Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention in Women

Abstract

Background: Antiretroviral medications that are used as prophylaxis can prevent acquisition of human immunodeficiency virus type 1 (HIV-1) infection. However, in clinical trials among African women, the incidence of HIV-1 infection was not reduced, probably because of low adherence. Longer-acting methods of drug delivery, such as vaginal rings, may simplify use of antiretroviral medications and provide HIV-1 protection.

Methods: We conducted a phase 3, randomized, double-blind, placebo-controlled trial of a monthly vaginal ring containing dapivirine, a non-nucleoside HIV-1 reverse-transcriptase inhibitor, involving women between the ages of 18 and 45 years in Malawi, South Africa, Uganda, and Zimbabwe.

Results: Among the 2629 women who were enrolled, 168 HIV-1 infections occurred: 71 in the dapivirine group and 97 in the placebo group (incidence, 3.3 and 4.5 per 100 person-years, respectively). The incidence of HIV-1 infection in the dapivirine group was lower by 27% (95% confidence interval [CI], 1 to 46; P=0.046) than that in the placebo group. In an analysis that excluded data from two sites that had reduced rates of retention and adherence, the incidence of HIV-1 infection in the dapivirine group was lower by 37% (95% CI, 12 to 56; P=0.007) than that in the placebo group. In a post hoc analysis, higher rates of HIV-1 protection were observed among women over the age of 21 years (56%; 95% CI, 31 to 71; P<0.001) but not among those 21 years of age or younger (-27%; 95% CI, -133 to 31; P=0.45), a difference that was correlated with reduced adherence. The rates of adverse medical events and antiretroviral resistance among women who acquired HIV-1 infection were similar in the two groups.

Conclusions: A monthly vaginal ring containing dapivirine reduced the risk of HIV-1 infection among African women, with increased efficacy in subgroups with evidence of increased adherence. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01617096 .).

Figure 1. Enrollment and Outcomes

Of the 5516 women who underwent screening, 2629 were enrolled, 2884 were not eligible, and 3 were eligible but did not enroll. The most common reason for ineligibility was seropositivity for HIV-1. Participants were enrolled at 15 study sites: 9 in South Africa, 3 in Zimbabwe, 2 in Malawi, and 1 in Uganda. Of the 2629 women who enrolled, 1426 (54%) were from South Africa, 678 (26%) from Zimbabwe, 272 (10%) from Malawi, and 253 (10%) from Uganda. The per-site enrollment numbers are provided inTable S1 in the Supplementary Appendix. Trial retention was defined as the provision of an HIV-1 test result, and women who withdrew early from the study were counted as having missed visits thereafter. Participants attended 91% of scheduled study visits (97% after accounting for early withdrawals from the study). Interruptions in the use of the study rings owing to pregnancy and breast-feeding accounted for 2% of study follow-up time, and protocol-required, safety-related temporary interruptions of product use accounted for less than 1%.

Figure 2. Cumulative Incidence of HIV-1 Infection in Two Analyses

Shown is the cumulative probability of HIV-1 acquisition, as estimated by means of Kaplan–Meier methods, in analyses performed in two populations. Panel A shows the results for the overall 15-site analysis, in which the HIV-1 incidence was 3.3 per 100 person-years (95% confidence interval [CI], 2.6 to 4.2) in the dapivirine group and 4.5 per 100 person-years (95% CI, 3.7 to 5.5) in the placebo group. Panel B shows the results after the exclusion of data from 2 sites because of lower-than-expected protocol and product adherence, in which the HIV-1 incidence was 2.8 per 100 person-years (95% CI, 2.1 to 3.6) in the dapivirine group and 4.4 per 100 person-years (95% CI, 3.5 to 5.5) in the placebo group. Insets show the same data on an enlarged y axis. Excluded from the analyses were data for 3 participants in the placebo group who had HIV-1 infection before enrollment and for 3 participants (1 in the dapivirine group and 2 in the placebo group) who became infected after the product-use period.

Figure 3. Cumulative Incidence of HIV-1 Infection, According to Age Group and Method of Dapivirine Detection

Panel A shows that the efficacy of HIV-1 protection in the dapivirine group was −27% (95% CI, −133 to 31) for those 18 to 21 years of age, 56% (95% CI, 19 to 76) for those 22 to 26 years of age, and 51% (95% CI, 8 to 74) for those 27 to 45 years of age, as compared with placebo. The combined efficacy of HIV-1 prevention for participants over the age of 21 years was 56% (95% CI, 31 to 71; P<0.001). Panel B shows the percentage of plasma samples with a dapivirine value of 95 pg per milliliter (the adherence cutoff), the percentage of used rings with a residual dapivirine level of less than 23.5 mg (also the adherence cutoff), and a composite of dapivirine levels in plasma and residual rings. In the plasma-and-ring analysis, adherence levels were higher by a factor of 1.6 (P = 0.07) among women 22 to 26 years of age and by a factor of 4.1 (P<0.001) among women 27 to 45 years of age than among women 18 to 21 years of age, as calculated by means of a generalized linear mixed-effects model with random intercepts and slopes and logit link after the exclusion of data from the first quarter because of small numbers. Returned rings were not available for the first calendar year of the trial, so the curves do not include all participants at all time points.