Pharmacokinetic Modeling to Guide Preclinical Development of an Islatravir-Eluting Reservoir-Style Biodegradable Implant for Long-Acting HIV PrEP.

Long-acting injectable cabotegravir is more effective than daily oral PrEP at preventing HIV transmission due to improved adherence, but requires bi-monthly large-volume intramuscular injections. Subcutaneous (SC) contraceptive implants can be formulated with antiretrovirals for extended-duration HIV PrEP. Islatravir (ISL) is a first-in-class, investigational antiretroviral with pharmacologic properties well-suited for implant delivery. We performed preclinical studies for the development of a reservoir-style, poly(ε-caprolactone) ISL-eluting implant by conducting a single-dose SC ISL dose-ranging pharmacokinetic (PK) study of 0.1, 0.3, and 1 mg/kg in adult Wistar rats. Non-compartmental analysis was conducted, and dose proportionality assessed for ISL plasma and intracellular islatravir-triphosphate (ISL-tp). Population PK models estimated ISL's unit impulse response to deconvolve ISL-implant in vivo absorption rate (mg/day) and cumulative mass (mg) from published rat plasma PK (n = 10). Drug release was interpreted using four kinetic models. Dose proportionality was affirmed for ISL and ISL-tp. A first-order, two-compartment model fitted the SC ISL bolus data. Mean (SD) absorption rate from 0 to 154 days was 0.072 ± 0.024 mg/day, and cumulative mass at 154 days was 8.67 ± 3.22 mg. ISL absorption was well-described by zero-order (r2 = 0.95) and Ritger-Peppas (r2 = 0.98). Our zero-order ISL-release poly(ε-caprolactone) implant is projected to achieve clinical PK above ISL-tp's PrEP efficacy threshold. Continued development for HIV PrEP applications is warranted.

Pharmacokinetic Study of Islatravir and Etonogestrel Implants in Macaques.

The prevention of HIV and unintended pregnancies is a public health priority. Multi-purpose prevention technologies capable of long-acting HIV and pregnancy prevention are desirable for women. Here, we utilized a preclinical macaque model to evaluate the pharmacokinetics of biodegradable ε-polycaprolactone implants delivering the antiretroviral islatravir (ISL) and the contraceptive etonogestrel (ENG). Three implants were tested: ISL-62 mg, ISL-98 mg, and ENG-33 mg. Animals received one or two ISL-eluting implants, with doses of 42, 66, or 108 µg of ISL/day with or without an additional ENG-33 mg implant (31 µg/day). Drug release increased linearly with dose with median [range] plasma ISL levels of 1.3 [1.0-2.5], 1.9 [1.2-6.3] and 2.8 [2.3-11.6], respectively. The ISL-62 and 98 mg implants demonstrated stable drug release over three months with ISL-triphosphate (ISL-TP) concentr54ations in PBMCs above levels predicted to be efficacious for PrEP. Similarly, ENG implants demonstrated sustained drug release with median [range] plasma ENG levels of 495 [229-1110] pg/mL, which suppressed progesterone within two weeks and showed no evidence of altering ISL pharmacokinetics. Two of the six ISL-98 mg implants broke during the study and induced implant-site reactions, whereas no reactions were observed with intact implants. We show that ISL and ENG biodegradable implants are safe and yield sufficient drug levels to achieve prevention targets. The evaluation of optimized implants with increased mechanical robustness is underway for improved durability and vaginal efficacy in a SHIV challenge model.

Participant experiences with a multipurpose vaginal ring for HIV and pregnancy prevention during a phase 1 clinical trial: learning from users to improve acceptability.

