Long-acting cabotegravir pharmacokinetics with and without oral lead-in for HIV PrEP.

Long-acting cabotegravir is approved for pre-exposure prophylaxis and combination HIV treatment, both initiated with optional short-term oral lead-in (OLI). We evaluated the impact of OLI on long-acting cabotegravir pharmacokinetics. Cabotegravir plasma concentrations were compared between HIV-positive participants initiating injections with (n = 278) or without (n = 110) OLI in phase III treatment study FLAIR and in HIV-negative participants using OLI (n = 263) in pivotal pre-exposure prophylaxis studies HPTN 083 and HPTN 084. Cabotegravir pharmacokinetic profiles were simulated in three populations (assigned-male-at-birth, 50%-assigned-female-at-birth, and assigned-female-at-birth) under three scenarios: first injection given (A) 1 or (B) 3 days after final OLI dose (OLI-injection gap) or (C) without OLI. The PK objective was 80% of participants achieving 4× in vitro protein-adjusted 90% maximal inhibitory concentration (PA-IC90) and 50% achieving 8× PA-IC90. Observed trough concentrations (Cτ) were similar with and without OLI (P > 0.3). With a 3-day OLI-injection gap, simulated pre-injection Cτ remained above PK objective. Approximately 1-2 weeks after the first injection, simulated PK profiles became nearly identical among all scenarios. Without OLI, it was predicted that 80% of participants achieve 4× PA-IC90 in 1.2, 1.8, and 2.8 days after the first injection in each population, respectively, and 50% achieve 8× PA-IC90 in 1.4, 2.1, and 3.8 days, respectively. Observed long-acting cabotegravir exposure was similar with or without OLI, supporting optional OLI use. Cabotegravir exposure was predicted to remain above PK objective for OLI-injection gaps of ≤3 days and rapidly achieve PK objective after first injection without OLI. Findings are consistent between assigned-male-at-birth and assigned-female-at-birth populations.This study is registered with ClinicalTrials.gov as NCT02720094.

Pharmacologic evaluation of delayed long-acting cabotegravir administration among cisgender women in HPTN 084.

HPTN 084 demonstrated the superiority of long-acting injectable cabotegravir (CAB-LA) compared with daily oral tenofovir disoproxil fumarate-emtricitabine (F/TDF) for HIV prevention in women. CAB-LA (600 mg) or placebo injections were administered 4 weeks after an initial dose (loading dose) and every 2 months (Q2M) thereafter; this is the approved regimen. Participants experienced both loading dose and Q2M delays during the trial. CAB concentrations were evaluated before a delay, at the visit associated with the delay, and the visit after a delayed injection was administered. During the blinded phase of the trial, 194 participants randomized to CAB-LA experienced at least one injection delay. Plasma CAB concentrations were maintained above the 4× protein adjusted 90% inhibitory concentration (4× PA-IC90; protocol-specific threshold) for all loading dose and 98% of Q2M delays when injections were administered up to 6 weeks late. The feasibility of shifting to an every 3-month (Q3M) regimen in females was interrogated via simulation studies using a population pharmacokinetic model. Q3M injections in both CAB-naïve (with a loading dose) and previously CAB-exposed females were predicted to yield higher steady-state exposures than in males on the approved Q2M regimen. Although there is observed forgiveness following an isolated delayed CAB-LA injection and simulations suggest acceptable CAB-LA exposures in women with a 600 mg CAB-LA Q3M regimen, empirical efficacy of this regimen has not been established, and transitioning to this dosing schema is not recommended. Future pharmacokinetic bridging studies are aimed at evaluating higher dose CAB-LA formulations administered less frequently. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT03164564.

Hoping to Adhere? Examining the Relationship Between Hope and Pre-exposure Prophylaxis Willingness, Adherence, and Persistence Among Young Women in South Africa and Zimbabwe (HPTN 082).

