related causes is on the decline Living with HIV has stabilized at 50% of total ART coverage of eligible women has increased to 53%

7 PrEP in Women Addressing Unique Challenges

8 Inability to negotiate safe sex due to gender inequity and harmful gender norms: Abusive and violent relationships Transactional survival sex Cross-generational (age-disparate) sex Absent social or economic power Unknowns of casual relationships: Improbability of abstinence & monogamy Unreliability of condom use & male circumcision Increased risk of transmission: Twice as vulnerable as men Twice as vulnerable during pregnancy

9 PrEP in Women Going Beyond Prevention

10 Prevention Through Empowerment little attention has been given to barriers to HIV transmission that depend on the woman and are under her control including the possibility of a topical virucide that might block transmission through the vaginal route. Am J Public Health 1990;80:

11 The History of PrEP

12 Non-specific Topical Antivirals

13 Class Agent Trials (#) Outcome Surfactants Polymers Nonoxynol-9 SAVVY (C31G) Cellulose Sulfate Carraguard PRO2000 BufferGel 4 Negative 8 Negative

14 Non-specific Topical Antivirals Specific Antiretroviral Agents (Topical & Systemic)

15 Tenofovir Disoproxyl Fumarate (TDF) Emtricitabine (FTC) Dapivirine (TMC120) Maraviroc

16 The History of PrEP Early Successes

17 Trial Intervention CAPRISA 004 Peri-coital Vaginal TDF Gel Partners PrEP Daily Oral TDF or TDF/FTC Tablets TDF2 Daily Oral TDF/FTC Tablets

18 CAPRISA 004 Abdool Karim Q. et al. Science 329: , 2010

19 CAPRISA 004 Phase IIb, Two Arm, Double-Blind RPCT Completed March 2010 Variable Datum Intervention Pericoital Vaginal TDF Gel (1%) Pericoital Vaginal Placebo Gel Participants 889 HIV(-) Heterosexual Women (at high risk) Ages 18 to 40 1 Outcome HIV Seroconversion Adherence Measure Returned Used Applicators

20 CAPRISA 004 Phase IIb, Two Arm, Double-Blind RPCT Completed March 2010 Variable Datum Intervention Peri-coital Vaginal TDF Gel (1%) Peri-coital Vaginal Placebo Gel Participants 889 HIV(-) Heterosexual Women Ages 18 to 40 1 Outcome HIV Seroconversion Results Low (<50%) adherence: Intermediate (50-80%) adherence: High (>80%) adherence: 28% protection 38% protection 54% protection

21 Lessons PrEP is accomplishable (proof of concept) PrEP efficacy is adherence-dependent 39% risk reduction is not good enough

22 TDF2 Key Facts:

23 TDF2 Phase IIb, Two Armed, Double-Blind RPCT Completed July 2011 Metric Datum Intervention Daily Oral TDF/FTC Tablets Daily Oral Placebo Tablets Participants 1219 HIV (-) Heterosexual Women Ages 18 to 39 1 Outcome HIV Seroconversion

24 TDF2 Phase IIb, Two Armed, Double-Blind RPCT Completed July 2011 Metric Datum Intervention Daily Oral TDF/FTC Tablets Daily Oral Placebo Tablets Participants 1219 HIV (-) Heterosexual Women Ages 18 to 39 1 Outcome HIV Seroconversion Results TDF/FTC afforded 76% protection to women Adherence Overall Adherence Rate (Residual Pill Count): 84%

25 Partners PrEP Press Release:

26 Partners PrEP Phase III, Three Arm, Double-Blind RPCT Completed July 2011 Metric Datum Intervention Daily Oral TDF Tablets to HIV (-) Partner Daily Oral TDF/FTC Tablets to HIV (-) Partner Daily Placebo Tablets to HIV (-) Partner Participants 4,758 stable heterosexual HIV-discordant couples 1 Outcome Seroconversion of HIV (-) Partner

27 Partners PrEP Phase III, Three Arm, Double-Blind RPCT Completed July 2011 Metric Datum Intervention Participants Daily Oral TDF Tablets to HIV (-) Partner Daily Oral TDF/FTC Tablets to HIV (-) Partner Daily Oral Placebo Tablets to HIV (-) Partner 4,758 Stable Heterosexual HIV-discordant Couples 1 Outcome Seroconversion of HIV (-) Partner Results TDF afforded 68% protection to women partners TDF/FTC afforded 62% protection to women partners Adherence Overall Adherence Rate (Residual Pill Count): 97%

