Tenofovir vaginal gel fails to protect women from HIV in phase 3 placebo trial

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CROI 2015, February 23-26, 2015, Seattle, Washington

Mark Mascolini

FACTS 001, a double-blind placebo-controlled phase 3 trial, found that tenofovir 1% vaginal gel did not protect South African women who used it before and after sex from acquiring HIV infection [1]. As in the VOICE trial [2], poor adherence appeared to contribute to tenofovir gel’s failure in the 2000-woman FACTS study. So far only a 900-woman phase 2b study, CAPRISA 004 [3], found that tenofovir gel protects women from HIV. FACTS findings proved particularly disappointing because the trial went to some length to encourage good adherence to gel use.

FACTS 001 enrolled 18- to 30-year-old HIV-negative sexually active women willing to use effective contraception and condoms. Researchers randomized over 2000 women to tenofovir 1% gel or to placebo and instructed women to apply the gel 12 hours before and within 12 hours after sex, the same schedule used in CAPRISA 004. All women received intensive ongoing counseling on gel adherence and HIV risk reduction. Study participants made monthly visits for HIV testing, safety checks, and new gel. A case-cohort substudy of 214 women assessed tenofovir levels in cervicovaginal fluid collected monthly.

The FACTS efficacy analysis involved 1015 women randomized to tenofovir and 1014 randomized to placebo More than 90% of women attended study visits. Median age of the study group stood at 23, collectively younger than women in VOICE or CAPRISA 004. Almost 90% of women were single, and almost two thirds were living with parents or siblings, so they probably were not having sex at home, where applying gel before and after sex would be more convenient.

In both study arms 56% of women had secondary or higher education. Only one third of women reported consistent condom use, and only 1% reported anal sex. Few study participants–18% in the tenofovir arm and 17% in the placebo arm–said they perceived greater than usual HIV risk in the past 28 days. Women had a median of 1 sex partner in the past 28 days.

After more than 1500 person-years of follow-up, the investigators counted 61 HIV infections in the tenofovir group and 62 in the placebo group. HIV incidence was precisely the same in both study arms–4.0 per 100 person-years (95% confidence interval [CI] 3.1 to 5.2). As a result the incidence rate ratio comparing the tenofovir group with the placebo group sat squarely at 1.0 (95% CI 0.7 to 1.4).

In the case-cohort analysis of 1075 samples from 214 women, tenofovir could be detected in 64% of cervicovaginal samples. Two thirds of women had detectable tenofovir at some quarterly visit, 22% had detectable drug at all quarterly visits, and 13% never had detectable tenofovir.

In an analysis adjusted for age, HSV-2 status, living with parents, and baseline factors related to HIV incidence, women who had detectable tenofovir in cervicovaginal samples and reporting sex in the past 10 days had lower HIV incidence that women using placebo (adjusted hazard ratio 0.48, 95% CI 0.23 to 0.97). That result indicated 52% protection with tenofovir (P = 0.04).

Considering all adherence data, the FACTS 001 team calculated that women used gel for an average of 50% to 60% of sex acts. The investigators concluded that “the majority of participants were not able to achieve sufficiently high levels of gel coverage required for protection.” They stressed the “urgent need for a range of HIV prevention options for young women which may be easier to integrate into their lives.”

References
1. Rees H, Delany-Moretlwe SA, Lombard C, et al. FACTS 001 phase III trial of pericoital tenofovir 1% gel for HIV prevention in women. CROI 2015. February 23-26, 2015. Seattle, Washington. Abstract 26LB.
2. Marrazzo JM, Ramjee G, Richardson BA, et al. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2015;372:509-518. http://www.nejm.org/doi/full/10.1056/NEJMoa1402269
3. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 2010;329:1168-1174. http://www.sciencemag.org/content/329/5996/1168.long

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