Meta-analysis of Pregnancy Events in Biomedical HIV Prevention Trials in Sub-Saharan Africa: Implications for Gender Transformative Trials.

Historically, pregnant and lactating populations (PLP) have been excluded or disenrolled from biomedical HIV prevention trials, despite being more likely to acquire HIV during pregnancy and the post-partum period. We conducted a meta-analysis of pregnancy events in biomedical HIV prevention trials in sub-Saharan Africa to support trialists moving toward more inclusive clinical and implementation studies. We searched peer-reviewed literature reporting pregnancy events and contraceptive requirements in HIV prevention trials between 2001 and 2022. We hypothesized four variables to explain variation: contraceptive requirements, study start year, study product, and sub-region. We fit a meta-analytic model to estimate individual effect sizes and sampling variances, then conducted sub-group analyses to assess moderating effects. We identified 38 references for inclusion, across which the proportion of pregnancy events was 8% (95% confidence interval [CI]: 6-10%) with high heterogeneity (I2 = 99%). Studies not requiring contraceptives (21%, 95%CI: 7-48%) reported a significantly higher proportion of pregnancy events than studies requiring two methods (5%, 95%CI: 2-10%). Studies launched between 2001 and 2007 (11%, 95%CI: 8-16%), microbicide gel trials (12%, 95%CI: 8-18%), and studies conducted in Western Africa (28%, 95%CI: 13-51%) reported higher proportions of pregnancy events than reference groups. Together, these variables have a moderating effect on pregnancy events (p < 0.0001), explaining 63% of heterogeneity in trials. Results describe how, over time, more stringent contraceptive requirements reduced pregnancy events, which ensured necessary statistical power but limited reproductive choice by participants. With the move toward continuing PLP on experimental products, trialists can utilize estimated pregnancy events reported here to inform strategies that accommodate participants' changing fertility preferences.

Reducing Partner Violence Against Women who Exchange Sex and use Drugs through a Combination Microfinance and HIV Risk Reduction Intervention: A Cluster Randomized Trial.

Women who exchange sex and use drugs (WESUD) are at high risk for HIV infection and partner violence. The few tested interventions at the intersection of HIV and IPV show mixed results. This analysis examined the impact of a combination HIV risk reduction (HIVRR) and microfinance (MF) intervention on reported paying and intimate partner violence against WESUD in Kazakhstan. This cluster randomized controlled trial enrolled 354 women from 2015 to 2018 and randomized them to either a combination of HIVRR and MF intervention or HIVRR alone. Outcomes were assessed at four time points over 15 months. Logistic regression within a Bayesian approach assessed change in odds ratio (OR) of recent physical, psychological, or sexual violence perpetrated by current or past intimate partners; and paying partners/clients by study arm over time. Compared to the control arm, the combination intervention decreased the odds of participants experiencing physical violence from past intimate partners by 14% (OR = 0.861, p = 0.049). Women in the intervention group reported significantly lower rates of sexual violence from paying partners (HIVRR + MF - HIVRR: 25.9%; OR = 0.741, p = 0.019) at 12-month follow-up. No significant differences in rates from current intimate partners were found. A combination HIVRR and microfinance intervention may reduce gender-based violence from paying and intimate partners among WESUD above and beyond HIVRR interventions alone. Future research should examine how microfinance reduces partner violence and how to implement combination interventions in diverse settings.

RESUMEN: Las mujeres que intercambian sexo y consumen drogas (WESUD) tienen un alto riesgo de infección por VIH y violencia por parte de sus parejas. Las pocas intervenciones que se han probado en la intersección del VIH y la violencia de pareja muestran resultados mixtos. Este ensayo controlado aleatorio por grupos inscribió a 354 mujeres de 2015 a 2018 y las asignó al azar a una intervención combinada de HIVRR y MF o HIVRR sola. Los resultados se evaluaron en 4 puntos temporales durante 15 meses. La regresión logística dentro de un enfoque bayesiano evaluó el cambio en la violencia reciente perpetrada por las parejas que pagan y/o las parejas y ex-parejas (p.ej. esposos, novios) por brazo de estudio, a través del tiempo. En comparación con el grupo de control, la intervención combinada disminuyó las probabilidades de que los participantes sufrieran violencia física por parte de sus parejas íntimas anteriores en un 14% (OR = 0,861, p = 0,049). Las mujeres en el grupo de intervención informaron tasas significativamente más bajas de violencia sexual por parte de parejas que pagan (HIVRR + MF - HIVRR: 25,9%; OR = 0,741, p = 0,019) a los 12 meses de seguimiento. No se encontraron diferencias significativas en las tasas de parejas íntimas actuales. La combinación de HIVRR y microfinanzas puede ofrecer mayores reducciones en la violencia de las parejas que pagan y las ex-parejas en esta población.