Introduction: With high concurrent global rates of HIV incidence and unintended pregnancy, there is a need to provide options beyond condoms to enable users to simultaneously prevent HIV acquisition and pregnancy. Multiple vaginal rings are in development as "MPTs" (multipurpose prevention technologies) as they are shown to provide several co-occurring benefits such as discretion, convenience, reversibility and user control. Methods: In this Phase 1 trial of a 3-month MPT ring in the U.S., 25 participants (low-risk for HIV and pregnancy) were randomized to use the study ring for 90 days continuously or in 28-day cycles with 2-day removal periods in between. All participants completed in-depth interviews at the end of their study participation. Results: Overall, the ring was well tolerated. Participants resoundingly endorsed the concept of an extended-use, dual-purpose vaginal ring, but reported too many functional challenges and side effects to endorse this particular ring. Participants assigned to the continuous regimen reported more positive experiences with ring use than those in the cyclic group. A minority of participants who experienced minimal side effects and did not experience challenges with vaginal retention of the ring found it appealing. However, the majority of participants experienced challenges (ring slippage, expulsions, side effects, vaginal bleeding changes) with product use that outweighed the potential benefits and led them to report that - in the future - they would not be interested in using this specific version of the ring in its current form. A subset expressed interest in using the current MPT ring under certain conditions (e.g., if fewer expulsions, less bleeding, higher risk for HIV/pregnancy). Discussion: User feedback regarding participant experiences and challenges with the study ring was continuously shared with the product developer, underscoring the value of early-stage end-user feedback in product development.

Synthesis of end-user research to inform future multipurpose prevention technologies in sub-Saharan Africa: a scoping review.

Introduction: Women in sub-Saharan Africa (SSA) experience disproportionately high rates of HIV infection and unintended pregnancy compared to their age-matched counterparts in other regions of the world. Multipurpose prevention technologies (MPTs) that offer protection against HIV and unintended pregnancy in a single product stand to address these dual sexual and reproductive health needs simultaneously. The aim of this scoping review is to identify factors that are important for optimizing the likelihood of MPT adoption by end users in SSA. Methods: Study inclusion criteria included MPT research (HIV and pregnancy prevention dual indication) published or presented in English from 2000 to 2022 and conducted in SSA amongst end-users (women aged 15-44), male partners, health care providers, and community stakeholders. References were identified by searching peer reviewed literature, grey literature, conference presentations (2015-2022), grant databases, and outreach to MPT subject matter experts. Of 115 references identified, 37 references met inclusion criteria and were extracted for analysis. A narrative synthesis approach was used to summarize findings within and across MPT products. Results: Studies were identified from six countries in SSA and a substantial proportion included a South African (n = 27) and/or Kenyan (n = 16) study site. Most studies utilized a qualitative study design (n = 22) and evaluated MPT acceptability and preferences by presenting hypothetical products through images or a list of product attributes (n = 21). The vaginal ring (n = 20), oral tablet (n = 20), and injection (n = 15) were examined most frequently. Across studies, there was high acceptability and demand for an HIV and pregnancy prevention MPT. End users valued choice in prevention product type as well as discreetness and long-acting options. Provider counseling and community sensitization were reported as essential for future introduction of novel MPT delivery forms. Conclusion: Recognizing the heterogeneity of women's preferences and changing reproductive and sexual health needs over the life course, choice is important in the delivery of pregnancy and HIV prevention products as well as amongst MPT products with distinct product profiles. End user research with active MPTs, vs. hypothetical or placebo MPTs, is necessary to advance understanding of end-user preferences and acceptability of future products.

Prospective acceptability of a multipurpose technology (MPT) implant in preclinical development to prevent HIV and unplanned pregnancy: Qualitative insights from women end users and health care providers in South Africa and Zimbabwe.