Hope is a powerful psychological construct which is linked to positive health. Greater hope is associated with improved antiretroviral therapy adherence; however, less is known about the impact of hope on oral pre-exposure prophylaxis (PrEP) outcomes. HIV Prevention Trials Network 082, was an open-label PrEP study among young women (ages 16-25) in South Africa and Zimbabwe. Hope was measured at baseline and follow-up using a subset of the Hope for the Future Scale (score range 6-24) and PrEP willingness was measured using a subscale of the HIV Prevention Readiness Measure (score range 6-30). Intracellular tenofovir-diphosphate (TFV-DP) concentrations were obtained from dried blood spot samples at weeks 13, 26, and 52; high PrEP adherence was defined as TFV-DP concentrations ≥ 700 fmol/punch. Persistence was defined as TFV-DP > 16 fmol/punch at weeks 26 and 52. Linear regression and generalized estimating equations were used to assess the relationship between hope and PrEP willingness, adherence, and persistence. The median age of participants (n = 432) was 21 years (interquartile range [IQR]: 19-22). The mean hope score at baseline was 21.0 (SD = 3.4). Although hope was positively associated with PrEP willingness (ß = 0.22, 95% CI 0.15, 0.37), it was not associated with high PrEP adherence (aRR = 1.00, 95% CI 0.96, 1.05), or persistence at follow-up (aRR = 1.02, 95% CI 0.99, 1.05). While cultivating hope may be an important strategy in building willingness to take oral PrEP, it may not be enough to sustain PrEP adherence or persistence.

Regional and country-level trends in cervical cancer screening coverage in sub-Saharan Africa: A systematic analysis of population-based surveys (2000-2020).

BACKGROUND: Sub-Saharan Africa (SSA) has the highest cervical cancer (CC) burden globally-worsened by its HIV epidemics. In 2020, the World Health Organization (WHO) introduced a CC elimination strategy with goals for vaccination, screening, and treatment. To benchmark progress, we examined temporal trends in screening coverage, percent screened at least twice by the age of 45, screening coverage among women living with HIV (WLHIV), and pre-cancer treatment coverage in SSA. METHODS AND FINDINGS: We conducted a systematic analysis of cross-sectional population-based surveys. It included 52 surveys from 28 countries (2000 to 2020) with information on CC screening among women aged 25 to 49 years (N = 151,338 women). We estimated lifetime and past 3-year screening coverage by age, year, country, and HIV serostatus using a Bayesian multilevel model. Post-stratification and imputations were done to obtain aggregate national, regional, and SSA-level estimates. To measure re-screening by age 45, a life table model was developed. Finally, self-reported pre-cancer treatment coverage was pooled across surveys using a Bayesian meta-analysis. Overall, an estimated 14% (95% credible intervals [95% CrI]: 11% to 21%) of women aged 30 to 49 years had ever been screened for CC in 2020, with important regional and country-level differences. In Eastern and Western/Central Africa, regional screening coverages remained constant from 2000 to 2020 and WLHIV had greater odds of being screened compared to women without HIV. In Southern Africa, however, screening coverages increased and WLHIV had equal odds of screening. Notably this region was found to have higher screening coverage in comparison to other African regions. Rescreening rates were high among women who have already been screened; however, it was estimated that only 12% (95% CrI: 10% to 18%) of women had been screened twice or more by age 45 in 2020. Finally, treatment coverage among 4 countries with data was 84% (95% CrI: 70% to 95%). Limitations of our analyses include the paucity of data on screening modality and the few countries that had multiple surveys. CONCLUSION: Overall, CC screening coverage remains sub-optimal and did not improve much over the last 2 decades, outside of Southern Africa. Action is needed to increase screening coverage if CC elimination is to be achieved.

Cabotegravir for the prevention of HIV-1 in women: results from HPTN 084, a phase 3, randomised clinical trial.