Prevention of HIV Transmission and the HPTN 052 Study.

The HIV Prevention Trials Network 052 study (HPTN 052) was a clinical trial designed to determine whether early treatment for HIV infection prevented transmission of the virus in couples where one partner was infected with HIV and the other was not, referred to as HIV serodiscordant or serodifferent couples. The study enrolled 1,763 couples at 13 sites in 9 countries in Asia, Africa, and the Americas. HPTN 052 demonstrated a minimum of 96% reduction of HIV in heterosexual couples ascribed to antiretroviral treatment; early treatment of HIV significantly reduced other infections in the HIV-infected subjects. This study, in conjunction with similar research, led to significant changes in international HIV treatment guidelines and the concept of treatment as prevention (TasP). This article provides the scientific background and history of how HPTN 052 came into being, the challenges it faced, and the ultimate impact it had on the fields of HIV treatment and prevention.

Freedom as Prevention: Mechanisms of Autonomy Support for Promoting HIV Pre-Exposure Prophylaxis Use and Condom Use among Black MSM in 3 US Cities-HPTN 073.

Healthcare providers who use controlling or coercive strategies may compel short-term enactment of HIV and sexually transmitted infection prevention behaviors but may inadvertently undermine their client's motivation to maintain those behaviors in the absence of external pressure. Autonomous motivation refers to the self-emanating and self-determined drive for engaging in health behaviors. It is associated with long-term maintenance of health behaviors. We used structural equation modeling to investigate whether autonomy support was associated with increased odds of therapeutic serum levels of pre-exposure prophylaxis, through a pathway that satisfies basic psychological needs for autonomous self-regulation and competence regarding pre-exposure prophylaxis use. We also investigated whether autonomy support was associated with decreased odds of condomless anal intercourse via the same psychological needs-satisfaction pathway of autonomous self-regulation and competence regarding condom use. We tested these two theorized pathways using secondary data from a longitudinal sample of Black men who have sex with men from across three cities in the US (N = 226). Data from the sample fit the theorized models regarding the pathways by which autonomy support leads to the presence of therapeutic PrEP levels in serum (χ2 = 0.56; RMSEA = 0.04; CFI = .99, TLI = 0.98) and how it also leads to decreased odds of condomless anal intercourse (χ2 = 0.58; RMSEA = 0.03; CFI = 0.99; TLI = 0.98). These findings provide scientific evidence for the utility of self-determination theory as a model to guide intervention approaches to optimize the implementation and impact of PrEP for Black men who have sex with men.

Factors associated with vaccination completion and retention among HIV negative female sex workers enrolled in a simulated vaccine efficacy trial in Kampala, Uganda.