BACKGROUND: Given the high rates of both HIV and unintended pregnancies in sub-Saharan Africa, the SCHIELD program aims to develop a multipurpose technology implant for HIV and pregnancy prevention. An end-user evaluation was undertaken with young women and health care providers to assess preferences for modifiable implant attributes to improve future adoption and rollout. METHODS: Focus group discussions were conducted with potential women end users, and health care providers experienced in implant insertion or removal participated in in-depth interviews. All participants were recruited from Harare, Zimbabwe, or Soshanguve, South Africa. The purposively stratified sampled women were either implant experienced or implant naïve and were categorized into three groups: nulliparous, postpartum, or engaged in transactional sex. Topics covered included duration (six months to three years), biodegradability, removability, and independent rod retrievability (per indication). Data were analyzed using Dedoose software and summarized into emerging themes. RESULTS: Participants identified three key areas that could facilitate rollout, uptake, and adherence of an implant for HIV and pregnancy prevention. First, discreetness was the most salient topic and was associated with implant characteristics such as anatomical location, flexibility, and biodegradability. Second, the ability to independently retrieve the HIV or pregnancy prevention component was preferred, as life circumstances may change and was favored by all participants, except for young women in Soshanguve. Third, there is a need for proper counseling, sensitization, provider training, and health campaigns to facilitate rollout of a 2-in-1 implant. CONCLUSIONS: A 2-in-1 implant was seen as highly desirable by most young women and health care providers. Participants discussed potential concerns and barriers to uptake of a biodegradable implant with dual HIV prevention and contraceptive properties, identifying key implant attributes that product developers can modify while still in preclinical stages.

Incorporating end-users' voices into the development of an implant for HIV prevention: a discrete choice experiment in South Africa and Zimbabwe.

BACKGROUND: Input from end-users during preclinical phases can support market fit for new HIV prevention technologies. With several long-acting pre-exposure prophylaxis (PrEP) implants in development, we aimed to understand young women's preferences for PrEP implants to inform optimal design. METHODS: We developed a discrete choice experiment and surveyed 800 young women in Harare, Zimbabwe and Tshwane, South Africa between September-November 2020. Women aged 18-30 years who were nulliparous, postpartum, or exchanged sex for money, goods or shelter in prior year were eligible; quotas were set for each subgroup. The DCE asked participants to choose between two hypothetical implants for HIV prevention in a series of nine questions. Implants were described by: size, number of rods and insertion sites, duration (6-months, 1-year, 2-years), flexibility, and biodegradability. Random-parameters logit models estimated preference weights. RESULTS: Median age was 24 years (interquartile range 21-27). By design, 36% had used contraceptive implants. Duration of protection was most important feature, with strong preference for a 2-year over 6-month implant. In Zimbabwe, the number of rods/insertion sites was second most important and half as important as duration. Nonetheless, to achieve an implant lasting 2-years, 74% were estimated to accept two rods, one in each arm. In South Africa, preference was for longer, flexible implants that required removal, although each of these attributes were one-third as important as duration. On average, biodegradability and size did not influence Zimbabwean women's choices. Contraceptive implant experience and parity did not influence relative importance of attributes. CONCLUSIONS: While duration of protection was a prominent attribute shaping women's choices for PrEP implants, other characteristics related to discreetness were relevant. Optimizing for longest dosing while also ensuring minimal detection of implant placement seemed most attractive to potential users.

Acceptability of the Dapivirine Vaginal Ring in Postmenopausal US Women.

For women in the United States who remain sexually active beyond child-bearing years, susceptibility to HIV infection remains, yet condom use is low. We assessed acceptability of the dapivirine vaginal ring (ring) among 96 postmenopausal US women enrolled in a placebo-controlled multisite phase II trial of the ring, using questionnaires and in-depth interviews. Three quarters of women reported "perfect" adherence (ring never out) over the 3-month trial period. At study exit, the ring was found to be very easy to use by 72%, very comfortable to wear by 65%, and 4% reported it ever interfered with their daily activities. The most common worries among participants at preinitiation had decreased significantly at study exit (e.g., worries about inserting the ring declined from 46% to 6%, discomfort during daily activities from 53% to 3%, ring not staying in place from 48% to 14%, all p < 0.0001). Despite some couples feeling the ring during sex, the ring was perceived as more suitable than condoms for prevention because it was not burdensome to use, did not interfere with erection, and provided (for some) additional vaginal lubrication. The ring is a promising, highly acceptable HIV prevention method that is suitable to the lives of postmenopausal women and their male partners and can provide them with an additional prevention choice. Clinical Trials Registration: NCT02010593.