BACKGROUND: Oral pre-exposure prophylaxis has been introduced in more than 70 countries, including many in sub-Saharan Africa, but women experience considerable barriers to daily pill-taking, such as stigma, judgement, and the fear of violence. Safe and effective long-acting agents for HIV prevention are needed for women. We aimed to evaluate the safety and efficacy of injectable cabotegravir compared with daily oral tenofovir diphosphate plus emtricitabine (TDF-FTC) for HIV prevention in HIV-uninfected women. METHODS: HPTN 084 was a phase 3, randomised, double-blind, double-dummy, active-controlled, superiority trial in 20 clinical research sites in seven countries in sub-Saharan Africa. Participants were eligible for enrolment if they were assigned female sex at birth, were aged 18-45 years, reported at least two episodes of vaginal intercourse in the previous 30 days, were at risk of HIV infection based on an HIV risk score, and agreed to use a long-acting reversible contraceptive method. Participants were randomly assigned (1:1) to either active cabotegravir with TDF-FTC placebo (cabotegravir group) or active TDF-FTC with cabotegravir placebo (TDF-FTC group). Study staff and participants were masked to study group allocation, with the exception of the site pharmacist who was responsible for study product preparation. Participants were prescribed 5 weeks of daily oral product followed by intramuscular injections every 8 weeks after an initial 4-week interval load, alongside daily oral pills. Participants who discontinued injections were offered open-label daily TDF-FTC for 48 weeks. The primary endpoints of the study were incident HIV infection in the intention-to-treat population, and clinical and laboratory events that were grade 2 or higher in all women who had received at least one dose of study product. This study is registered with ClinicalTrials.gov, NCT03164564. FINDINGS: From Nov 27, 2017, to Nov 4, 2020, we enrolled 3224 participants (1614 in the cabotegravir group and 1610 in the TDF-FTC group). Median age was 25 years (IQR 22-30); 1755 (54·7%) of 3209 had two or more partners in the preceding month. 40 incident infections were observed over 3898 person-years (HIV incidence 1·0% [95% CI 0·73-1·40]); four in the cabotegravir group (HIV incidence 0·2 cases per 100 person-years [0·06-0·52]) and 36 in the TDF-FTC group (1·85 cases per 100 person-years [1·3-2·57]; hazard ratio 0·12 [0·05-0·31]; p<0·0001; risk difference -1·6% [-1·0% to -2·3%]. In a random subset of 405 TDF-FTC participants, 812 (42·1%) of 1929 plasma samples had tenofovir concentrations consistent with daily use. Injection coverage was 93% of the total number of person-years. Adverse event rates were similar across both groups, apart from injection site reactions, which were more frequent in the cabotegravir group than in the TDF-FTC group (577 [38·0%] of 1519 vs 162 [10·7%] of 1516]) but did not result in injection discontinuation. Confirmed pregnancy incidence was 1·3 per 100 person-years (0·9-1·7); no congenital birth anomalies were reported. INTERPRETATION: Although both products for HIV prevention were generally safe, well tolerated, and effective, cabotegravir was superior to TDF-FTC in preventing HIV infection in women. FUNDING: National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and the Bill & Melinda Gates Foundation. Additional support was provided through the National Institute of Mental Health, the National Institute on Drug Abuse, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. ViiV Healthcare and Gilead Sciences provided pharmaceutical support.

High prevalence and incidence of gonorrhoea and chlamydia in young women eligible for HIV pre-exposure prophylaxis in South Africa and Zimbabwe: results from the HPTN 082 trial.

