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Use of a Vaginal Ring Containing Dapivirine for
HIV-1 Prevention in Women (ASPIRE)
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NEJM Feb 22 2016
Download the PDF here
Jared M. Baeten, M.D., Ph.D., Thesla Palanee-Phillips, Ph.D., Elizabeth R. Brown, Sc.D., Katie Schwartz, M.P.H., Lydia E. Soto-Torres, M.D., M.P.H., Vaneshree Govender, M.B., B.Ch., Nyaradzo M. Mgodi, M.B., Ch.B., Flavia Matovu Kiweewa, M.B., Ch.B., Gonasagrie Nair, M.B., Ch.B., M.P.H., Felix Mhlanga, M.B., Ch.B., Samantha Siva, M.Med.Sci., Linda-Gail Bekker, M.B., Ch.B., Ph.D., Nitesha Jeenarain, B.Pharm., Zakir Gaffoor, M.Med.Sci., Francis Martinson, M.B., Ch.B., Ph.D., Bonus Makanani, M.B., B.S., Arendevi Pather, B.Pharm., Logashvari Naidoo, M.B., Ch.B., Marla Husnik, M.S., Barbra A. Richardson, Ph.D., Urvi M. Parikh, Ph.D., John W. Mellors, M.D., Mark A. Marzinke, Ph.D., Craig W. Hendrix, M.D., Ariane van der Straten, Ph.D., M.P.H., Gita Ramjee, Ph.D., Zvavahera M. Chirenje, M.D., Clemensia Nakabiito, M.B., Ch.B., Taha E. Taha, M.B., B.S., Ph.D., Judith Jones, M.S., Ashley Mayo, M.S.P.H., Rachel Scheckter, M.P.H., Jennifer Berthiaume, M.P.H., Edward Livant, M.P.H., Cindy Jacobson, Pharm.D., Patrick Ndase, M.B., Ch.B., M.P.H., Rhonda White, B.S., Karen Patterson, M.P.H., Donna Germuga, B.S.N., Beth Galaska, M.I.D., Katherine Bunge, M.D., Devika Singh, M.D., M.P.H., Daniel W. Szydlo, M.Sc., Elizabeth T. Montgomery, Ph.D., Barbara S. Mensch, Ph.D., Kristine Torjesen, M.D., M.P.H., Cynthia I. Grossman, Ph.D., Nahida Chakhtoura, M.D., Annalene Nel, M.B., Ch.B., Ph.D., Zeda Rosenberg, Sc.D., Ian McGowan, M.D., D.Phil., and Sharon Hillier, Ph.D., for the MTN-020-ASPIRE Study Team*
http://www.nejm.org/doi/full/10.1056/NEJMoa1506110
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=0.05) 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.)
Results
Study Participants
Of 5516 women who underwent screening, 2629 were enrolled: 1313 in the dapivirine group and 1316 in the placebo group (Figure 1). The median age was 26 years (interquartile range, 22 to 31). Less than half (41%) were married, and 85% had completed some secondary schooling. Nearly all (99.5%) reported having had a primary sex partner during the 3 months before trial enrollment, and 17% reported more than one partner; 57% reported the use of a condom with the most recent sex act. Transactional sex in the previous year was reported by 6%, and anal sex during the previous 3 months by 2%. Nearly two thirds (64%) reported that their primary partner was aware that they would be using a vaginal ring in a research trial. Characteristics were similar in the two groups (Table 1).
Follow-up and Adherence
The rate of retention of participants for assessment of incident HIV-1 infection was 85% or more during follow-up (Figure 1), with 2614 participants (99.4%) completing at least one post-randomization HIV-1 test and 4280 total person-years of follow-up accrued for assessment of HIV-1 incidence. The median follow-up was 1.6 years (interquartile range, 1.1 to 2.3), and the maximum follow-up was 2.6 years; 1024 women contributed more than 2 years of follow-up. The most common reason for not dispensing the study ring was pregnancy, which occurred at an incidence of 3.9 per 100 person-years in the dapivirine group and 4.0 per 100 person-years in the placebo group (P=0.82).
