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Antiretroviral-based interventions for HIV-1 prevention, including antiretroviral therapy (ART) to reduce the infectiousness of HIV-1 infected persons and pre-exposure prophylaxis (PrEP) to reduce the susceptibility of HIV-1 uninfected persons, showed high efficacy for HIV-1 protection in randomized clinical trials. We conducted a prospective implementation study to understand the feasibility and effectiveness of these interventions in delivery settings. Between November 5, 2012, and January 5, 2015, we enrolled and followed 1,013 heterosexual HIV-1-serodiscordant couples in Kenya and Uganda in a prospective implementation study. ART and PrEP were offered through a pragmatic strategy, with ART promoted for all couples and PrEP offered until 6 mo after ART initiation by the HIV-1 infected partner, permitting time to achieve virologic suppression. One thousand thirteen couples were enrolled, 78% of partnerships initiated ART, and 97% used PrEP, during a median follow-up of 0.9 years. Objective measures of adherence to both prevention strategies demonstrated high use (≥85%). Given the low HIV-1 incidence observed in the study, an additional analysis was added to compare observed incidence to incidence estimated under a simulated counterfactual model constructed using data from a prior prospective study of HIV-1-serodiscordant couples. Counterfactual simulations predicted 39.7 HIV-1 infections would be expected in the population at an incidence of 5.2 per 100 person-years (95% CI 3.7-6.9). However, only two incident HIV-1 infections were observed, at an incidence of 0.2 per 100 person-years (95% CI 0.0-0.9, p < 0.0001 versus predicted). The use of a non-concurrent comparison of HIV-1 incidence is a potential limitation of this approach; however, it would not have been ethical to enroll a contemporaneous population not provided access to ART and PrEP. Integrated delivery of time-limited PrEP until sustained ART use in African HIV-1-serodiscordant couples was feasible, demonstrated high uptake and adherence, and resulted in near elimination of HIV-1 transmission, with an observed HIV incidence of <0.5% per year compared to an expected incidence of >5% per year.

As pre-exposure prophylaxis (PrEP) becomes more widely used in heterosexual populations, an important consideration is its safety in infants who are breastfed by women taking PrEP. We investigated whether tenofovir and emtricitabine are excreted into breast milk and then absorbed by the breastfeeding infant in clinically significant concentrations when used as PrEP by lactating women. We conducted a prospective short-term, open-label study of daily oral emtricitabine-tenofovir disoproxil fumarate PrEP among 50 HIV-uninfected breastfeeding African mother-infant pairs between 1-24 wk postpartum (ClinicalTrials.gov Identifier: NCT02776748). The primary goal was to quantify the steady-state concentrations of tenofovir and emtricitabine in infant plasma ingested via breastfeeding. PrEP was administered to women through daily directly observed therapy (DOT) for ten consecutive days and then discontinued thereafter. Non-fasting peak and trough samples of maternal plasma and breast milk were obtained at drug concentration steady states on days 7 and 10, and a single infant plasma sample was obtained on day 7. Peak blood and breast milk samples were obtained 1-2 h after the maternal DOT PrEP dose, while maternal trough samples were obtained at the end of the PrEP dosing interval (i.e., 23 to 24 h) after maternal DOT PrEP dose. Tenofovir and emtricitabine concentrations were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays. Of the 50 mother-infant pairs enrolled, 48% were ≤12 wk and 52% were 13-24 wk postpartum, and median maternal age was 25 y (interquartile range [IQR] 22-28). During study follow-up, the median (IQR) daily reported frequency of infant breastfeeding was 15 times (12 to 18) overall, 16 (14 to 19) for the ≤12 weeks, and 14 (12 to 17) for the 13-24 wk infant age groups. Overall, median (IQR) time-averaged peak concentrations in breast milk were 3.2 ng/mL (2.3 to 4.7) for tenofovir and 212.5 ng/mL (140.0 to 405.0) for emtricitabine. Similarly, median (IQR) time-averaged trough concentrations in breast milk were 3.3 ng/mL (2.3 to 4.4) for tenofovir and 183.0 ng/mL (113.0 to 250.0) for emtricitabine, reflecting trough-to-peak breast milk concentration ratios of 1.0 for tenofovir and 0.8 for emtricitabine, respectively. In infant plasma, tenofovir was unquantifiable in 46/49 samples (94%), but emtricitabine was detectable in 47/49 (96%) (median [IQR] concentration: 13.2 ng/mL [9.3 to 16.7]). The estimated equivalent doses an