1. ADAORA A. ADIMORA, MD, MPH PROFESSOR, SCHOOL OF MEDICINE UNIVERSITY OF NORTH CAROLINA- CHAPEL HILL NEW DEVELOPMENTS IN HIV PREVENTION RESEARCH: WHAT DO THEY MEAN FOR BLACK WOMEN IN THE US?

2. WHAT DO YOU RECOMMEND? In addition to condoms, what preventive measures would you recommend for the following sexually active HIV- Black women? 19 yo living in KwaZulu Natal, S Africa has a boyfriend who has other female partners 33 yo is married to an HIV+ man who takes ART only intermittently; his viral load typically exceeds 2,000 copies/ml. 18 yo college student in Wash, DC 27 yo uses crack regularly and exchanges sex to support herself.

3. HIV incidence among U.S. Black women PrEP data Treatment as prevention: how are we doing Cash transfer for prevention of HIV infection OUTLINE

4. MARKED RACIAL DISPARITIES IN HIV INFECTION AMONG US WOMEN CDC estimates HIV incidence among US Black women of 0.0397% – 0.0508% between 2006 and 2009 Prejean J. PLosOne 2011;e17502 What is incidence among Black women at very high risk?

5. HPTN 064 (ISIS): OBJECTIVES Accurately estimate new HIV incidence in a group of women at risk for HIV in the US Evaluate new lab methods for identification of new HIV infections Describe factors in participants lives that impacted HIV risks For example, partner risks, alcohol/drug use, financial factors, condom use

6. ISIS INCLUSION CRITERIA Self identifies as a woman ages 18-44 years Residence in area with relatively high rates of HIV prevalence and poverty Unprotected sex with a man during the previous 6 months AND at least one additional risk factor

7. ISIS INCLUSION CRITERIA CONT. At least ONE of the following: INDVIDUAL RISKS Illicit drug use (injecting and non-injecting) ETOH dependence and/or binge drinking Incarceration – within past 5 years STI (GC, Chlamydia, Trichomonis, Syphilis) Exchange of sex for commodities PARTNER RISKS Illicit drug use (injecting and non-injecting) ETOH and/or dependence or binge drinking Incarceration – within past 5 years STIs HIV diagnosis

8. STUDY SITES Decatur and Atlanta, GA Durham and Raleigh, NC Washington, DC Bronx and Harlem, NY North and South Newark, NJ Baltimore, MD 10 distinct communities within 6 geographic locations Qualitative data collected in four communities

9. HIGH HIV INCIDENCE AND HIGH MORTALITY RATE OBSERVED Age-adjusted annual mortality rate for ISIS cohort 0.61%/year Expected mortality rate for similar aged cohort is 0.11%/year 1 Incidence of 0.24% (95%CI 0.09 to 0.65) is more than 5 times the age-adjusted CDC national estimates for Black women 1. Murphy S, et al. Deaths: Preliminary Data for 2010 National Vital Statistics Reports. Hyattsville, MD: National Center for Health Statistics; 2012.

10. FDA APPROVES TRUVADA FOR PrEP FDA approved Truvada for preventing HIV infection among individuals at high risk of HIV infection and who may engage in sexual activity with HIV- infected partners.(July 16, 2012) During approval process some panel members expressed concern that not enough safety or efficacy data was available for African American women. (May 10, 2012)

11. STUDYPOPULATIONAGENTEFFICACYADHERENCE CAPRISA 004 889 high-risk South African women BAT24 TDF gel BAT 24 placebo 39% (54% in those > 80% adherent) ~38% reported >80% adherence Partners in PrEP 4747 serodiscordant couples (~1788 HIV neg women) – Kenya, Uganda Daily oral TDF Daily oral Truvada Daily oral placebo 67% TDF, 75% Truvada (Women: 71% TDF; 66% Truvada) Estimated ~ 97% dispensed doses taken TDF2 1200 Heterosexual men (n =656 ) and women (n =544 ) - Botswana Daily oral Truvada62% overallReported 80% Adapted from Caroline Mitchell, MD

12. StudyPopulationAgentEfficacyAdherence FemPrEP 1951 young Kenya, S Africa, Tanzania women Daily oral Truvada Stopped for futility Reported > 90%; < 50% by drug levels VOICE 5000 women (1000 each arm) – Uganda, S Africa, Zimbabwe Daily oral Truvada, Tenofovir or placebo Daily vaginal TDF gel or placebo TDF gel and oral Tenofovir arms stopped for futility Not yet reported Adapted from Caroline Mitchell, MD