In the dapivirine group, the drug was detected in 82% of plasma samples at levels of more than 95 pg per milliliter (Fig. S2 in the Supplementary Appendix). Detection increased during the first year of use and was relatively stable thereafter. In the subgroup of visits in which returned rings were available, 84% contained less than 23.5 mg of dapivirine, and dapivirine levels in plasma and in returned rings were correlated (Fig. S3 in the Supplementary Appendix). In general, for visits at which plasma dapivirine levels were less than 95 pg per milliliter, the residual dapivirine levels in used rings were similar to levels in unused dapivirine rings, whereas residual dapivirine levels in used rings were lower for visits at which plasma dapivirine levels were more than 95 pg per milliliter. However, a range of residual dapivirine levels was observed, with low levels observed for some visits with low plasma dapivirine levels and high levels observed for some visits with plasma dapivirine levels of more than 95 pg per milliliter.
Effect of Dapivirine Vaginal Ring on HIV-1 Acquisition
Across all 15 sites in the trial, a total of 168 incident HIV-1 infections occurred during the product-use period: 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=0.05) than that in the placebo group (Figure 2A). At the two sites that were excluded from the primary analysis because of lower-than-expected protocol and product adherence when the groups were still masked, 29 HIV-1 infections were reported: 17 in the dapivirine group and 12 in the placebo group. After the exclusion of the data from these sites, there were a total of 139 infections among 2395 participants: 54 in the dapivirine group and 85 in the placebo group. 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 (Figure 2B). An efficacy of HIV-1 protection of less than 25% was not ruled out in either analysis (P=0.88 for 15 sites and P=0.30 for 13 sites).
In subgroup analyses, HIV-1 protection was generally similar to that seen overall (Fig. S4 in the Supplementary Appendix). However, the efficacy of HIV-1 protection differed significantly according to age, with an efficacy of 61% (95% CI, 32 to 77; P<0.001) among women 25 years of age or older and 10% (95% CI, -41 to 43; P=0.64) among those under the age of 25 years (P=0.02 for interaction).
To better characterize the relationship between age and HIV-1 protection seen in the prespecified subgroup analysis (age <25 vs. ≥25 years), an exploratory analysis was conducted post hoc. Age-categorized subgroups with balanced statistical power were created after dividing the 2395 participants into three groups with approximately equal numbers of those with HIV-1 infection as follows: ages 18 to 21 years, 451 participants with 44 HIV-1 infections (incidence in the placebo group, 5.4 per 100 person-years; 95% CI, 3.2 to 8.4); ages 22 to 26 years, 752 participants with 51 HIV-1 infections (incidence in the placebo group, 6.1 per 100 person-years; 95% CI, 4.3 to 8.3); and ages 27 to 45 years, 1192 participants with 44 HIV-1 infections (incidence in the placebo group, 3.0 per 100 person-years; 95% CI, 2.0 to 4.4) (Figure 3A). Lack of HIV-1 protection, along with lower adherence, was seen in participants who were 18 to 21 years of age, with an efficacy of HIV-1 protection of -27% (95% CI, -133 to 31; P=0.45) (Figure 3B). For women who were older than 21 years of age, the efficacy of HIV-1 protection was 56% (95% CI, 31 to 71; P<0.001), and the rate of adherence was more than 70% overall, as defined by dapivirine detection in plasma, in returned rings, and in the composite of those two measures.
Safety
There were no significant between-group differences in the frequency of the primary safety end points (Table 2, and Table S6 in the Supplementary Appendix) or in other adverse events commonly detected in the trial population (Fig. S5 in the Supplementary Appendix). Incident sexually transmitted infections occurred at a similar rate in the two groups (Table S7 in the Supplementary Appendix). Finally, among participants who acquired HIV-1 infection, there was no significant between-group difference in the numbers of participants with non-nucleoside reverse-transcriptase inhibitor mutations suggesting antiviral resistance (8 of 68 participants [12%] in the dapivirine group and 10 of 96 [10%] in the placebo group, P=0.80) (Table S8 in the Supplementary Appendix).