infant would ingest daily from breastfeeding were 0.47 μg/kg (IQR 0.35 to 0.71) for tenofovir and 31.9 μg/kg (IQR 21.0 to 60.8) for emtricitabine, translating into a <0.01% and 0.5% relative dose when compared to the 6 mg/kg dose that is proposed for therapeutic treatment of infant HIV infection and for prevention of infant postnatal HIV infection; a dose that has not shown safety concerns. No serious adverse effects were recorded during study follow-up. The key study limitation was that only a single infant sample was collected to minimize venipunctures for the children. However, maternal daily DOT and specimen collection at drug concentration steady state provided an adequate approach to address the key research question. Importantly, there was minimal variation in breast milk concentrations of tenofovir and emtricitabine (respective median trough-to-peak concentration ratio ~1), demonstrating that infants were exposed to consistent drug dosing via breast milk. In this short-term study of daily directly observed oral PrEP in HIV-uninfected breastfeeding women, the estimated infant doses from breast milk and resultant infant plasma concentrations for tenofovir and emtricitabine were 12,500 and >200-fold lower than the respective proposed infant therapeutic doses, and tenofovir was not detected in 94% of infant plasma samples. These data suggest that PrEP can be safely used during breastfeeding with minimal infant drug exposure. ClinicalTrials.gov, Identifier: NCT02776748.

Disruptions of vaginal microbiota might increase women's susceptibility to HIV infection. Advances in molecular microbiology have enabled detailed examination of associations between vaginal bacteria and HIV acquisition. Therefore, this study aimed to evaluate the association between the concentrations of specific vaginal bacteria and increased risk of HIV acquisition in African women. We did a nested case-control study of participants from eastern and southern Africa. Data from five cohorts of African women (female sex workers, pregnant and post-partum women, and women in serodiscordant relationships) were used to form a nested case-control analysis between women who acquired HIV infection versus those who remained seronegative. Deep sequence analysis of broad-range 16S rRNA gene PCR products was applied to a subset of 55 cases and 55 controls. From these data, 20 taxa were selected for bacterium-specific real-time PCR assays, which were examined in the full cohort as a four-category exposure (undetectable, first tertile, second tertile, and third tertile of concentrations). Conditional logistic regression was used to generate odds ratios (ORs) and 95% CIs. Regression models were stratified by cohort, and adjusted ORs (aORs) were generated from a multivariable model controlling for confounding variables. The Shannon Diversity Index was used to measure bacterial diversity. The primary analyses were the associations between bacterial concentrations and risk of HIV acquisition. Between November, 2004, and August, 2014, we identified 87 women who acquired HIV infection (cases) and 262 controls who did not acquire HIV infection. Vaginal bacterial community diversity was higher in women who acquired HIV infection (median 1·3, IQR 0·4–2·3) than in seronegative controls (0·7, 0·1–1·5; p=0·03). Seven of the 20 taxa showed significant concentration-dependent associations with increased odds of HIV acquisition: Parvimonas species type 1 (first tertile aOR 1·67, 95% CI 0·61–4·57; second tertile 3·01, 1·13–7·99; third tertile 4·64, 1·73–12·46; p=0·005) and type 2 (first tertile 3·52, 1·63–7·61; second tertile 0·85, 0·36–2·02; third tertile 2·18, 1·01–4·72; p=0·004), Gemella asaccharolytica (first tertile 2·09, 1·01–4·36; second tertile 2·02, 0·98–4·17; third tertile 3·03, 1·46–6·30; p=0·010), Mycoplasma hominis (first tertile 1·46, 0·69–3·11; second tertile 1·40, 0·66–2·98; third tertile 2·76, 1·36–5·63; p=0·048), Leptotrichia/Sneathia (first tertile 2·04, 1·02–4·10; second tertile 1·45, 0·70–3·00; third tertile 2·59, 1·26–5·34; p=0·046), Eggerthella species type 1 (first tertile 1·79, 0·88–3·64; second tertile 2·62, 1·31–5·22; third tertile 1·53, 0·72–3·28; p=0·041), and vaginal Megasphaera species (first tertile 3·15, 1·45–6·81; second tertile 1·43, 0·65–3·14; third tertile 1·32, 0·57–3·05; p=0·038). Differences in the vaginal microbial diversity and concentrations of key bacteria were associated with greater risk of HIV acquisition in women. Defining vaginal bacterial taxa associated with HIV risk could point to mechanisms that influence HIV susceptibility and provide important targets for future prevention research. National Institute of Child Health and Human Development.