BACKGROUND: Female sex workers (FSWs) at substantial risk of HIV are potentially a suitable group for HIV prevention trials including vaccine trials. Few HIV vaccine preparatory studies have been conducted among FSWs in Sub-Saharan Africa (SSA); data are therefore limited on acceptability of vaccine trial procedures. We determined vaccination completion and one-year retention among FSWs in Kampala, Uganda. METHODS: We conducted a prospective study that simulated a vaccine efficacy trial among HIV negative FSWs (18-49 years). Hepatitis B vaccine (Engerix B) was used to mimic an HIV vaccine product. Volunteers received 1 ml intramuscular injection at 0, 1 and 6 months, and made additional visits (3 days post-vaccination and months 3, 9 and 12). They were censored at that visit if diagnosed as HIV positive or pregnant. We collected socio-demographic, behavioral and clinical data at baseline, 6 and 12 months and fitted Poisson regression models with robust standard error to find factors associated with vaccination completion and retention. RESULTS: We enrolled 290 volunteers (median age 27 years) of whom 230 reached a study end-point as follows: 7 became HIV infected, 11 became pregnant and 212 completed both the vaccination schedule and 12-month visit giving a retention of 77.9% (212/272). Vaccination completion was 82.4%. Non-retention at 1 year was more likely among those reporting symptoms of genital ulcer disease (GUD) in the past 3 months (IRR 1.90; 95% CI 1.09-3.32) and those < 35 years; (IRR 6.59; 95% CI 2.11-20.57). Non-completion of the vaccination schedule was associated with being < 35 years (IRR 13.10; 95% CI 1.89-90.92, reporting GUD symptoms (IRR 3.02; 95% CI 1.71-5.33) and reporting consistent condom use with new sexual partners (IRR 2.57; 95% CI 1.10-6.07). CONCLUSIONS: FSWs are at substantial risk of HIV infection and yet willing to participate in HIV vaccine and prevention research; young FSWs should be empowered, and those reporting GUD symptoms need close follow up to improve participation in future HIV vaccine trials.

The "3 Ps" of EmPowerment, Partnership and Protection - Stakeholder Perceptions of Beneficial Outcomes of Engagement in HIV Prevention Trials.

Background: Stakeholder engagement is increasingly recognized as a key component of ethical research in leading ethics guidelines. Ethics commentators have also argued that engagement has several beneficial outcomes for the field. Aim: This paper reports on the beneficial outcomes of stakeholder engagement in HIV prevention trials as perceived by stakeholders in the field. Method: We conducted 28 interviews between 2019 and 2021 with interviewees from various stakeholder groups in 12 countries and used thematic analysis to analyze the transcripts. Findings: We found three major themes - namely emPowerment where engagement is perceived to empower stakeholders, Partnerships where engagement is perceived to build equitable relationships and Protections where engagement is perceived to strengthen protections for participants and community stakeholders and to improve science. Conclusions: These findings map closely onto beneficial outcomes envisaged by ethics guidelines, however, the relationship between outcomes seen as beneficial deserves further exploration.

Understanding effective post-test linkage strategies for HIV prevention and care: a scoping review.

INTRODUCTION: Following HIV testing services (HTS), the World Health Organization recommends prompt linkage to prevention and treatment. Scale-up of effective linkage strategies is essential to achieving the global 95-95-95 goals for maintaining low HIV incidence by 2030 and reducing HIV-related morbidity and mortality. Whereas linkage to care including same-day antiretroviral therapy (ART) initiation for all people with HIV is now routinely implemented in testing programmes, linkage to HIV prevention interventions including behavioural or biomedical strategies, for HIV-negative individuals remains sub-optimal. This review aims to evaluate effective post-HTS linkage strategies for HIV overall, and highlight gaps specifically in linkage to prevention. METHODS: Using the five-step Arksey and O'Malley framework, we conducted a scoping review searching existing published and grey literature. We searched PubMed, Cochrane Library, CINAHL, Web of Science and EMBASE databases for English-language studies published between 1 January 2010 and 30 November 2023. Linkage interventions included as streamlined interventions-involving same-day HIV testing, ART initiation and point-of-care CD4 cell count/viral load, case management-involving linkage coordinators developing personalized HIV care and risk reduction plans, incentives-financial and non-financial, partner services-including contact tracing, virtual-like social media, quality improvement-like use of score cards, and peer-based interventions. Outcomes of interest were linkage to any form of HIV prevention and/or care including ART initiation. RESULTS: Of 2358 articles screened, 66 research studies met the inclusion criteria. Only nine linkage to prevention studies were identified (n = 9/66, 14%)-involving pre-exposure prophylaxis, voluntary medical male circumcision, sexually transmitted infection and cervical cancer screening. Linkage to care studies (n = 57/66, 86%) focused on streamlined interventions in the general population and on case management among key populations. DISCUSSION: Despite a wide range of HIV prevention interventions available, there was a dearth of literature on HIV prevention programmes and on the use of messaging on treatment as prevention strategy. Linkage to care studies were comparatively numerous except those evaluating virtual interventions, incentives and quality improvement. CONCLUSIONS: The findings give insights into linkage strategies but more understanding of how to provide these effectively for maximum prevention impact is needed.