Ring-ing in the Future: Participant and Male Partner Perspectives Regarding Future Use of the Dapivirine Vaginal Ring for HIV Prevention.

Women account for a disproportionate percentage of new HIV infections in sub-Saharan Africa indicating a need for female-initiated HIV prevention options congruent with their lifestyles. The dapivirine vaginal ring for HIV prevention is one such option. We explored the interest of women, who used this ring during the Microbicide Trials Network's ASPIRE and HOPE studies, in using the ring post-licensure and what they perceived as important considerations for future use. We also explored perspectives of HOPE participants' male partners on their involvement in their partners' future ring use. Women appeared keen to use the ring in the future and expressed desires for easy access, support for both ongoing and new users and intense community engagement. In parallel, male partners indicated high levels of interest in supporting their partners' ring use and being involved in ring use decision making. These data offer important insights for ring rollout planning and engagement activities.

Acceptability and Preference for 3-Month Versus 1-Month Vaginal Rings for HIV-1 Risk Reduction Among Participants in a Phase 1 Trial.

Background: The monthly dapivirine vaginal ring provides partial protection against HIV, and a longer duration ring may reduce user burden and improve adherence. We examined acceptability and preference for 3-month versus 1-month rings for HIV-1 risk reduction in a phase 1 clinical trial. Materials and Methods: In Microbicide Trials Network-036/International Partnership for Microbicides 047, 49 HIV-negative participants aged 18-45 were randomized to one of two 3-month rings or the 1-month ring. Acceptability ratings were collected at enrollment, week 4, and study exit (week 13). At exit, ring preference was assessed quantitatively among all participants and a randomly selected subset of 24 participants completed in-depth interviews. Quantitative and qualitative findings were integrated to explore factors influencing acceptability and preference. Results: Acceptability of each ring was initially moderate and increased during the trial. Ratings were lower in the 3-month ring arms than the 1-month arm at each time point, including baseline. Most participants (34/47; 72%) preferred a 3-month ring at exit; however, this proportion was significantly lower within some subgroups characterized by site, education, race/ethnicity, and experiences with ring use. Qualitative interviews revealed reservations about hygiene and safety of the 3-month ring, including discomfort with use during menses, but these were usually outweighed by its increased convenience. Conclusions: Both ring durations were highly acceptable at study exit. Although most participants preferred a 3-month ring, preference was more divided in certain subgroups, highlighting the benefit of offering different duration options. Providing additional support to address concerns about hygiene and safety may improve acceptability of a 3-month vaginal ring.

Impact and experience of participant engagement activities in supporting dapivirine ring use among participants enrolled in the phase III MTN-020/ASPIRE study.

BACKGROUND: Low adherence to investigational products can negatively impact study outcomes, limiting the ability to demonstrate efficacy. To continue advancing potential new HIV prevention technologies, efforts are needed to improve adherence among study participants. In MTN-020/ASPIRE, a phase III randomized, double-blind, placebo-controlled study of the dapivirine vaginal ring carried out across 15 sites in sub-Saharan Africa, a multifaceted approach to adherence support was implemented, including a strong focus on participant engagement activities (PEAs). In this manuscript, we describe PEAs and participant attendance, and analyze the potential impact of PEAs on ring use. METHODS: All sites implemented PEAs and submitted activity and attendance reports to the study management team throughout the study. Participant demographics were collected via case report forms. Residual dapivirine remaining in the last ring returned by each participant was used to estimate drug released from the ring, which was then adjusted for time participants had the ring to calculate probable use categorized into three levels (low/intermittent/high). Product use was connected to PEA attendance using participant identification numbers. We used multivariate Poisson regression with robust standard errors to explore differences in ring use between PEA attendance groups and reviewed qualitative reports for illustrative quotes highlighting participant experiences with PEAs. RESULTS: 2312 of 2629 study participants attended at least one of 389 PEAs conducted across sites. Participant country and partner knowledge of study participation were most strongly associated with PEA attendance (p < 0.005) with age, education, and income status also associated with event attendance (p < 0.05). When controlling for these variables, participants who attended at least one event were more likely to return a last ring showing at least some use (RR = 1.40) than those who never attended an event. There was a stronger correlation between a last returned ring showing use and participant attendance at multiple events (RR = 1.52). CONCLUSIONS: Our analysis supports the growing body of work illustrating the importance of meaningfully engaging research participants to achieve study success and aligns with other analyses of adherence support efforts during ASPIRE. While causation between PEA attendance and product use cannot be established, residual drug levels in returned rings strongly correlated with participant attendance at PEAs, and the benefits of incorporating PEAs should be considered when designing future studies of investigational products.

