OBJECTIVE: To assess the effect of oral and injectable contraceptive use compared to nonhormonal contraceptive use on HIV acquisition among Southern African women enrolled in a microbicide trial. STUDY DESIGN: This is a prospective cohort study using data from women enrolled in HIV Prevention Trials Network protocol 035. At each quarterly visit, participants were interviewed about self-reported contraceptive use and sexual behaviors and underwent HIV testing. Cox proportional hazards regression was used to assess the effect of injectable and oral hormonal contraceptive use on HIV acquisition. RESULTS: The analysis included 2830 participants, of whom 106 became HIV infected (4.07 per 100 person-years). At baseline, 1546 (51%) participants reported using injectable contraceptives and 595 (21%) reported using oral contraceptives. HIV incidence among injectable, oral and nonhormonal contraceptive method users was 4.72, 2.68 and 3.83 per 100 person-years, respectively. Injectable contraceptive use was associated with a nonstatistically significant increased risk of HIV acquisition [adjusted hazard ratio (aHR)=1.17; 95% confidence interval (CI) 0.70, 1.96], while oral contraceptive use was associated with a nonstatistically significant decreased risk of HIV acquisition (aHR=0.76; 95% CI 0.37,1.55). CONCLUSION: In this secondary analysis of randomized trial data, a marginal, but nonstatistically significant, increase in HIV risk among women using injectable hormonal contraceptives was observed. No increased HIV risk was observed among women using oral contraceptives. Our findings support the World Health Organizations recommendation that women at high risk for acquiring HIV, including those using progestogen-only injectable contraception, should be strongly advised to always use condoms and other HIV prevention measures. IMPLICATIONS: Among Southern African women participating in an HIV prevention trial, women using injectable hormonal contraceptives had a modest increased risk of HIV acquisition; however, this association was not statistically significant. Continued research on the relationship between widely used hormonal contraceptive methods and HIV acquisition is essential.

Background

As the effect of biomedical prevention interventions on the natural history of HIV-1 infection in participants who seroconvert is unknown, the Microbicide Trials Network (MTN) established a longitudinal study (MTN-015) to monitor virologic, immunological, and clinical outcomes, as well as behavioral changes among women who become HIV-infected during MTN trials. We describe the rationale, study design, implementation, and enrollment of the initial group of participants in the MTN seroconverter cohort.

Methods

Initiated in 2008, MTN-015 is an ongoing observational cohort study enrolling participants who acquire HIV-1 infection during effectiveness studies of candidate microbicides. Eligible participants from recently completed and ongoing MTN trials are enrolled after seroconversion and return for regular follow-up visits with clinical and behavioral data collection. Biologic samples including blood and genital fluids are stored for future testing.

Results

MTN-015 was implemented initially at six African sites and enrolled 100/139 (72%) of eligible women who seroconverted in HIV Prevention Trials Network protocol 035 (HPTN 035, conducted by the MTN). The median time from seroconversion in HPTN 035 to enrollment in MTN-015 was 18 months. Retention was good with >70% of visits completed. Implementation challenges included regulatory reviews, translation, and testing of questionnaires, and site readiness.

Conclusions

Enrollment of HIV-seroconverters into a longitudinal observational follow-up study is feasible and acceptable to participants. Data and samples collected in this protocol will be used to assess safety of investigational HIV microbicides and answer other important public health questions for HIV infected women.

Objective

To assess the effect of oral and injectable contraceptive use compared to nonhormonal contraceptive use on HIV acquisition among Southern African women enrolled in a microbicide trial.

Study design

This is a prospective cohort study using data from women enrolled in HIV Prevention Trials Network protocol 035. At each quarterly visit, participants were interviewed about self-reported contraceptive use and sexual behaviors and underwent HIV testing. Cox proportional hazards regression was used to assess the effect of injectable and oral hormonal contraceptive use on HIV acquisition.

Results

The analysis included 2830 participants, of whom 106 became HIV infected (4.07 per 100 person-years). At baseline, 1546 (51%) participants reported using injectable contraceptives and 595 (21%) reported using oral contraceptives. HIV incidence among injectable, oral and nonhormonal contraceptive method users was 4.72, 2.68 and 3.83 per 100 person-years, respectively. Injectable contraceptive use was associated with a nonstatistically significant increased risk of HIV acquisition [adjusted hazard ratio (aHR)=1.17; 95% confidence interval (CI) 0.70, 1.96], while oral contraceptive use was associated with a nonstatistically significant decreased risk of HIV acquisition (aHR=0.76; 95% CI 0.37,1.55).

Conclusion

In this secondary analysis of randomized trial data, a marginal, but nonstatistically significant, increase in HIV risk among women using injectable hormonal contraceptives was observed. No increased HIV risk was observed among women using oral contraceptives. Our findings support the World Health Organization's recommendation that women at high risk for acquiring HIV, including those using progestogen-only injectable contraception, should be strongly advised to always use condoms and other HIV prevention measures.

Implications

Among Southern African women participating in an HIV prevention trial, women using injectable hormonal contraceptives had a modest increased risk of HIV acquisition; however, this association was not statistically significant. Continued research on the relationship between widely used hormonal contraceptive methods and HIV acquisition is essential.

Background

Randomized-trial data on the risks and benefits of antiretroviral therapy (ART) as compared with zidovudine and single-dose nevirapine to prevent transmission of the human immunodeficiency virus (HIV) in HIV-infected pregnant women with high CD4 counts are lacking.