My Way: development and preliminary evaluation of a novel delivery system for PrEP and other sexual health needs of young women in Western Kenya.

INTRODUCTION: Young women in sub-Saharan Africa are a priority population for HIV prevention, yet challenges with adherence and persistence to HIV pre-exposure prophylaxis (PrEP) are common. This study involved the development and pilot testing of My Way-a novel delivery system for PrEP and co-packaged sexual health services. METHODS: My Way was developed in Kisumu, Kenya through a user-centred design process (2020). The intervention involves peer-delivery and support for HIV testing and PrEP use, self-collected vaginal swabs for sexually transmitted infection (STI) testing, pregnancy testing, oral contraceptive pills, self-injectable medroxyprogesterone and/or condoms. My Way was assessed among 16- to 24-year-old sexually active women in a randomized controlled trial versus standard of care (SoC; 2021-2022). Use of PrEP and other sexual health services were tracked at 1, 3 and 6 months for feasibility. Acceptability was determined by questionnaire. The effect of the intervention on tenofovir diphosphate (TFV-DP) levels was assessed by chi-square test (primary outcome); other predictors were explored with regression analysis. RESULTS: Among 150 women, the median age was 22 years and the median number of sexual partners was 2. Moderate/severe depression was common (60%). In the intervention arm, peers made 88% (198/225) of possible kit deliveries (177 with PrEP) and 49 STIs were diagnosed. In the SoC arm, 24% (55/225) of expected clinic visits occurred (53 with PrEP); no STI testing was performed. TVF-DP was detected in 16 participants at 6 months: 16% (12/75) in the intervention arm versus 5% (4/75) in the SoC arm (p = 0.03). Persistence among those with ongoing HIV prevention needs (i.e. prevention-effective persistence) was 18% (12/67) versus 7% (4/56; p = 0.08). No women acquired HIV. The intervention was significantly associated with detectable TFV-DP (OR 3.5, 1.1-11.4; p = 0.04); moderate/severe depression trended towards an association with TFV-DP (OR 0.2, 0.03-1.6; p = 0.13). CONCLUSIONS: My Way is a promising delivery system for PrEP and other sexual health services among young women in Western Kenya. We found high feasibility and acceptability. PrEP use was modest, but higher with My Way compared to SoC. Long-acting PrEP formulations may overcome important barriers to PrEP use and should be explored in combination with the My Way delivery model.

Accelerating investigation of new HIV drugs in pregnancy: advancing the research agenda from theory to action.

INTRODUCTION: Historical approaches to clinical development of novel therapeutics for treatment and prevention of HIV have led to unacceptable delays in the generation of data to support optimal antiretroviral drug use in pregnancy. Over the last 5 years, multiple stakeholders have voiced their concerns around the exclusion of pregnant women from drug trials, and some progress has been made to consolidate principles and forge consensus. Building on ongoing efforts, the World Health Organization (WHO) and the International Maternal Paediatric Adolescent AIDS Clinical Trials Network (IMPAACT) convened a technical consultation designed to move the discussion from theory to practice. DISCUSSION: Accelerating the inclusion of pregnant women in pre-licensure clinical trials, with a goal to have pharmacokinetics (PK) and preliminary safety data for all new HIV agents in pregnancy available at the time of drug approval, requires: (1) performing non-clinical developmental and reproductive toxicology studies early in drug development for all new HIV agents; (2) recognizing and acting on the central role of women of childbearing potential affected by HIV through the research being conducted and the dissemination of associated results; (3) enrolling pregnant women in studies to specifically determine pregnancy PK and preliminary safety, as soon as late non-clinical studies are completed with no negative signals, for all new HIV agents that have demonstrated preliminary evidence of safety and efficacy from phase 2 trials; (4) investigating adverse pregnancy and birth outcomes through dedicated pregnancy safety studies for all new priority HIV agents; and (5) expanding active surveillance of drug safety in pregnancy for rare events, such as birth defects. Strategic actions to pursue include developing tools and resources to support designing and implementing studies among pregnant and breastfeeding women, identifying and promoting modifications of the regulatory framework that are supportive of systematic ethical investigation of new drugs in pregnancy, coordinating surveillance efforts, mobilizing key stakeholders and promoting transparency and accountability for all involved. CONCLUSIONS: With more than 19 million women living with HIV worldwide, ensuring greater inclusion of pregnant women in research on novel therapeutics is a priority to support drug optimization and effective introduction of innovations for treatment and prevention of HIV.