Advances in long-acting injectables, implants, and vaginal rings for contraception and HIV prevention.

Worldwide, women face compounding reproductive health risks, including human immunodeficiency virus (HIV), sexually-transmitted infections (STIs), and unintended pregnancy. Multipurpose prevention technologies (MPTs) offer combined protection against these overlapping risks in singular prevention products that offer potential for simplified use, lower burden, higher acceptability, and increased public health benefits. Over the past decade, substantial progress has been made in development of extended-release MPTs, which have further potential to grant sexual and reproductive health autonomy to women globally and to offer choice for women to accommodate varying needs during their reproductive lives. Here, we highlight the advances made in injectable, implant, and ring delivery forms, and the importance of incorporating end-user preferences early in the research and development of these products.

Similarities in Maternal Weight and Birth Weight Across Pregnancies and Across Sisters.

Objectives The current study examined how prepregnancy body mass index (BMI), gestational weight gain, and birth weight cluster between births within women and between women who are sisters. Methods Using data from the National Longitudinal Survey of Youth 1979 cohort, we utilized nested, multivariable hierarchical linear models to examine the correlation of these three outcomes between births (n = 6006) to women (n = 3605) and sisters (n = 3170) so that we can quantify the clustering by sibship and by woman for these three pregnancy-related outcomes. Results After controlling for confounding covariates, prepregnancy BMI (intraclass correlation (ICC) 0.24, 95% CI 0.16, 0.32), gestational weight gain (ICC 0.23, 95% CI 0.16, 0.31), and infant's birthweight (ICC 0.07, 95% CI 0.003, 0.13) were correlated between sisters. Additionally, all three outcomes were significantly correlated between births for each sister, suggesting that prepregnancy BMI (ICC 0.82, 95% CI 0.81, 0.83), gestational weight gain (ICC 0.45, 95% CI 0.42, 0.49), and birth weight (ICC 0.31, 95% CI 0.28, 0.35) track between pregnancies in the same woman. Conclusions for Practice The observed clustering both within women and between sisters suggests that shared genetic and environmental factors among sisters play a role in pregnancy outcomes above and beyond that of women's own genetic and environmental factors. Findings suggest that asking a woman about her sisters' pregnancy outcomes could provide insight into the possible outcomes for her current pregnancy. Future research should test if collecting such a family history and providing tailored clinical recommendations accordingly would be useful.

Long acting systemic HIV pre-exposure prophylaxis: an examination of the field.

Oral pre-exposure prophylaxis for the prevention of HIV-1 transmission (HIV PrEP) has been widely successful as demonstrated by a number of clinical trials. However, studies have also demonstrated the need for patients to tightly adhere to oral dosing regimens in order to maintain protective plasma and tissue concentrations. This is especially true for women, who experience less forgiveness from dose skipping than men in clinical trials of HIV PrEP. There is increasing interest in long-acting (LA), user-independent forms of HIV PrEP that could overcome this adherence challenge. These technologies have taken multiple forms including LA injectables and implantables. Phase III efficacy trials are ongoing for a LA injectable candidate for HIV PrEP. This review will focus on the design considerations for both LA injectable and implantable platforms for HIV PrEP. Additionally, we have summarized the existing LA technologies currently in clinical and pre-clinical studies for HIV PrEP as well as other technologies that have been applied to HIV PrEP and contraceptives. Our discussion will focus on the potential application of these technologies in low resource areas, and their use in global women's health.