Observational and laboratory studies suggest that some hormonal contraceptive methods, particularly intramuscular depot medroxyprogesterone acetate (DMPA-IM), might increase women's susceptibility to HIV acquisition. We aimed to compare DMPA-IM, a copper intrauterine device (IUD), and a levonorgestrel (LNG) implant among African women seeking effective contraception and living in areas of high HIV incidence. We did a randomised, multicentre, open-label trial across 12 research sites in eSwatini, Kenya, South Africa, and Zambia. We included HIV-seronegative women aged 16–35 years who were seeking effective contraception, had no medical contraindications to the trial contraceptive methods, agreed to use the assigned method for 18 months, and reported not using injectable, intrauterine, or implantable contraception for the previous 6 months. Participants were randomly assigned (1:1:1) to receive an injection of 150 mg/mL DMPA-IM every 3 months, a copper IUD, or a LNG implant with random block sizes between 15 and 30, stratified by site. Participants were assigned using an online randomisation system, which was accessed for each randomisation by study staff at each site. The primary endpoint was incident HIV infection in the modified intention-to-treat population, including all randomised participants who were HIV negative at enrolment and who contributed at least one HIV test. The primary safety endpoint was any serious adverse event or any adverse event resulting in method discontinuation, until the trial exit visit at 18 months and was assessed in all enrolled and randomly assigned women. This study is registered with ClinicalTrials.gov, number NCT02550067. Between Dec 14, 2015, and Sept 12, 2017, 7830 women were enrolled and 7829 were randomly assigned to the DMPA-IM group (n=2609), the copper IUD group (n=2607), or the LNG implant group (n=2613). 7715 (99%) participants were included in the modified intention-to-treat population (2556 in the DMPA-IM group, 2571 in the copper IUD group, and 2588 in the LNG implant group), and women used their assigned method for 9567 (92%) of 10 409 woman-years of follow-up time. 397 HIV infections occurred (incidence 3·81 per 100 woman-years [95% CI 3·45–4·21]): 143 (36%; 4·19 per 100 woman-years [3·54–4·94]) in the DMPA-IM group, 138 (35%: 3·94 per 100 woman-years [3·31–4·66]) in the copper IUD group, and 116 (29%; 3·31 per 100 woman-years [2·74–3·98]) in the LNG implant group. In the modified intention-to-treat analysis, the hazard ratios for HIV acquisition were 1·04 (96% CI 0·82–1·33, p=0·72) for DMPA-IM compared with copper IUD, 1·23 (0·95–1·59, p=0·097) for DMPA-IM compared with LNG implant, and 1·18 (0·91–1·53, p=0·19) for copper IUD compared with LNG implant. 12 women died during the study: six in the DMPA-IM group, five in the copper IUD group, and one in the LNG implant group. Serious adverse events occurred in 49 (2%) of 2609 participants in the DMPA-IM group, 92 (4%) of 2607 participants in the copper IUD group, and 78 (3%) of 2613 participants in the LNG implant group. Adverse events resulting in discontinuation of the randomly assigned method occurred in 109 (4%) women in the DMPA-IM group, 218 (8%) women in the copper IUD group, and 226 (9%) women in the LNG implant group (p<0·0001 for DMPA-IM vs copper IUD and for DMPA-IM vs LNG implant). 255 pregnancies occurred: 61 (24%) in the DMPA-IM group, 116 (45%) in the copper IUD group, and 78 (31%) in the LNG implant group. 181 (71%) pregnancies occurred after discontinuation of randomly assigned method. We did not find a substantial difference in HIV risk among the methods evaluated, and all methods were safe and highly effective. HIV incidence was high in this population of women seeking pregnancy prevention, emphasising the need for integration of HIV prevention within contraceptive services for African women. These results support continued and increased access to these three contraceptive methods. Bill & Melinda Gates Foundation, US Agency for International Development and the President's Emergency Plan for AIDS Relief, Swedish International Development Cooperation Agency, South African Medical Research Council, and UN Population Fund. Contraceptive supplies were donated by the Government of South Africa and US Agency for International Development.