13. SIGNIFICANT CHANGES IN BONE MINERAL DENSITY HAVE BEEN NOTED AMONG TENOFOVIR RECIPIENTS Decline in bone mineral density (BMD) TDF2: No fx – but  t scores and z scores for BMD at forearm, hip, lumbar spine among TDF-FTC recipients (p=0.004). (Thigpen MC. NEJM 2012) HIV- men enrolled in PrEP trial, 1.1% (95% CI: 0.4% - 1.9%) net  in BMD at femoral neck among TDF vs placebo (Liu AY. PLoS ONE 6(8): e23688. doi:10.1371) A5224s: Among HIV+ (85% men), BMD changes from baseline after 96 wks. ABC-3TC vs TDF-3TC: Spine = - 1.3% vs -3.3% (p=.004); hip = -2.6% vs -4.0% (p=.024). (McComsey GA. JID 2011;203:1791

14. RATES OF ADVERSE EFFECTS VARY AMONG PREP STUDIES FOR WOMEN PARTNERS PrEP : No difference in adverse effects (Baeten JM NEJM 2012) TDF2 : TDF-FTC group had higher rates of: Nausea (18.5% vs 7.1%, p =.03 Vomiting (11.3% vs 7.1%, p =.008) Dizziness (15.1% vs 11.0%, p =.03) (Thigpen MD NEJM 2012) FEM-PrEP : TDF-FTC group had higher rates of Nausea (p=.04), vomiting (0<.001) and ALT (p=.03) (Van Damme L. NEJM 2012) No evidence of increased renal toxicity in Partners PrEP or TDF2 BUT FEM-PrEP: Higher rates of drug discontinuation due to hepatic or renal abnormalities in TDF-FTC group (4.7%) than placebo (3.0%, p =.051) (Van Damme L. NEJM 2012)

15. ANTIRETROVIRAL RESISTANCE MUTATIONS OCCURRED (IN A FEW PARTICIPANTS) IN ALL 3 ORAL PrEP STUDIES PARTNERS PrEP No participants who acquired HIV after randomization developed resistance mutations Of 8 TDF, TDF-FTC participants infected at randomization who took either TDF or TDF-FTC, resistance noted in 2: 1(TDF) with K65R 1 (TDF-FTC) with M184V TDF2 1 TDF-FTC participant with unrecognized wild type acute infection at enrollment developed K65R, M184V, and A62V FEM-PrEP TDF-FTC group M184V (3), M184I (1)

16. STUDY POPULATIONS AND ADHERENCE IN PREP STUDIES VARY CAPRISA Median age = 23; 3.6-6.5% married. Urban HIV incidence rate = 15.6%, rural = 11. Adherence (based on returned applicators): mean of 72.2% (median 60.2%) of sex acts in last 30 days were covered by 2 doses of gel. PARTNERS PREP Serodiscordant couples, aged 18->45, ~97% married, living together median of 7 yrs Estimates (returned study bottles): 97% of tablets taken TDF2 Men and women, 18-39 yrs old (5-6% married), Botswana Adherence (pill counts) ~84%

17. STUDY POPULATIONS AND ADHERENCE IN PREP STUDIES VARY (2) FEM-PrEP PLACE used to recruit high risk participants 99% had primary partner; 26% had other, non-primary partner 13% exchanged sex for $ or gifts with non-primary partner in past 4 wks Perceived risk as low: 70% baseline, 75% last visit Adherence Self report: 95% “usually or always” took pills. Pill count suggested adherence Drug-levels low: Plasma TDF levels > 10 ng/ml if drug taken in preceding 48 h; target level attained in only 15%-26% of seroconverters

18. INTERMITTENT AND COITALLY DEPENDENT ORAL PREP DOSING: LOW ADHERENCE MSM (N=67) and FSW (N=5) in Kenya randomized to Daily oral TDF-FTC or placebo, or Intermittent (Mon, Fri, and within 2 h of sex) Adherence assessed via MEMS; sexual activity data collected Acceptability of PrEP high, regardless of dosing regimen - BUT Adherence 83% daily dosing 55% fixed intermittent doses 26% post-coital doses Mutua G. PLoS ONE 2012;7(4) e33103

19. EXPOSURE TO TDF, FTC, AND ACTIVE METABOLITES VARIES WIDELY IN DIFFERENT MUCOSAL TISSUES Vaginal and cervical tissue levels of TDF are low after oral dosing 24 hr after oral dose of TDF-FTC, median TDF-DP (active metabolite) concentration was 2.2 logs lower in vaginal tissue than in rectum and below detectable in cervical tissue. Patterson KB. Sci Transl Med 2011;3:112re4.

