Felix Mhlanga

Characteristics of Women Enrolled into a Randomized Clinical Trial of Dapivirine Vaginal Ring for HIV-1 Prevention.

Introduction Women in sub-Saharan Africa are a priority population for evaluation of new biomedical HIV-1 prevention strategies. Antiretroviral pre-exposure prophylaxis is a promising prevention approach; however, clinical trials among young women using daily or coitally-dependent products have found low adherence. Antiretroviral-containing vaginal microbicide rings, which release medication over a month or longer, may reduce these adherence challenges. Methods ASPIRE (A Study to Prevent Infection with a Ring for Extended Use) is a phase III, randomized, double-blind, placebo-controlled trial testing the safety and effectiveness of a vaginal ring containing the non-nucleoside reverse transcriptase inhibitor dapivirine for prevention of HIV-1 infection. We describe the baseline characteristics of African women enrolled in the ASPIRE trial. Results Between August 2012 and June 2014, 5516 women were screened and 2629 HIV-1 seronegative women between 18–45 years of age were enrolled from 15 research sites in Malawi, South Africa, Uganda, and Zimbabwe. The median age was 26 years (IQR 22–31) and the majority (59%) were unmarried. Nearly 100% of participants reported having a primary sex partner in the prior three months but 43% did not know the HIV-1 status of their primary partner; 17% reported additional concurrent partners. Nearly two-thirds (64%) reported having disclosed to primary partners about planned vaginal ring use in the trial. Sexually transmitted infections were prevalent: 12% had Chlamydia trachomatis, 7% Trichomonas vaginalis, 4% Neisseria gonorrhoeae, and 1% syphilis. Conclusions African HIV-1 seronegative women at risk of HIV -1 infection were successfully enrolled into a phase III trial of dapivirine vaginal ring for HIV-1 prevention.

Impact of contraceptive initiation on vaginal microbiota

Background Data evaluating the impact of contraceptives on the vaginal microbiome are limited and inconsistent. Objective We hypothesized that women initiating copper intrauterine device use would have increased bacterial vaginosis and bacterial vaginosis‐associated microbes with use compared to women initiating and using hormonal contraceptive methods. Study Design Vaginal swabs (N = 1047 from 266 participants seeking contraception) for Nugent score determination of bacterial vaginosis and quantitative polymerase chain reaction analyses for assessment of specific microbiota were collected from asymptomatic, healthy women aged 18‐35 years in Harare, Zimbabwe, who were confirmed to be free of nonstudy hormones by mass spectrometry at each visit. Contraception was initiated with an injectable (depot medroxyprogesterone acetate [n = 41], norethisterone enanthate [n = 44], or medroxyprogesterone acetate and ethinyl estradiol [n = 40]), implant (levonorgestrel [n = 45] or etonogestrel [n = 48]), or copper intrauterine device (n = 48) and repeat vaginal swabs were collected after 30, 90, and 180 days of continuous use. Self‐reported condom use was similar across all arms at baseline. Quantitative polymerase chain reaction was used to detect Lactobacillus crispatus, L jensenii, L gasseri/johnsonii group, L vaginalis, L iners, Gardnerella vaginalis, Atopobium vaginae, and Megasphaera‐like bacterium phylotype I from swabs. Modified Poisson regression and mixed effects linear models were used to compare marginal prevalence and mean difference in quantity (expressed as gene copies/swab) prior to and during contraceptive use. Results Bacterial vaginosis prevalence increased in women initiating copper intrauterine devices from 27% at baseline, 35% at 30 days, 40% at 90 days, and 49% at 180 days (P = .005 compared to marginal prevalence at enrollment). Women initiating hormonal methods had no change in bacterial vaginosis prevalence over 180 days. The mean increase in Nugent score was 1.2 (95% confidence interval, 0.5–2.0; P = .001) in women using copper intrauterine devices. Although the frequency and density of beneficial lactobacilli did not change among intrauterine device users over 6 months, there was an increase in the log concentration of G vaginalis (4.7, 5.2, 5.8, 5.9; P = .046) and A vaginae (3.0, 3.8, 4.6, 5.1; P = .002) between baseline and 30, 90, and 180 days after initiation. Among other contraceptive groups, women using depot medroxyprogesterone acetate had decreased L iners (mean decrease log concentration = 0.8; 95% confidence interval, 0.3–1.5; P = .004) and there were no significant changes in beneficial Lactobacillus species over 180 days regardless of contraceptive method used. Conclusion Copper intrauterine device use may increase colonization by bacterial vaginosis–associated microbiota, resulting in increased prevalence of bacterial vaginosis. Use of most hormonal contraception does not alter vaginal microbiota.