Background Increased risk of HIV acquisition during pregnancy and lactation among women is evident, necessitating their inclusion in the evaluation of new HIV prevention interventions. Pregnant and postpartum women specifically face challenges with oral PrEP associated with stigma, and the burden of using other tablets. Long-acting products may address challenges related to oral PrEP, however, there is limited data on product-specific preferences and acceptability among pregnant and lactating women. Methods We conducted a mixed-method study to assess the preferences and acceptability of long-acting PrEP modalities either under development or already established among pregnant and lactating women. We conducted quantitative surveys ( n  = 434) and in-depth interviews ( n  = 80) in central and western Kenya. We used descriptive statistics and categorical variables to summarize frequencies and proportions. Inductive and deductive content analytic approaches were used for in-depth interviews. Results The median age of respondents was 25 years (IQR 19.3–31.0). Majority were married (263/434, 61%), had completed high school (222/434, 51%), with no condoms use in the prior 3 months (348/434, 80%). The most preferred PrEP formulations were injectable (251/434, 57%) and implantable (175/434, 40%) options. Participants who preferred injectable PrEP had 8.56 times higher odds of considering ease of use as a reason. (aOR = 8.56, 95% CI [3.81–20.48]) and 3.71 odds of choosing perceived discreteness (aOR = 3.71, 95% CI (1.57–9.97)) as their preference reasons. Participants who preferred Implant for HIV prevention had 2.31 odds of considering it due to perceived effectiveness in preventing HIV as a preference reason (aOR = 2.31, 95% CI (1.21—4.66)) and 2.53-fold of considering discreteness as a preference reason (aOR = 2.53, 95% CI (1.46—4.59)). From the in-depth interviews, women reported prospective acceptability due to the perceived convenience of LA products, perceived effectiveness, reduced cost, improved privacy, and reduced stigma. Women had concerns regarding the safety and efficacy of the products during pregnancy and lactation. Conclusion Acceptability of LA products underscores the importance of considering the unique needs of pregnant and breastfeeding women in the development of future prevention interventions . Aligning preferences and needs would enhance the uptake and adherence outcomes of HIV prevention products.

Introduction In Kenya, pre-exposure prophylaxis (PrEP) for HIV prevention is almost exclusively delivered at HIV clinics. Developing novel PrEP delivery models is important for increasing the reach of PrEP. Delivery of PrEP through pharmacies is one approach utilized in the US to improve accessibility. Retail pharmacies are commonly used as a first-line access point for medical care in Kenya, but have not been utilized for PrEP delivery. We conducted a collaborative consultative meeting of stakeholders to develop a care pathway for pharmacy-based PrEP delivery in Kenya. Methods In January 2020, we held a one-day meeting in Nairobi with 36 stakeholders from PrEP regulatory, professional, healthcare service delivery, civil society, and research organizations. Attendees reviewed a theory of change model, results from formative qualitative research with pharmacy providers and clients, and anticipated core components of pharmacy-based PrEP delivery: counseling, HIV testing, prescribing, and dispensing. Stakeholders participated in small and large group discussions to identify potential challenges and solutions. We synthesized the key findings from these discussions. Results Stakeholders were enthusiastic about a model for pharmacy-based PrEP delivery. Potential challenges identified included insufficient pharmacy provider knowledge and skills, regulatory hurdles to providing affordable HIV testing at pharmacies, and undefined pathways for PrEP procurement. Potential solutions identified included having pharmacy providers complete the Kenya Ministry of Health-approved PrEP training, use of a PrEP prescribing checklist with remote clinician oversight and provider-assisted HIV self-testing, and having the government provide PrEP and HIV self-testing kits to pharmacies during a pilot test. A care pathway was developed over the course of the meeting. Conclusions PrEP delivery stakeholders in Kenya were strongly supportive of developing and testing a model for pharmacy-based PrEP delivery to increase PrEP access. We collaboratively developed a care pathway for pilot testing that has the potential to expand PrEP delivery options in Kenya and other similar settings.