Discussion
In this multicountry trial, a vaginal ring containing 25 mg of dapivirine that was renewed every month showed evidence of HIV-1 protection, demonstrating the efficacy of a sustained-release approach to delivering antiretroviral prophylaxis. As seen in other studies of HIV-1 prophylaxis,5,7 the protective effect of the dapivirine vaginal ring, as compared with placebo, was significant but not as high as hypothesized in the design of the trial. Greater HIV-1 protection was observed among subgroups of women who had evidence of higher rates of adherence than among those with lower rates of adherence. HIV-1 protection was not observed for women between the ages of 18 and 21 years, and objective markers of adherence were lower in this subgroup than in those older than 21 years.
Strong relationships between adherence and HIV-1 protection have been seen in studies of HIV-1 prophylaxis, with several studies among African women showing low adherence.3,4,9 In our trial, a majority of participants had objective evidence of adherence to the use of the dapivirine ring. We predefined dapivirine levels in plasma and in used rings to indicate adherence on the basis of phase 1 and 2 studies. However, our definitions could have led to an overestimation of adherence because participants were categorized as being adherent even though they may have used the ring for only a portion of the month (and possibly only for a few hours before a clinic visit). Further pharmacokinetic analysis may help define whether there is a threshold of use of dapivirine that provides protection against HIV-1, analogous to investigations that followed the initial clinical trials of tenofovir-based strategies.22,23 Some studies of other treatment and prevention interventions have shown that use and resultant benefits often decline over time.2,22 In contrast, we found that adherence appeared to increase after the first months of use, which may indicate that some time was needed for participants to become comfortable with the ring, and HIV-1 protection was sustained during follow-up of 24 months or more. Qualitative analyses showed that nonadherence to HIV-1 prophylaxis strategies in clinical trials may be related to characteristics of the participant (e.g., a younger age), the product (e.g., side effects), and the research process (e.g., concern about unproven safety and efficacy).24,25 Notably, studies of the oral antiretroviral agent tenofovir have shown higher adherence in open-label studies after a demonstration of safety and efficacy than had been seen in the initial blinded, placebo-controlled trials.26-28
Both behavioral and biologic effects may have contributed to a lack of HIV-1 protection in women between the ages of 18 and 21 years in this trial. Adherence to use of the ring appeared to be lower in this group than in women above 21 years of age; lower adherence to HIV-1 treatment and use of contraceptives has been reported among persons from 18 to 21 years of age.29,30 The genital tract of women in this age group may be more susceptible to HIV-1 infection and potentially also more difficult to protect with antiretroviral prophylaxis strategies.31,32 Further research is needed to understand the unique prevention needs of young women, including open-label evaluations that may allay concern about the efficacy of HIV-1 prevention, safety, or use of placebo. In addition, studies are needed to assess whether HIV-1 protection could be achieved in younger women with levels of adherence that were greater than those seen in this trial. The dapivirine ring significantly reduced HIV-1 incidence by more than half among women over the age of 21 years; women between the ages of 22 and 26 in the placebo group had an annualized incidence of HIV-1 of more than 6%, a finding that emphasizes the great need for prevention strategies for this population.
The concept of a topical microbicide for vaginal or rectal use for HIV-1 prevention was first proposed more than two decades ago.33 Microbicide products — including gels, films, foams, and rings — have been evaluated in multiple studies among at-risk women and men. Microbicides can provide personal control over HIV-1 prevention and offer the ability to be used discreetly. Affordability is an important challenge to HIV-1 prophylaxis interventions, and topical delivery of antiretroviral drugs may allow minimal toxicity monitoring, which would improve cost-effectiveness. Only one previous trial, a phase 2 evaluation of a vaginal gel containing tenofovir, showed evidence of HIV-1 protection,2 but this result was not confirmed in subsequent studies.3,9 The results of an ongoing second phase 3 trial of the dapivirine vaginal ring (the Ring Study; ClinicalTrials.gov number, NCT01539226) will be important for improving our understanding of this intervention.
African women bear a disproportionate burden of the global HIV-1 epidemic. In the placebo group in our trial, the annualized HIV-1 incidence was more than 4%, despite monthly HIV-1 testing and risk-reduction counseling, testing of male partners, screening and treatment of sexually transmitted infections, and provision of free condoms. Our results show that a vaginal ring containing an antiretroviral drug can provide some protection against HIV-1 acquisition.
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