Stated product formulation preferences for HIV pre-exposure prophylaxis among women in the VOICE-D (MTN-003D) study.

INTRODUCTION: The effectiveness of HIV pre-exposure prophylaxis (PrEP) requires consistent and correct product use, thus a deeper understanding of women's stated product formulation preferences, and the correlates of those preferences, can help guide future research. VOICE-D (MTN-003D), a qualitative ancillary study conducted after the VOICE trial, retrospectively explored participants' tablet and gel use, as well as their preferences for other potential PrEP product formulations. METHODS: We conducted an analysis of quantitative and qualitative data from VOICE-D participants. During in-depth interviews, women were presented with pictures and descriptions of eight potential PrEP product formulations, including the oral tablet and vaginal gel tested in VOICE, and asked to discuss which product formulations they would prefer to use and why. Seven of the original product formulations displayed were combined into preferred product formulation categories based on exploratory factor and latent class analyses. We examined demographic and behavioural correlates of these preferred product formulation categories. In-depth interviews with participants were conducted, coded, and analysed for themes related to product preference. RESULTS: Of the 68 female participants who completed in-depth interviews (22 South Africa, 24 Zimbabwe, 22 Uganda), median age was 28 (range 21-41), 81% were HIV negative, and 49% were married or living with a partner. Four preferred product formulation categories were identified via exploratory factor analysis: 1) oral tablets; 2) vaginal gel; 3) injectable, implant, or vaginal ring; and 4) vaginal film or suppository. A majority of women (81%) expressed a preference for product formulations included in category 3. Characteristics significantly associated with each preferred product category differed. Attributes described by participants as being important in a preferred product formulation included duration of activity, ease of use, route of administration, clinic- versus self-administration, and degree of familiarity with product. CONCLUSIONS: While there was interest in a variety of potential PrEP product formulations, a majority of VOICE-D participants preferred long-acting methods. More research is needed to gain insight into end-users' product formulation preference to inform messaging and market segmentation for different PrEP products and resources to invest in products that target populations are most interested in using. CLINICAL TRIAL NUMBER: NCT02358616.

Impact of a workplace intervention on attitudes and practices related to gender equity in Bengaluru, India.

We describe the evaluation of a participatory, garment factory-based intervention to promote gender equity. The intervention comprised four campaigns focused on gender and violence against women, alcoholism, sexual and reproductive health, and HIV/AIDS, which were implemented using information displays (standees and posters) and interactive methods (street play, one-to-one interactions, experience-sharing, and health camps). Each campaign lasted six days and the entire intervention was implemented over 10 months. We evaluated the intervention using a quasi-experimental design in which one factory served as the intervention site and a second as a delayed control. Two mobile-phone-based cross-sectional surveys were conducted at baseline and 12 months with separate systematic random samples of employees from each site. Data on socio-demographic characteristics and knowledge and attitudes related to gender equity, intimate partner violence (IPV) and alcohol use were assessed, and differences in these variables associated with the intervention were examined using difference-in-difference estimation. Analyses of data from 835 respondents revealed substantial, statistically significant improvements in attitudes related to gender equity, unacceptability of IPV, and awareness of IPV and alcohol-related support services. In conclusion, our study offers compelling evidence on the effectiveness of workplace-based interventions in advancing gender equity.

A Tunable, Biodegradable, Thin-Film Polymer Device as a Long-Acting Implant Delivering Tenofovir Alafenamide Fumarate for HIV Pre-exposure Prophylaxis.