A qualitative exploration to understand barriers and facilitators to daily oral PrEP uptake and sustained adherence among HIV-negative women planning for or with pregnancy in rural Southwestern Uganda.

INTRODUCTION: Antiretroviral pre-exposure prophylaxis (PrEP) may reduce periconception and pregnancy HIV incidence among women in settings, where gender power imbalances limit HIV testing, engagement in care and HIV viral suppression. We conducted qualitative interviews to understand factors influencing periconception and pregnancy PrEP uptake and use in a cohort of women (Trial registration: NCT03832530) offered safer conception counselling in rural Southwestern Uganda, where PrEP uptake was high. METHODS: Between March 2018 and January 2019, in-depth interviews informed by conceptual frameworks for periconception risk reduction and PrEP adherence were conducted with 37 women including those with ≥80% and <80% adherence to PrEP doses measured by electronic pill cap, those who never initiated PrEP, and seven of their male partners. Content and dyadic analyses were conducted to identify emergent challenges and facilitators of PrEP use within individual and couple narratives. RESULTS: The median age for women was 33 years (IQR 28, 35), 97% felt likely to acquire HIV and 89% initiated PrEP. Individual-level barriers included unwillingness to take daily pills while healthy, side effects and alcohol use. Women overcame these barriers through personal desires to have control over their HIV serostatus, produce HIV-negative children and prevent HIV transmission within partnerships. Couple-level barriers included nondisclosure, mistrust and gender-based violence; facilitators included shared goals and perceived HIV protection, which improved communication, sexual intimacy and emotional support within partnerships through a self-controlled method. Community-level barriers included multi-level stigma related to HIV, ARVs/PrEP and serodifference; facilitators included active peer, family or healthcare provider support as women aspired to safely meet socio-cultural expectations to conceive and preserve serodifferent relationships. Confidence in PrEP effectiveness was promoted by positive peer experiences with PrEP and ongoing HIV testing. CONCLUSIONS: Multi-level forms of HIV-, serodifference- and disclosure-related stigma, side effects, pill burden, alcohol use, relationship dynamics, social, professional and partnership support towards adaptation and HIV risk reduction influence PrEP uptake and adherence among HIV-negative women with plans for pregnancy in rural Southwestern Uganda. Confidence in PrEP, individually controlled HIV prevention and improved partnership communication and intimacy promoted PrEP adherence. Supporting individuals to overcome context-specific barriers to PrEP use may be an important approach to improving uptake and prolonged use.

Modeling the Probability of HIV Infection over Time in High-Risk Seronegative Participants Receiving Placebo in Five Randomized Double-Blind Placebo-Controlled HIV Pre-Exposure Prophylaxis Trials: A Patient-Level Pooled Analysis.

The World Health Organization recommends pre-exposure prophylaxis (PrEP) for individuals at substantial risk of HIV infection. The aim of this analysis is to quantify the individual risk of HIV infection over time, using a large database of high-risk individuals (n = 5583). We used data from placebo recipients in five phase III PrEP trials: iPrEx, conducted in men who have sex with men and transgender women; VOICE, conducted in young women at high sexual risk; Partners PrEP, conducted in HIV serodiscordant heterosexual couples; TDF2, conducted in high-risk heterosexual men and women; and BTS, conducted in persons who inject drugs. The probability of HIV infection over time was estimated using NONMEM7.4. We identified predictors of HIV risk and found a substantial difference in the risk of infection among and within trial populations, with each study including a mix of low, moderate, and high-risk individuals (p < 0.05). Persons who were female at birth were at a higher risk of HIV infection than people who were male at birth. Final models were integrated in a tool that can assess person-specific risk and simulate cumulative HIV risk over time. These models can be used to optimize future PrEP clinical trials by identifying potential participants at highest risk.

Comparison between daily and on-demand PrEP (pre-exposure prophylaxis) regimen in covering condomless anal intercourse for men who have sex with men in Hong Kong: A randomized, controlled, open-label, crossover trial.