20. ORAL TDF PHARMACOKINETICS AND VAGINAL SEX: NO FORGIVENESS FOR LOW ADHERENCE Threshold concentration for protection against HIV is not yet established, but likely that > 1000 fmol/mg TDF-DP needed for gel. Vaginal gel yields 1000 fold greater TDF-DP vaginal tissue levels than oral dosing. TDF-DP concentration after oral dose: only 206 fmol/mg in rectum and 2 fmol/mg in vaginal tissue. Oral dose yields 100-fold greater concentrations of TDF-DP in rectum than vagina Abdool Karim SS. Lancet 2011;378:279

21. HPTN 052: EARLY ART REDUCES HIV TRANSMISSION AND CLINICAL PROGRESSION 96% reduction in HIV transmission among discordant couples. Virologic failure among 5% in early therapy group; >95% adherence among 79% of participants; What about “the real world” outside a clinical trial setting?

22. ONLY A SMALL PROPORTION OF HIV+ PEOPLE IN THE US HAVE UNDETECTABLE VIRAL LOADS Deficiencies in diagnosis, linkage to care, retention in care, receipt of ART, adherence. Of the 24% of PLWH who are on ART, 20% have detectable viral loads Gardner EM. CID 2011;52:795

23. RACIAL DISPARITIES IN ART RECEIPT AND OUTCOMES: CDC MEDICAL MONITORING PROJECT, US, 2008-2010 RACE/ETHNICITYPRESCRIPTION OF ART, % (95% CI) AMONG THOSE PRESCRIBED ART, MOST RECENT VIRAL LOAD < 200 COPIES/ML, % (95% CI) Black86 (83-88)70 (66-74) Hispanic89 (86-92)79 (75-82) White92 (91-94)84 (80-87) Compared to Whites, Blacks are less likely to be prescribed ART and, when ART is prescribed, less likely to have low HIV viral load. CDC. MMWR 2011;60:1618.

24. AND NOW FOR SOMETHING COMPLETELY DIFFERENT… CONDI- TIONAL CASH TRANSFER CURRENT POVERTY EDUCATION FUTURE POVERTY

25. CASH TRANSFER PROGRAM REDUCED HIV/HSV-2 PREVALENCE AMONG SCHOOLGIRLS IN MALAWI Cluster randomized trial of never-married women, aged 13-22 to receive cash payment or nothing At follow-up, among girls enrolled in school at baseline, those who received $ less likely to have: HIV (1.2% vs 3.0%; OR 0.36, 95% CI 0.14-0.91) (18 mos) HSV-2 (0.7% vs 3.0%; OR 0.24, 0.09-0.65) Older male partner (0.5% vs 2.5%; OR 0.20, 0.07–0.59)(12 mos) Sexual intercourse once per wk (3.0% vs 6.5%; OR 0.46, 0.26-0.82) No difference between intervention and control groups in adjusted estimates for pregnancy, sexual debut, condom use; HIV knowledge or education No effect of intervention on girls who had already dropped out of school at baseline Baird SJ. Lancet 2012;379:1320

26. IMPLEMENTATION OF THE AFFORDABLE CARE ACT IS ESSENTIAL TO IMPROVE HIV PREVENTION AND CARE IN THE US ~15% of the US population lacks health insurance Among those with insurance, substantial proportion is underinsured Proper implementation of the ACA could conceivably increase response in each component of HIV treatment cascade – and decrease ongoing transmission Individuals with incomes 134%-400% fed poverty eligible to purchase subsidized private insurance Expansion of preventive coverage for women’s health, including annual counseling and testing for HIV and other STIs Coverage for ART

27. SUMMARY Anti-retroviral PrEP can prevent men and women from acquiring HIV Issues with currently available drugs: TDF-FTC achieves lower concentrations in vaginal than rectal tissues and therefore seems less forgiving of low adherence for vaginal sex than anal sex – hence conflicting results of studies Early ART of infected people can prevent men and women from acquiring HIV But only a small proportion of HIV+ people in the US achieve viral suppression Adherence varies widely by context Economic interventions can reduce risk of HIV infection

28. WHAT DO WE NEED FOR THE WAY FORWARD? Understand Threshold tissue concentration of drug that is required to prevent HIV infection Drug concentration attainable at exposed site Extent of adherence needed to achieve threshold concentration Adherence, factors that affect it, and how to increase it Better biomedical products Safe, effective Products that don’t require adherence Dual contraception/HIV/STI prevention Others that allow fertility while preventing acquisition of HIV/STIs Health care coverage that permits implementation of the recent advances in HIV prevention and care Change the context of people’s lives that structures their risk for acquiring HIV in the first place

29. ACKNOWLEDGMENTS Catalina Ramirez, MPH Mike Cohen Sally Hodder

30. THANK YOU