INTRODUCTION: We investigated the prevalence, incidence and factors associated with sexually transmitted infections (STIs) among young African women seeking HIV pre-exposure prophylaxis (PrEP). METHODS: HPTN 082 was a prospective, open-label PrEP study enrolling HIV-negative sexually active women aged 16-25 years in Cape Town and Johannesburg, South Africa, and Harare, Zimbabwe. Endocervical swabs from enrolment, months 6 and 12 were tested for Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) by nucleic acid amplification, and Trichomonas vaginalis (TV) by a rapid test. Intracellular tenofovir-diphosphate (TFV-DP) concentrations in dried blood spots were measured at months 6 and 12. Associations between risk characteristics and STI outcomes were assessed using Poisson regression. RESULTS: Of 451 enrolled participants, 55% had an STI detected at least once. CT incidence was 27.8 per 100 person-years (py) (95% CI 23.1, 33.2), GC incidence was 11.4 per 100 py (95% CI 8.5, 15.0) and TV incidence was 6.7 per 100 py (95% CI 4.5, 9.5). 66% of incident infections were diagnosed in women uninfected at baseline. Baseline cervical infection (GC or CT) risk was highest in Cape Town (relative risk (RR) 2.38, 95% CI 1.35, 4.19) and in those not living with family (RR 1.87, 95% 1.13, 3.08); condom use was protective (RR 0.67, 95% CI 0.45, 0.99). Incident CT was associated with baseline CT (RR 2.01; 95% CI 1.28, 3.15) and increasing depression score (RR 1.05; 95% CI 1.01, 1.09). Incident GC was higher in Cape Town (RR 2.40; 95% CI 1.18, 4.90) and in participants with high PrEP adherence (TFV-DP concentrations ≥700 fmol/punch) (RR 2.04 95% CI 1.02, 4.08). CONCLUSION: Adolescent girls and young women seeking PrEP have a high prevalence and incidence of curable STIs. Alternatives to syndromic management for diagnosis and treatment are needed to reduce the burden of STIs in this population. TRIAL REGISTRATION NUMBER: NCT02732730.

The Effect of Disclosure of PrEP Use on Adherence Among African Young Women in an Open-Label PrEP Study: Findings from HPTN 082.

To develop effective PrEP adherence interventions, it is important to understand the interplay between disclosure of pre-exposure prophalxis (PrEP) use, social support, and PrEP adherence. We leveraged the HPTN 082 study conducted among 451 adolescent girls and young women (AGYW) (ages 16 to 25 years, 2016 to 2019) in South Africa and Zimbabwe. Among the 349 who had month three disclosure and PrEP adherence data, 60% (n = 206) felt supported by adults, and 89% (n = 309) disclosed PrEP use to at least one person. PrEP disclosure was not associated with increased adherence, measured by intracellular tenofovir-diphosphate concentrations in dried blood spots. Women who reported having supportive adults, and disclosed to their parents, had higher adherence at 6 months with an increase of 177 fmol/punch (95% CI 12 to 343, t = 2.11, p = 0.04). PrEP interventions that help AGYW identify supportive relationships and effectively communicate the benefits of PrEP may improve PrEP adherence.Clinicaltrials.gov ID number: NCT02732730.

Trust in the provider and accurate self-reported PrEP adherence among adolescent girls and young women in South Africa and Zimbabwe: HPTN 082 study.

BACKGROUND: Trust is an important cornerstone of patient-provider communication. Accurate reporting of pre-exposure prophylaxis (PrEP) adherence is vital for providers to determine who needs adherence support, especially adolescent girls and young women (AGYW) disproportionately affected by newly diagnosed HIV. METHODS: This is a secondary analysis of the HPTN 082 open-label PrEP demonstration trial. From 2016-2018, 451 AGYW aged 16-25 years were enrolled in South Africa (Cape Town and Johannesburg) and Zimbabwe (Harare). PrEP was initiated by 427, and 354 (83%) had month three patient-reported adherence responses and intracellular tenofovir diphosphate (TFV-DP) measurements. The patient-reported adherence response to 'In the past month, how often did you take the tablet?' was dichotomized as 'high' if the response was every day or most days, and 'low' if some days or not many days or never. The biomarker marker evidence of adherence in dried blood spots was defined as 'high' if TFV-DP ≥ 700, and 'low' if < 350 fmol/punch. We used multinomial logistic regression to examine if trust in the PrEP provider was associated with concordance between patient-reported adherence and intracellular tenofovir-diphosphate (TFV-DP). RESULTS: AGYW who reported trust in their providers were almost four-fold (aOR 3.72, 95% CI 1.20-11.51) more likely to have concordant adherence (high self-reported adherence and high TFV-DP concentrations) compared to discordant non-adherence (high self-reported adherence and low TFV-DP concentrations). CONCLUSION: Education and training of providers to build trusting relationships with AGYW may lead to more accurate reporting of PrEP adherence. With accurate reporting, adequate support can be provided to bolster adherence. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02732730.