Background Cost remains an important barrier to HIV pre-exposure prophlyaxis (PrEP) delivery in Africa. Simplified delivery models that reduce costs without compromising PrEP outcomes are needed. The JiPime-JiPrEP trial tested a model of six-month PrEP dispensing supported with interim HIV self-testing (HIVST) and found non-inferior HIV testing, PrEP refilling, and adherence compared to three-month PrEP dispensing and quarterly clinic visits, the standard-of-care (SOC). We estimated the cost of this novel differentiated PrEP delivery model compared to SOC in Kenya. Methods Using activity-based micro-costing (payer perspective) and time-and-motion observations, we estimated the cost of PrEP delivery (per client-month) in the intervention and SOC between May 2018 to December 2019. Data from budgets and expense reports, published documents, and interviews informed our estimates. We calculated costs over a one-year horizon for: 1) the trial scenario (i.e., costs within the trial), and 2) the Ministy of Health (MOH) scenario (i.e., hypothetical costs at public clinics). Estimates were in 2019 US dollars and excluded research-related costs. Results The mean personnel time attributable to PrEP delivery was 76 minutes per visit and 152 minutes projected over a year in the intervention and 54 minutes per visit and 282 minutes per year in the SOC. In the trial scenario, PrEP delivery cost $17.73 per client-month in the intervention (n=2039 PrEP-months) and $25.50 in the SOC (n=913 PrEP-months). The projected cost of PrEP delivery in the MOH scenario was $11.94 in the intervention and $14.76 in the SOC, with the addition of HIVST kits in the intervention more than offset by personnel savings. In this scenario, personnel (intervention: 55%; SOC: 44%) and medication (intervention: 16%; SOC: 32%) were the primary cost drivers. Including serum creatine testing twice a year in the MOH scenario resulted in a slight increase in the cost of PrEP delivery in the intervention ($12.88 per client-month) versus SOC ($16.17 per client-month). Conclusions Six-month PrEP with interim HIVST demonstrated lower costs than three-month dispensing, with decreased personnel time. Scale-up of PrEP delivery requires efficient use of limited resources; the savings in this model of PrEP delivery could be redirected towards currently unmet medical needs. Clinial trial number NCT03593629|| https://www.clinicaltrials.gov/ with the Clinical Trial Registry (Registration date: 2018-07-20).

Adolescent girls and young women (AGYW) are at high risk of sexually transmitted infections (STIs). It is unknown whether beginning to have sexual intercourse results in changes to immune mediators in the cervicovaginal tract that contribute to this risk. We collected cervicovaginal lavages from Kenyan AGYW in the months before and after first penile-vaginal sexual intercourse and measured the concentrations of 20 immune mediators. We compared concentrations pre- and post-first sex using mixed effect models. We additionally performed a systematic review to identify similar studies and combined them with our results by meta-analysis of individual participant data. We included 180 samples from 95 AGYW, with 44% providing only pre-first sex samples, 35% matched pre and post, and 21% only post. We consistently detected 19/20 immune mediators, all of which increased post-first sex (p<0.05 for 13/19; Holm-Bonferroni-adjusted p<0.05 for IL-1β, IL-2, and CXCL8). Effects remained similar after excluding samples with STIs and high Nugent scores. Concentrations increased cumulatively over time after date of first sex, with an estimated doubling time of about 5 months.Our systematic review identified two eligible studies, one of 93 Belgian participants, and the other of 18 American participants. Nine immune mediators were measured in at least two-thirds of studies. Meta-analysis confirmed higher levels post-first sex for 8/9 immune mediators (p<0.05 for six mediators, most prominently IL-1α, IL-1β, and CXCL8). Cervicovaginal immune mediator concentrations were higher in women who reported that they started sexual activity. Results were consistent across three studies conducted on three different continents. This research was funded by R01 HD091996-01 (ACR), by P01 AI 030731-25 (Project 1) (AW), R01 AI116292 (FH), R03 AI154366 (FH) and by the Center for AIDS Research (CFAR) of the University of Washington/Fred Hutchinson Cancer Research Center AI027757.