INTRODUCTION: Both daily and on-demand regimens have been proven effective for pre-exposure prophylaxis (PrEP) against HIV in men who have sex with men (MSM). We aimed to compare the two regimens on their coverage of condomless anal intercourse (CLAI) in MSM. METHODS: A randomized, controlled, open-label, crossover trial was conducted in a teaching hospital in Hong Kong. Participants were sexually active HIV-negative MSM aged 18 years or above with normal renal function and without chronic hepatitis B infection. Oral tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg (TDF/FTC) tablets were prescribed for PrEP. After a 2-week lead-in with daily TDF/FTC for treatment-naïve MSM for tolerance assessment, participants were randomly assigned in a 1:1 ratio with a block size of four to either daily-first or on-demand-first arm based on the IPERGAY study, for receiving PrEP for 16 weeks, then crossed-over to the alternative regimen for another 16 weeks. The primary outcome was the proportion of days with PrEP-covered CLAI by intention-to-treat analysis. The trial is registered with the CCRB Clinical Trials Registry, CUHK, CUHK_CCRB00606, and is closed to accrual. RESULTS: Between 25 August 2018 and 23 March 2019, 119 eligible participants were assigned to daily-first arm (n = 59) and on-demand-first arm (n = 60) with an 87% overall completion rate (n = 103). With 96% and 54% of days on PrEP during daily and on-demand periods, respectively, the proportion of days with PrEP-covered CLAI between two arms were not statistically different (92% vs. 92%, p = 0.93). About half (47%) were diagnosed with at least one episode of incident sexually transmitted infection. Mild and time-limited adverse events, including diarrhoea, headache, nausea and dizziness, were reported in 37 (31%) and 10 (8%) during the daily and on-demand periods, respectively. At the end of the study, a similar proportion favoured daily or on-demand regimen. CONCLUSIONS: High prevention-effective adherence, as reflected from the coverage of CLAI, was achievable by either daily or on-demand PrEP among MSM, albeit a higher number of tablets taken for daily PrEP. As both regimens were well accepted, a flexible approach adopting either or both regimens with possible switching is warranted in order to suit individual health needs.

Greater dapivirine release from the dapivirine vaginal ring is correlated with lower risk of HIV-1 acquisition: a secondary analysis from a randomized, placebo-controlled trial.

INTRODUCTION: A vaginal ring containing 25 mg of the antiretroviral dapivirine has demonstrated efficacy in reducing women's risk of sexually acquiring HIV-1; however, imperfect ring use likely diluted efficacy estimates in clinical trials. The amount of dapivirine remaining in returned rings may reflect the extent of product use, permitting estimation of HIV protection in the context of consistent use. METHODS: We measured the amount of dapivirine in returned rings from a placebo-controlled trial of the dapivirine vaginal ring conducted between August 2012 and June 2015 among 2629 African women. Phase I/II studies established that greater than 4 mg of dapivirine on average is released from the ring when used consistently over 28 days and ≤0.9 mg released suggested non-use. We assessed the relative risk reduction associated with levels of ring use using residual dapivirine in returned rings as a time-dependent covariate for HIV-1 infection in multivariable Cox models, including multiple exploratory analyses designed to estimate upper limits of efficacy given uncertainty in timing of HIV-1 acquisition. All models were adjusted for baseline covariates associated with HIV risk and adherence. RESULTS: Residual dapivirine levels indicating at least some use (>0.9 mg released over a month) were associated with a 48% relative reduction in HIV-1 acquisition risk (95% confidence interval (CI): 21% to 66%; p = 0.002) compared to the placebo. Exploratory analyses accounting for potential misclassification in timing of HIV-1 acquisition estimated 75% to 91% HIV-1 risk reduction with> 4 mg released when compared to placebo. Results limited to the subgroup of women <25 years of age, who tended to have lower adherence, were generally consistent to those overall. CONCLUSIONS: Residual dapivirine levels, an objective measure of adherence, were correlated with HIV-1 protection in a secondary analysis of a randomized trial. Periods of ring use were associated with approximately 50% protection, with exploratory analyses suggesting higher protection with more consistent use. The dapivirine vaginal ring is the first method to fulfil the promise of a fully reversible, long-acting, woman-initiated approach for discreet HIV-1 prevention.