PURPOSE: The effectiveness of Tenofovir based HIV pre-exposure prophylaxis (PrEP) is proven, but hinges on correct and consistent use. User compliance and therapeutic effectiveness can be improved by long acting drug delivery systems. Here we describe a thin-film polymer device (TFPD) as a biodegradable subcutaneous implant for PrEP. METHODS: A thin-film polycaprolactone (PCL) membrane controls drug release from a reservoir. To achieve membrane controlled release, TAF requires a formulation excipient such as PEG300 to increase the dissolution rate and reservoir solubility. Short-term In vitro release studies are used to develop an empirical design model, which is applied to the production of in vitro prototype devices demonstrating up to 90-days of linear release and TAF chemical stability. RESULTS: The size and shape of the TFPD are tunable, achieving release rates ranging from 0.5 to 4.4 mg/day in devices no larger than a contraceptive implant. Based on published data for oral TAF, subcutaneous constant-rate release for HIV PrEP is estimated at <2.8 mg/day. Prototype devices demonstrated linear release at 1.2 mg/day for up to 90 days and at 2.2 mg/day for up to 60 days. CONCLUSIONS: We present a biodegradable TFPD for subcutaneous delivery of TAF for HIV PrEP. The size, shape and release rate of the device are tunable over a >8-fold range.

Social network recruitment for Yo Puedo: an innovative sexual health intervention in an underserved urban neighborhood­sample and design implications.

Most existing evidence-based sexual health interventions focus on individual-level behavior, even though there is substantial evidence that highlights the influential role of social environments in shaping adolescents' behaviors and reproductive health outcomes. We developed Yo Puedo, a combined conditional cash transfer and life skills intervention for youth to promote educational attainment, job training, and reproductive health wellness that we then evaluated for feasibility among 162 youth aged 16-21 years in a predominantly Latino community in San Francisco, CA. The intervention targeted youth's social networks and involved recruitment and randomization of small social network clusters. In this paper we describe the design of the feasibility study and report participants' baseline characteristics. Furthermore, we examined the sample and design implications of recruiting social network clusters as the unit of randomization. Baseline data provide evidence that we successfully enrolled high risk youth using a social network recruitment approach in community and school-based settings. Nearly all participants (95%) were high risk for adverse educational and reproductive health outcomes based on multiple measures of low socioeconomic status (81%) and/or reported high risk behaviors (e.g., gang affiliation, past pregnancy, recent unprotected sex, frequent substance use; 62%). We achieved variability in the study sample through heterogeneity in recruitment of the index participants, whereas the individuals within the small social networks of close friends demonstrated substantial homogeneity across sociodemographic and risk profile characteristics. Social networks recruitment was feasible and yielded a sample of high risk youth willing to enroll in a randomized study to evaluate a novel sexual health intervention.

Perspectives on use of oral and vaginal antiretrovirals for HIV prevention: the VOICE-C qualitative study in Johannesburg, South Africa.

INTRODUCTION: Antiretroviral (ARV)-based pre-exposure prophylaxis (PrEP) is a promising new HIV prevention strategy. However, variable levels of adherence have yielded mixed results across several PrEP trials and populations. It is not clear how taking ARV - traditionally used for HIV treatment - is perceived and how that perception may affect the use of these products as preventives. We explored the views and experiences of VOICE participants, their male partners and community members regarding the use of ARV as PrEP in the VOICE trial and the implications of these shared meanings for adherence. METHODS: VOICE-C was a qualitative ancillary study conducted at the Johannesburg site of VOICE, a multisite, double-blind, placebo-controlled randomised trial testing tenofovir gel, oral tenofovir and oral Truvada for HIV PrEP. We interviewed 102 randomly selected female VOICE participants, 22 male partners and 40 community members through in-depth interviews, serial ethnography, or focus group discussions. All interviews were audiotaped, transcribed, translated and coded thematically for analysis. RESULTS: The concept of ARV for prevention was understood to varying degrees across all study groups. A majority of VOICE participants understood that the products contained ARV, more so for the tablets than for the gel. Although participants knew they were HIV negative, ARV was associated with illness. Male partners and community members echoed these sentiments, highlighting confusion between treatment and prevention. Concerned that they would be mistakenly identified as HIV positive, VOICE participants often concealed use of or hid their study products. This occasionally led to relationship conflicts or early trial termination. HIV stigma and its association with ARV, especially the tablets, was articulated in rumour and gossip in the community, the workplace and the household. Although ARV were recognised as potent and beneficial medications, transforming the AIDS body from sickness to health, they were regarded as potentially harmful for those uninfected. CONCLUSIONS: VOICE participants and others in the trial community struggled to conceptualise the idea of using ARV for prevention. This possibly influenced willingness to adopt ARV-based prevention in the VOICE clinical trial. Greater investments should be made to increase community understanding of ARV for prevention and to mitigate pervasive HIV stigma.