Cost-effectiveness of safer reproduction strategies to prevent HIV in Zimbabwe

Abstract Background HIV discordance in stable couples is a major driver of new infections, and discordant couples trying to conceive may be particularly at risk. Strategies that can reduce the risk of HIV transmission in these couples include antiretroviral therapy with adequate viral load suppression (ART/VL), oral pre-exposure prophylaxis (PrEP), artificial vaginal insemination (AVI), and semen washing (SW). Understanding the cost-effectiveness of these strategies is important, particularly in HIV endemic settings. Leveraging the ongoing SAFER study in Zimbabwe, we examined the cost-effectiveness of offering these strategies compared to current practice. Methods The SAFER study is an observational cohort of discordant couples who are trying to conceive. SAFER participants are given a package of safer reproduction services, including counselling and a choice of one or more HIV prevention strategies: ART/VL, PrEP, AVI, or SW. We developed decision models to simulate the use of these strategies and to estimate their cost-effectiveness individually and in combination. Patient uptake of strategies was based on SAFER data. Total net costs and outcomes were assessed over a 30-year horizon from a health system perspective. Costs were derived from SAFER activities using micro-costing, including time and motion observations, and from published literature. Health outcomes were estimated using published literature and were measured in terms of disability-adjusted life-years (DALYs) associated with HIV infection. Incremental cost-effectiveness ratios (ICERs) were calculated using discounted total net health-care costs associated with each safer strategy versus current practice, and discounted DALYs for the seronegative partner and infant. Findings Providing safer reproduction counselling and a choice of strategies is cost-effective compared with current practice, per the WHO standard of annual gross domestic product (GDP) per capita (US

Implementation of a prospective pregnancy registry for antiretroviral based HIV prevention trials

1008 in Zimbabwe), and remains cost-effective up to 97% ART coverage in the general population. Each individual strategy is more cost-effective than current practice, and each has an ICER less than

HIV disease progression among women following seroconversion during a tenofovir-based HIV prevention trial

875 per DALY averted. Both AVI and ART/VL are cost-saving for couples with an HIV-positive woman, and ART/VL and SW were the most cost-effective strategies for couples with an HIV-positive man. Interpretation Modelling suggests that offering safer reproduction counselling and services to HIV-discordant couples trying to conceive is likely to be highly cost-effective for HIV prevention. Our findings may inform implementation of these strategies in Zimbabwe, and sub-Saharan Africa. Funding None.

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

Background: Safety data on pregnancy and fetal outcomes among women in HIV prevention trials are urgently needed to inform use of effective antiretroviral agents for HIV prevention. We describe an effective, efficient, and novel method to prospectively collect perinatal safety data concurrent with on-going parent clinical trials. Methods: The Microbicide Trials Network (MTN)-016 study is a multinational prospective pregnancy exposure registry designed to capture pregnancy and neonatal outcomes. Studies currently contributing data to this registry included phase I and II safety trials with planned exposures to candidate HIV prevention agents, as well as phase IIB and III efficacy trials capturing data on pregnancy and infant outcomes following inadvertent fetal exposure during study participation. Results: To date, participants from two phase I studies and two effectiveness trials have participated in MTN-016, resulting in 420 pregnant women and 381 infants enrolled. Infant retention has been high, with 329 of 381 (86%) infants completing the 12-month follow-up visit. Conclusion: In a research setting context, it is feasible to establish and implement a prospective, multinational HIV chemoprophylaxis pregnancy registry that will generate pregnancy exposure data in a robust fashion.

Misreporting of contraceptive hormone use among clinical research participants

Background Little is known regarding HIV disease outcomes among individuals who become infected with HIV while receiving antiretroviral medications for prevention. We compared HIV disease parameters among women who seroconverted while receiving tenofovir-containing oral or vaginal pre-exposure prophylaxis (PrEP) to placebo. Methods Participants with HIV seroconversion in a randomized placebo-controlled trial of oral tenofovir, oral tenofovir/emtricitabine, and vaginal tenofovir gel (MTN-003) were followed in a longitudinal cohort study (MTN-015). The effect of oral and vaginal tenofovir-containing PrEP on HIV disease progression was compared to placebo using linear mixed effects and Cox proportional hazard models, as appropriate. Additional analyses were performed to compare the outcomes among participants with detectable tenofovir or emtricitabine in plasma at the first quarterly visit in MTN-003. Results A total of 224 participants were included in the analysis; 93% from South Africa and 94% clade C virus. No differences in HIV RNA at steady state or the trajectory over 12 months were observed for each active arm compared to placebo; tenofovir gel recipients had higher CD4+ T cell counts (722 vs 596 cells/mm3; p = 0.02) at 90 days after estimated HIV seroconversion and higher average rates of change over 12 months compared to placebo (-181 vs -92 cells/mm3 per year; p = 0.08). With a median follow-up of 31 months, no significant differences were observed for time to CD4+ T cell count ≤350 cells/mm3, or the composite endpoint of CD4+ T cells ≤350 cells/mm3, initiation of antiretroviral therapy or death for each active arm compared to placebo. Additionally, there were no significant differences in the HIV RNA or CD4+ T cell counts at baseline, the change to month 12, or any disease progression outcomes among participants with oral drug detected and no oral drug detected compared to placebo. Conclusions No clinically significant differences in HIV seroconversion outcomes were observed among women randomized to tenofovir-containing oral or vaginal PrEP regimens, however low overall adherence limits the generalizability of these findings.