Joint modeling of time-varying HIV exposure and infection for estimation of per-act efficacy in HIV prevention trials.

OBJECTIVES: Using the MTN-020/ASPIRE HIV prevention trial as a motivating example, our objective is to construct a joint model for the HIV exposure process through vaginal intercourse and the time to HIV infection in a population of sexually active women. By modeling participants' HIV infection in terms of exposures, rather than time exposed, our aim is to obtain a valid estimate of the per-act efficacy of a preventive intervention. METHODS: Within the context of HIV prevention trials, in which the frequency of sex acts is self-reported periodically by the participants, we model the exposure process of the trial participants with a non-homogeneous Poisson process. This approach allows for variability in the rate of sexual contacts between participants as well as variability in the rate of sexual contacts over time. The time to HIV infection for each participant is modeled as the time to the exposure that results in HIV infection, based on the modeled sexual contact rate. We propose an empirical Bayes approach for estimation. RESULTS: We report the results of a simulation study where we evaluate the performance of our proposed approachandcompareittothetraditionalapproachofestimatingtheoverallreductioninHIVincidenceusing a Proportional Hazards Cox model. The proposed approach is also illustrated with data from the MTN-020/ASPIRE trial. CONCLUSIONS: The proposed joint modeling, along with the proposed empirical Bayes estimation approach, can provide valid estimation of the per-exposure efficacy of a preventive intervention.

Estimation of new HIV diagnosis rates among high-risk, PrEP-eligible individuals using HIV surveillance data at the Metropolitan Statistical Area level in the United States.

INTRODUCTION: New HIV diagnoses have fallen in the past decade due to increased HIV testing, earlier diagnosis, earlier antiretroviral treatment, improved linkage to care and engagement in care, and the recent increased uptake of pre-exposure prophylaxis (PrEP). We propose a novel method to compute the rate of new HIV diagnoses at the Metropolitan Statistical Area (MSA) level in the US to support the evaluation of comprehensive treatment and prevention efforts over time. METHODS: The number of new HIV diagnoses, number of individuals with a PrEP indication and aggregated person-time exposed to PrEP during the years 2012 to 2017 were used to compute a new HIV diagnosis rate for people at risk of HIV excluding those already on PrEP for the 105 MSAs in the US with published HIV surveillance data. In our calculation of person-time with a PrEP indication, time-at-risk excluded time on PrEP and time after an HIV diagnosis. We used a multivariate Poisson regression model to estimate HIV diagnosis rates by year and location. RESULTS: From 2012 to 2017, the aggregate HIV diagnoses rate among high-risk individuals with an indication for PrEP in the 105 MSAs decreased from 4.14 per 100 person-years (PY) (95% CI 4.10 to 4.19) to 3.26 per 100 PY (95% CI 3.22 to 3.30). For the 25 US MSAs that overlapped with an ongoing large randomized clinical trial of PrEP in men who have sex with men (MSM), the HIV diagnosis rate from 2012 to 2017 decreased from 4.86 per 100 PY (95% CI 4.80 to 4.93) to 3.61 per 100 PY (95% CI 3.56 to 3.66), a decline that was more rapid than in non-study MSAs (IRR for trial site 1.19, 95% CI 1.18 to 1.20). CONCLUSIONS: We propose a model to estimate the background HIV diagnosis rate in people at risk for HIV and with a PrEP indication in US MSAs (excluding those on PrEP) using publically available surveillance data which can evaluate trends over time. Data generated using this methodology could be used by policy makers and local HIV prevention specialists to evaluate and monitor their prevention efforts for the population at risk in their communities.

Participant satisfaction with clinical trial experience and post-trial transitioning to HIV care in Kenya.

We conducted an exploratory analysis of former HIV Prevention Trials Network 052 (HPTN 052) clinical trial participants in 2016 to assess their (1) satisfaction with the HPTN 052 clinical trial care and treatment, and reasons for joining the trial; and (2) perspectives about the post-trial transition to public HIV care centers. Quantitative data showed that, of the 70 survey participants, 94.3% (n = 66) reported being very satisfied with the care and treatment they received while participating in the clinical trial and 51.4% (n = 36) reported they joined the study because they would receive information to improve their own or their partner's health. Qualitative data (five in-depth interviews and two focus group discussions) analysis revealed the following themes: transition experiences; perceived superior clinical trial care; study benefits not offered at public HIV care centers; and the public HIV care centers' indifference to the uninfected partner. For some HPTN 052 participants, transition to HIV care clinics was disappointing. Clinical trial investigators and local Institutional Review Boards should consider the need for safeguards and oversight of post-trial health care for trial participants after the trial ends, especially in resource-constrained settings, to avoid negative health outcomes.