Real-time electronic adherence monitoring involves “smart” pill boxes that record and monitor openings as a proxy for pill taking and may be useful in understanding and supporting PrEP use; however, acceptability and/or feasibility for PrEP users is uncertain. We sought to understand the experiences of using a real-time electronic adherence monitor for PrEP delivery among young women in Kisumu and Thika, Kenya. We used the Wisepill device to monitor PrEP use among 18-24-year-old women for two years. Half of the participants were randomized to also receive SMS adherence reminders (daily or as needed for missed doses). We assessed acceptability quantitatively and qualitatively according to the four constructs of Unified Theory of Acceptance and Use of Technology (UTAUT): performance expectancy, effort expectancy, social influence, and facilitating conditions. We assessed feasibility by monitor functionality during periods of PrEP use. We analyzed quantitative data descriptively and compared by site and over time; qualitative data were analyzed inductively and deductively. The median age was 21 years (IQR 19–22), median education was 12 years (IQR 10–13), 182 (53%) had disclosed PrEP use, and 55 (16%) reported recent intimate partner violence. Most participants reported high levels of usefulness and high interest in using the monitor with few problems or worries reported throughout follow-up. Feasibility was high overall with some differences by site (96% functional monitor days in Kisumu vs 88% in Thika). Few monitors were reported lost (N = 29; 8%) or dysfunctional (N = 11; 3%). In qualitative interviews, electronic monitoring was perceived as useful because it supported privacy, confidentiality, easy storage, and PrEP adherence. Effort was generally considered low. Participants expressed some concern for stigma from monitor and/or PrEP use. Facilitating conditions involved the monitor size, color, and battery life. Overall, real-time electronic adherence monitoring was a highly acceptable and feasible approach to understand PrEP adherence among young women in a sub-Saharan African setting.

Hormonal contraceptives are used widely but their effects on HIV-1 risk are unclear. We aimed to assess the association between hormonal contraceptive use and risk of HIV-1 acquisition by women and HIV-1 transmission from HIV-1-infected women to their male partners. In this prospective study, we followed up 3790 heterosexual HIV-1-serodiscordant couples participating in two longitudinal studies of HIV-1 incidence in seven African countries. Among injectable and oral hormonal contraceptive users and non-users, we compared rates of HIV-1 acquisition by women and HIV-1 transmission from women to men. The primary outcome measure was HIV-1 seroconversion. We used Cox proportional hazards regression and marginal structural modelling to assess the effect of contraceptive use on HIV-1 risk. Among 1314 couples in which the HIV-1-seronegative partner was female (median follow-up 18·0 [IQR 12·6–24·2] months), rates of HIV-1 acquisition were 6·61 per 100 person-years in women who used hormonal contraception and 3·78 per 100 person-years in those who did not (adjusted hazard ratio 1·98, 95% CI 1·06–3·68, p=0·03). Among 2476 couples in which the HIV-1-seronegative partner was male (median follow-up 18·7 [IQR 12·8–24·2] months), rates of HIV-1 transmission from women to men were 2·61 per 100 person-years in couples in which women used hormonal contraception and 1·51 per 100 person-years in couples in which women did not use hormonal contraception (adjusted hazard ratio 1·97, 95% CI 1·12–3·45, p=0·02). Marginal structural model analyses generated much the same results to the Cox proportional hazards regression. Women should be counselled about potentially increased risk of HIV-1 acquisition and transmission with hormonal contraception, especially injectable methods, and about the importance of dual protection with condoms to decrease HIV-1 risk. Non-hormonal or low-dose hormonal contraceptive methods should be considered for women with or at-risk for HIV-1. US National Institutes of Health and the Bill & Melinda Gates Foundation.