Methods

We randomly assigned HIV-infected women at 14 or more weeks of gestation with CD4 counts of at least 350 cells per cubic millimeter to zidovudine and single-dose nevirapine plus a 1-to-2-week postpartum "tail" of tenofovir and emtricitabine (zidovudine alone); zidovudine, lamivudine, and lopinavir-ritonavir (zidovudine-based ART); or tenofovir, emtricitabine, and lopinavir-ritonavir (tenofovir-based ART). The primary outcomes were HIV transmission at 1 week of age in the infant and maternal and infant safety.

Results

The median CD4 count was 530 cells per cubic millimeter among 3490 primarily black African HIV-infected women enrolled at a median of 26 weeks of gestation (interquartile range, 21 to 30). The rate of transmission was significantly lower with ART than with zidovudine alone (0.5% in the combined ART groups vs. 1.8%; difference, -1.3 percentage points; repeated confidence interval, -2.1 to -0.4). However, the rate of maternal grade 2 to 4 adverse events was significantly higher with zidovudine-based ART than with zidovudine alone (21.1% vs. 17.3%, P=0.008), and the rate of grade 2 to 4 abnormal blood chemical values was higher with tenofovir-based ART than with zidovudine alone (2.9% vs. 0.8%, P=0.03). Adverse events did not differ significantly between the ART groups (P>0.99). A birth weight of less than 2500 g was more frequent with zidovudine-based ART than with zidovudine alone (23.0% vs. 12.0%, P<0.001) and was more frequent with tenofovir-based ART than with zidovudine alone (16.9% vs. 8.9%, P=0.004); preterm delivery before 37 weeks was more frequent with zidovudine-based ART than with zidovudine alone (20.5% vs. 13.1%, P<0.001). Tenofovir-based ART was associated with higher rates than zidovudine-based ART of very preterm delivery before 34 weeks (6.0% vs. 2.6%, P=0.04) and early infant death (4.4% vs. 0.6%, P=0.001), but there were no significant differences between tenofovir-based ART and zidovudine alone (P=0.10 and P=0.43). The rate of HIV-free survival was highest among infants whose mothers received zidovudine-based ART.

Conclusions

Antenatal ART resulted in significantly lower rates of early HIV transmission than zidovudine alone but a higher risk of adverse maternal and neonatal outcomes. (Funded by the National Institutes of Health; PROMISE ClinicalTrials.gov numbers, NCT01061151 and NCT01253538 .).

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 .).

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 .).

Background

Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world.

Methods and findings

1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure. An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72-1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54-0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39-0.64 for women; HR 0.79, CI 0.62-1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12-2.04; p = 0.007).

Conclusion

EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen.

Trial registration

www.ClinicalTrials.gov NCT00084136. Please see later in the article for the Editors' Summary.

Background

Two phase 3 clinical trials showed that use of a monthly vaginal ring containing 25 mg dapivirine was well tolerated and reduced HIV-1 incidence in women by approximately 30% compared with placebo. We aimed to evaluate use and safety of the dapivirine vaginal ring (DVR) in open-label settings with high background rates of HIV-1 infection, an important step for future implementation.

Methods

We did a phase 3B open-label extension trial of the DVR (MTN-025/HIV Open-label Prevention Extension [HOPE]). Women who were HIV-1-negative and had participated in the MTN-020/ASPIRE phase 3 trial were offered 12 months of access to the DVR at 14 clinical research centres in Malawi, South Africa, Uganda, and Zimbabwe. At each visit (monthly for 3 months, then once every 3 months), women chose whether or not to accept the offer of the ring. Used, returned rings were tested for residual amounts of dapivirine as a surrogate marker for adherence. HIV-1 serological testing was done at each visit. Dapivirine amounts in returned rings and HIV-1 incidence were compared with data from the ASPIRE trial, and safety was assessed. This study is registered with ClinicalTrials.gov, NCT02858037.

Findings

Between July 16, 2016, and Oct 10, 2018, of 1756 women assessed for eligibility, 1456 were enrolled and participated in the study. Median age was 31 years (IQR 27-37). At baseline, 1342 (92·2%) women chose to take the DVR; ring acceptance was more than 79% at each visit up until 12 months and 936 (73·2%) of 1279 chose to take the ring at all visits. 12 530 (89·3%) of 14 034 returned rings had residual dapivirine amounts consistent with some use during the previous month (>0·9 mg released) and the mean dapivirine amount released was greater than in the ASPIRE trial (by 0·21 mg; p<0·0001). HIV-1 incidence was 2·7 per 100 person-years (95% CI 1·9-3·8, 35 infections), compared with an expected incidence of 4·4 per 100 person-years (3·2-5·8) among a population matched on age, site, and presence of a sexually transmitted infection from the placebo group of ASPIRE. No serious adverse events or grade 3 or higher adverse events observed were assessed as related to the DVR.

Interpretation

High uptake and persistent use in this open-label extension study support the DVR as an HIV-1 prevention option for women. With an increasing number of HIV-1 prophylaxis choices on the horizon, these results suggest that the DVR will be an acceptable and practical option for women in Africa.

Funding

The Microbicide Trials Network and the National Institute of Allergy and Infectious Diseases, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health, all components of the US National Institutes of Health.