28 On the Importance of Couple Trials The sub-saharan Example 75% of adults (20 49) are in cohabiting unions 50% of cohabiting HIV (+) adults have an HIV (-) partner Women are as likely as men to be the index partner Serodiscordant couples are likely HIV status agnostic New infections are on the rise in serodiscordant couples

29 The History of PrEP Recent Failures

30 Trial Intervention FEM PrEP Daily Oral TDF/FTC Tablets VOICE Daily Oral TDF Tablets or Vaginal TDF Gel

31 FEM-PrEP Press Release:

32 FEM PrEP Phase III, Two Arm, Double-Blind RPCT Variable Datum Intervention Daily Oral TDF/FTC Tablets Daily Oral Placebo Tablets Participants 1951 HIV(-) Heterosexual Women (at high risk) Ages 18 to 35 1 Outcome HIV Seroconversion

33 FEM PrEP Phase III, Two Arm, Double-Blind RPCT Variable Datum Intervention Participants Daily Oral TDF/FTC Tablets Daily Oral Placebo Tablets 1951 HIV(-), Heterosexual, 18 to 35 Year-Old Women 1 Outcome HIV Seroconversion Results Trial halted 4/18/11 by the IDMC* for futility Adherence Overall Adherence Rate (Residual Pill Count): 95% *Independent Data Monitoring Committee

34 Why did FEM-PrEP Fail? The FEM PrEP trial failed, at least in part, due to poor product adherence. Post Hoc Analysis Only 26% of the women in the treatment arm displayed detectable serum levels of TDF at the last visit prior to seroconversion.

35 Possible Drivers of Poor Adherence Youthful perception of invincibility Duration of the study ( Study Fatigue ) Failure to refill drug supplies (i.e. skipped visits) Lingering stigma of HIV Presumed assignment to the placebo arm Pill sharing between trial participants

36 VOICE* Projected Results: Late 2012 *VOICE=Vaginal and Oral Interventions to Control the Epidemic

37 VOICE Phase IIb, Five Arm, Double-Blind RPCT Variable Datum Intervention Daily Oral TDF Tablets Daily Oral TDF/FTC Tablets Daily Vaginal TDF Gel Daily Placebo Tablets or Placebo Vaginal Gel Participants 5029 HIV(-) Heterosexual Women Ages 18 to 45 1 Outcome HIV Seroconversion Results Oral TDF arm halted by the DSMB* on 9/16/11 for futility Vaginal TDF arm halted by the DSMB* on 11/17/11 for futility Post hoc analysis is pending Oral TDF/FTC arm is ongoing *Data and Safety Monitoring Board

38 Going Forward Current and Upcoming Phase III PrEP Trials Results are Expected in 2014

39 Trial Intervention FACTS 001 Peri-coital TDF Vaginal Gel ASPIRE Long-Acting Dapivirine-Releasing Vaginal Ring IPM 027 Long-Acting Dapivirine-Releasing Vaginal Ring

40 Regulatory Approval

41 FDA Advisory Committee: May 10, 2012 Truvada tablets be approved for PrEP in: Men having sex with men HIV (-) negative partners in serodiscordant couples Others at risk due to sexual activity Tenofovir vaginal gel or oral tablets are not candidates for approval as PrEP at this time

42 Final Thoughts The promise of PrEP for the 1 prevention of HIV in at-risk women is still best viewed as work in progress Regulatory approval is likely to be granted to Truvada tablets as PrEP in serodiscordant couples and in women deemed to be at high risk. Regulatory approval of the Tenofovir Vaginal gel as PrEP is contingent on the outcome of FACTS 001 and thus is not anticipated until 2015 at the earliest.

43 Final Thoughts Stable serodiscordant couples may be better served by treatment of the HIV (+) partner (96% protection) than by PrEP of the HIV (-) partner (73% protection) PrEP effectiveness may be well served by: Favoring multi-agent paradigms capable of targeting several especially earlier phases of the HIV life cycle Focusing on user-independent PrEP strategies i.e. vaginal rings, injectables, implantables, and transdermal patches

44 Conclusions The effectiveness of longacting reversible contraception (IUD or Implants) is superior to that of contraceptive pills, patch, or ring. New Engl J Med 366: , 2012

45 Residual All Important Matters Impact of PrEP on disease burden Optimal population target (s) Implementational costs Implementational Logistics Cost-effectiveness Prioritization by donors/payers Risk Compensation Resistance development Drug safety

46 The End