Impact of Male Partner Involvement on Women's Adherence to the Dapivirine Vaginal Ring During a Phase III HIV Prevention Trial.

Although vaginal microbicides for HIV prevention are designed to be female-initiated, male partner influence has been identified as one of the most significant factors impacting women's willingness and ability to use them. As a result, research teams have sought to increase male partner involvement by encouraging disclosure of product use to male partners, promoting male partner engagement in the study through attendance at the study clinic, and helping women to garner male partner support for product use. This paper aims to assess the impact of these three elements of male partner involvement on women's adherence to the dapivirine vaginal ring during MTN-020/ASPIRE, a phase III randomized placebo-controlled clinical trial involving 2629 women in Malawi, South Africa, Uganda, and Zimbabwe. During the study, 64-80% of participants reported disclosure of ring use at each quarterly visit, and 13% reported that their partners had attended the study clinic at some point during the study. At study exit, 66% reported that their partner was supportive, 18% unsupportive, and 17% were unsure. After adjusting for age, site and time in study, women were more likely to have low ring adherence if they had an unsupportive male partner (aRR 1.29, 95% CI 1.03-1.62). Neither disclosure nor clinic attendance directly predicted ring adherence, but disclosure increased the probability of having a supportive partner (aRRR 24.17, 95% CI 16.38-35.66) or an unsupportive partner (aRRR 4.10, 95% CI 2.70-6.24), relative to an unknown level of partner support. Women were also more likely to have a supportive partner if their partner had attended the clinic (aRRR 3.77, 95% CI 1.36-10.42). This study suggests that although the vaginal ring is relatively discreet, lack of support from male partners remains a relevant barrier to use. Though both disclosure and clinic attendance may increase partner support, disclosure may also increase partner opposition. Interventions to reduce male partner opposition are needed to maximize the potential impact of the ring and other PrEP products for HIV prevention.

Greater dapivirine release from the dapivirine vaginal ring is correlated with lower risk of HIV-1 acquisition: a secondary analysis from a randomized, placebo-controlled trial.

INTRODUCTION: A vaginal ring containing 25 mg of the antiretroviral dapivirine has demonstrated efficacy in reducing women's risk of sexually acquiring HIV-1; however, imperfect ring use likely diluted efficacy estimates in clinical trials. The amount of dapivirine remaining in returned rings may reflect the extent of product use, permitting estimation of HIV protection in the context of consistent use. METHODS: We measured the amount of dapivirine in returned rings from a placebo-controlled trial of the dapivirine vaginal ring conducted between August 2012 and June 2015 among 2629 African women. Phase I/II studies established that greater than 4 mg of dapivirine on average is released from the ring when used consistently over 28 days and ≤0.9 mg released suggested non-use. We assessed the relative risk reduction associated with levels of ring use using residual dapivirine in returned rings as a time-dependent covariate for HIV-1 infection in multivariable Cox models, including multiple exploratory analyses designed to estimate upper limits of efficacy given uncertainty in timing of HIV-1 acquisition. All models were adjusted for baseline covariates associated with HIV risk and adherence. RESULTS: Residual dapivirine levels indicating at least some use (>0.9 mg released over a month) were associated with a 48% relative reduction in HIV-1 acquisition risk (95% confidence interval (CI): 21% to 66%; p = 0.002) compared to the placebo. Exploratory analyses accounting for potential misclassification in timing of HIV-1 acquisition estimated 75% to 91% HIV-1 risk reduction with> 4 mg released when compared to placebo. Results limited to the subgroup of women <25 years of age, who tended to have lower adherence, were generally consistent to those overall. CONCLUSIONS: Residual dapivirine levels, an objective measure of adherence, were correlated with HIV-1 protection in a secondary analysis of a randomized trial. Periods of ring use were associated with approximately 50% protection, with exploratory analyses suggesting higher protection with more consistent use. The dapivirine vaginal ring is the first method to fulfil the promise of a fully reversible, long-acting, woman-initiated approach for discreet HIV-1 prevention.

Tenofovir 1% vaginal gel for prevention of HIV-1 infection in women in South Africa (FACTS-001): a phase 3, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Young women in southern Africa have substantial risk of HIV acquisition. Female-controlled biomedical interventions are needed to mitigate this risk. We aimed to assess the safety and efficacy of a pericoitally applied tenofovir 1% gel. METHODS: We did a phase 3, double-blind, randomised, placebo-controlled trial at nine community-based clinical trial sites in South Africa to evaluate the safety and efficacy of tenofovir 1% gel. Sexually active women who were HIV negative and aged 18-30 years were enrolled. Participants were randomly assigned (1:1) using sequential participant numbers to either tenofovir 1% gel or a placebo gel (one dose within 12 h before sex and one dose within 12 h after sex [BAT-24 regimen]), using dynamic permuted block sizes of 8 and 16 within each site. Women received monthly HIV-1 testing, risk reduction support, physical examinations, and product dispensing for up to 27 months. The primary efficacy outcome was incident HIV infection and the primary safety outcome was occurrence of grade 2-4 adverse events, both analysed in the modified intention-to-treat population. To assess the efficacy of tenofovir gel, the cumulative probability of HIV infection was calculated for each treatment using the Kaplan-Meier method. This trial is registered with ClinicalTrials.gov, number NCT01386294. FINDINGS: From Oct 11, 2011, to Aug 29, 2014, 3844 women were screened, 2059 enrolled, and 2029 included in the primary analysis (1032 in the tenofovir group and 1027 in the placebo group); 39 (4%) in the tenofovir group and 36 (4%) in the placebo group were lost to follow-up. 123 HIV-1 infections occurred over 3036 woman-years of observation; 61 in the tenofovir group (HIV incidence 4·0 per 100 woman-years, 95% CI 3·1-5·2) and 62 in the placebo group (4·0 per 100 woman-years, 3·1-5·2; incidence rate ratio [IRR] 0·98, 95% CI 0·7-1·4). A higher incidence of grade 2 adverse events was observed in the tenofovir group than in the placebo group (IRR 1·09, 95% CI 1·0-1·2; p=0·02). The most common grade 2 or higher product-related adverse events were hypophosphataemia (n=22 for tenofovir vs n=22 for placebo), genital symptoms (n=6 for tenofovir vs n=2 for placebo), or elevated transaminases (n=2 for tenofovir vs n=2 for placebo). No product-related serious adverse events were reported, and no differences in product-related adverse events (p=0·78), grade 3 events (p=0·64), or grade 4 events (p=0·74) were observed between treatment groups. INTERPRETATION: Overall, pericoital tenofovir gel did not prevent HIV-1 acquisition in this population of young women at risk of HIV infection in South Africa. Alternate safe and effective products that are less user dependent than this product or do not require high adherence are needed. FUNDING: The US Agency for International Development (USAID), the Bill & Melinda Gates Foundation, and the South African Department of Science and Technology and Department of Health.