Characterization of Human Immunodeficiency Virus (HIV) Infections in Women Who Received Injectable Cabotegravir or Tenofovir Disoproxil Fumarate/Emtricitabine for HIV Prevention: HPTN 084.

BACKGROUND: HIV Prevention Trials Network 084 demonstrated that long-acting injectable cabotegravir (CAB) was superior to daily oral tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC) for preventing human immunodeficiency virus (HIV) infection in sub-Saharan African women. This report describes HIV infections that occurred in the trial before unblinding. METHODS: Testing was performed using HIV diagnostic assays, viral load testing, a single-copy RNA assay, and HIV genotyping. Plasma CAB, plasma TFV, and intraerythrocytic TFV-diphosphate concentrations were determined by liquid chromatography-tandem mass spectrometry. RESULTS: Forty HIV infections were identified (CAB arm, 1 baseline infection, 3 incident infections; TDF/FTC arm, 36 incident infections). The incident infections in the CAB arm included 2 with no recent drug exposure and no CAB injections and 1 with delayed injections; in 35 of 36 cases in the TDF/FTC arm, drug concentrations indicated low or no adherence. None of the cases had CAB resistance. Nine women in the TDF/FTC arm had nonnucleoside reverse-transcriptase inhibitor resistance; 1 had the nucleoside reverse-transcriptase inhibitor resistance mutation, M184V. CONCLUSIONS: Almost all incident HIV infections occurred in the setting of unquantifiable or low drug concentrations. CAB resistance was not detected. Transmitted nonnucleoside reverse-transcriptase inhibitor resistance was common; 1 woman may have acquired nucleoside reverse-transcriptase inhibitor resistance from study drug exposure.

The impact of conditional cash transfers for HIV prevention on peer relationships: perspectives from female recipients and non-recipients in HPTN 068.

CCTs are currently being explored for HIV prevention among adolescent girls and young women (AGYW) in Southern Africa. However, little is known about how CCT geared towards adolescents' influence peer relationships, despite evidence that peer relationships form a critical part of development in adolescence. This article presents findings from a qualitative study that explored CCT recipients' and non-recipients' perspectives on the impact of CCTs paid to AGYW on peer relationships.HPTN 068 was a randomised controlled trial that assessed whether providing CCT to AGYW and their households reduces AGYW's risk of acquiring HIV. As part of this trial, we conducted interviews and focus group discussions with sub-samples of AGYW (n = 39), who were both cash recipients and non-recipients. Through content analysis, we explored ways in which the CCT positively or negatively impacted on peer relationships.From the recipients' viewpoint, the CCT improved their social standing within their peer groups. It facilitated peer identity and promoted social connectedness among AGYW receiving the CCT. Receipt of the CCT enabled AGYW to resemble and behave like their peers who had money, allowing their poverty to become "invisible". The CCT facilitated social interactions, information sharing, and instrumental social support among AGYW. CCT recipients experienced an increase in their social capital, evident in their ability to network, share, and reciprocate with others. However, the CCT also evoked negative emotions such as jealousy, anxiety, and resentment among non-recipients and led to a deterioration of personal relationships.CCTs have enormous benefits for AGYW, but they may also have a negative impact on peer relationships. The implementation of HIV prevention interventions focused on structural drivers needs to be conscious of these dynamics and ensure that the negative consequences do not outweigh benefits.