Strengthening stakeholder engagement through ethics review in biomedical HIV prevention trials: opportunities and complexities.

INTRODUCTION: Clinical trials of biomedical HIV prevention modalities require the cooperation of multiple stakeholders. Key stakeholders, such as community members, may have stark vulnerabilities. Consequently, calls for HIV prevention researchers to implement "stakeholder engagement" are increasingly common. Such engagement is held to benefit inter-stakeholder relations, stakeholders themselves and the research itself. The ethics review process presents a unique opportunity to strengthen stakeholder engagement practices in HIV prevention trials. However, this is not necessarily straightforward. In this article, we consider several complexities. First, is stakeholder engagement a legitimate component of what Research Ethics Committees (RECs) should review for HIV prevention trials? Second, what are the core features of engagement that should be under ethics review? Third, what are the key practices that should be highlighted in ethics review? METHODS: To address these questions, we examined the international ethics guidelines specialized for such trials (UNAIDS 2012, UNAIDS-AVAC GPP 2011) and directly applicable to such trials (CIOMS 2016; WHO 2011). Thematic analysis was used to code and analyse these guidelines. RESULTS AND DISCUSSION: Ethics guidelines support REC review of engagement. Guidance recommends that engagement be broad and inclusive; early and sustained; and dynamic and responsive. Broad engagement practices include evaluating the context, planning in writing, and resourcing. RECs should assess engagement as part of a comprehensive review, and recommend revisions where necessary. Researchers should profile key elements of engagement valued in ethics guidance, when they draft ethics submissions. Importantly, the ethics review process should not undermine the 'dynamic responsiveness' required for excellent engagement in this field. CONCLUSIONS: As evidence-informed engagement strategies emerge, these should inform the ethics submission and review process. Both parties in the review process should strive to avoid a superficial, check-list type approach that caricatures what should be a thorough, nuanced ethics review of a rich, responsive engagement process.

". . . I've Gone Through This My Own Self, So I Practice What I Preach . . . ".

There has not been enough study of the processes by which site staff help participating community members and potential participants to understand complicated concepts for HIV vaccine trials. This article describes strategies reported in six focus group discussions with Community Advisory Board members, educators, and consent counselors at an active HIV vaccine trial site in South Africa. Thematic analysis identified a considerable range of strategies, and findings suggest that such staff do not only try to promote understanding of critical information but also try to build trust in communicated information, to respect cultural differences, and to promote voluntariness. Findings also suggest occasional tensions between these implicit goals. Actual engagement and consent encounters at HIV vaccine trial sites should be observed, recorded, and analyzed; and the relationship between practices and valued outcomes should be assessed. These efforts may help to make consent-related encounters as "potent" as possible given finite resources.

Taking culture seriously in biomedical HIV prevention trials: a meta-synthesis of qualitative studies.

A substantial gap exists between widespread acknowledgement of the importance of incorporating cultural sensitivity in biomedical HIV prevention trials and empirical evidence to guide the operationalization of cultural sensitivity in these trials. We conducted a systematic literature search and qualitative meta-synthesis to explore how culture is conceptualized and operationalized in global biomedical HIV prevention trials. Across 29 studies, the majority (n = 17) were conducted in resource-limited settings. We identified four overarching themes: (1) semantic cultural sensitivity - challenges in communicating scientific terminology into local vernaculars; (2) instrumental cultural sensitivity - understanding historical experiences to guide tailoring of trial activities; (3) budgetary, logistical, and personnel implications of operationalizing cultural sensitivity; and (4) culture as an asset. Future investigations should address how sociocultural considerations are operationalized across the spectrum of trial preparedness, implementation, and dissemination in particular sociocultural contexts, including intervention studies and evaluations of the effectiveness of methods used to operationalize culturally sensitive practices.