Effective approaches for programming to reduce adolescent vulnerability to HIV infection, HIV risk, and HIV-related morbidity and mortality: a systematic review of systematic reviews.

BACKGROUND: In 2012, an estimated 2.1 million adolescents were living with HIV. Though there are effective interventions to prevent and treat HIV infection, adolescents face specific barriers in accessing them. As a result, new infections and poor outcomes among HIV-infected adolescents are common. HIV programming for adolescents should focus on interventions of proven effectiveness and address underlying factors driving incidence and lack of effective treatment and care in this age group. METHODS: We conducted a systematic review of systematic reviews to summarize the global data on effectiveness of 20 intervention types, to identify characteristics of effective interventions, and to explore evidence of how adolescents can access interventions with proven effectiveness. Interventions were in 2 broad categories: those designed primarily for adults and those designed specifically for adolescents. Where available, we evaluated the evidence of impact on the key outcomes: HIV risk, HIV transmission, and HIV morbidity and mortality. RESULTS: Among the interventions designed for adolescents, there was high-quality evidence that in-school interventions and some interventions in geographically defined communities can positively impact important HIV-related outcomes, such as self-reported sexual risk behaviors. Interventions designed primarily for adults that had high-quality, consistent biological evidence of efficacy included voluntary medical male circumcision (VMMC), antiretrovirals for the prevention of mother-to-child transmission, HIV testing and counseling, HIV treatment, condom use, and provision of sterile injecting equipment to people who inject drugs. There was also an evidence of potential efficacy for oral preexposure prophylaxis and behavior change interventions among certain populations. There was a dearth of systematic review data on how best to enable adolescents to access the intervention types identified as having proven effectiveness among adults. CONCLUSIONS: This series of reviews allowed us to rigorously and systematically review a large number of intervention types at once using a standard, transparent methodology. Eight key interventions showed clear evidence of effectiveness, with evidence of potential efficacy for some additional interventions among certain populations. DISCUSSION: These priority interventions with proven effectiveness should be included in all HIV prevention programming for adolescents. There is a pressing need for more rigorous research on how best to enable adolescents to access these effective interventions.

Provider counseling to young women seeking family planning services.

CONTEXT: Contraceptive nonuse and misuse contribute to rates of unintended pregnancy and STDs among young women in the United States. Clinical providers assume an important role in guiding youths' contraceptive method choices. METHODS: Sixty-seven women aged 16-21 were recruited as part of a cohort study, conducted in 2009-2012, that examined provider-patient interactions during family planning visits at six San Francisco clinics. Interactions between patients and providers were audio-recorded. Participants completed questionnaires about method preference immediately before seeing the provider; they reported on method choice immediately after the visit and by telephone three and six months later. Transcripts were analyzed to examine providers' strategies for guiding decision making and addressing youths' contraceptive concerns. Missed opportunities for promoting young women's reproductive health were identified. RESULTS: Twenty-one percent of young women who did not report desiring a hormonal or long-acting reversible method (IUD or implant) before seeing their provider chose one after counseling. Use of a hormonal or long-acting reversible contraceptive method at follow-up was more common among women who had received interactive counseling by providers who guided them to consider contextual influences than among those who had not received such counseling. Attention to relationship characteristics, sexual behavior patterns and STD risk was largely absent from contraceptive counseling. CONCLUSION: High-quality strategies used by providers to guide contraceptive decision making were tailored to adolescents' developmental and environmental needs. Several areas of counseling require increased attention and seem vital to providing comprehensive reproductive health care to adolescents.