Diagnostic accuracy of cervical cancer screening and screening-triage strategies among women living with HIV-1 in Burkina Faso and South Africa: A cohort study.

BACKGROUND: Cervical cancer screening strategies using visual inspection or cytology may have suboptimal diagnostic accuracy for detection of precancer in women living with HIV (WLHIV). The optimal screen and screen-triage strategy, age to initiate, and frequency of screening for WLHIV remain unclear. This study evaluated the sensitivity, specificity, and positive predictive value of different cervical cancer strategies in WLHIV in Africa. METHODS AND FINDINGS: WLHIV aged 25-50 years attending HIV treatment centres in Burkina Faso (BF) and South Africa (SA) from 5 December 2011 to 30 October 2012 were enrolled in a prospective evaluation study of visual inspection using acetic acid (VIA) or visual inspection using Lugol's iodine (VILI), high-risk human papillomavirus DNA test (Hybrid Capture 2 [HC2] or careHPV), and cytology for histology-verified high-grade cervical intraepithelial neoplasia (CIN2+/CIN3+) at baseline and endline, a median 16 months later. Among 1,238 women (BF: 615; SA: 623), median age was 36 and 34 years (p < 0.001), 28.6% and 49.6% ever had prior cervical cancer screening (p < 0.001), and 69.9% and 64.2% were taking ART at enrolment (p = 0.045) in BF and SA, respectively. CIN2+ prevalence was 5.8% and 22.4% in BF and SA (p < 0.001), respectively. VIA had low sensitivity for CIN2+ (44.7%, 95% confidence interval [CI] 36.9%-52.7%) and CIN3+ (56.1%, 95% CI 43.3%-68.3%) in both countries, with specificity for ≤CIN1 of 78.7% (95% CI 76.0%-81.3%). HC2 had sensitivity of 88.8% (95% CI 82.9%-93.2%) for CIN2+ and 86.4% (95% CI 75.7%-93.6%) for CIN3+. Specificity for ≤CIN1 was 55.4% (95% CI 52.2%-58.6%), and screen positivity was 51.3%. Specificity was higher with a restricted genotype (HPV16/18/31/33/35/45/52/58) approach (73.5%, 95% CI 70.6%-76.2%), with lower screen positivity (33.7%), although there was lower sensitivity for CIN3+ (77.3%, 95% CI 65.3%-86.7%). In BF, HC2 was more sensitive for CIN2+/CIN3+ compared to VIA/VILI (relative sensitivity for CIN2+ = 1.72, 95% CI 1.28-2.32; CIN3+: 1.18, 95% CI 0.94-1.49). Triage of HC2-positive women with VIA/VILI reduced the number of colposcopy referrals, but with loss in sensitivity for CIN2+ (58.1%) but not for CIN3+ (84.6%). In SA, cytology high-grade squamous intraepithelial lesion or greater (HSIL+) had best combination of sensitivity (CIN2+: 70.1%, 95% CI 61.3%-77.9%; CIN3+: 80.8%, 95% CI 67.5%-90.4%) and specificity (81.6%, 95% CI 77.6%-85.1%). HC2 had similar sensitivity for CIN3+ (83.0%, 95% CI 70.2%-91.9%) but lower specificity compared to HSIL+ (42.7%, 95% CI 38.4%-47.1%; relative specificity = 0.57, 95% CI 0.52-0.63), resulting in almost twice as many referrals. Compared to HC2, triage of HC2-positive women with HSIL+ resulted in a 40% reduction in colposcopy referrals but was associated with some loss in sensitivity. CIN2+ incidence over a median 16 months was highest among VIA baseline screen-negative women (2.2%, 95% CI 1.3%-3.7%) and women who were baseline double-negative with HC2 and VIA (2.1%, 95% CI 1.3%-3.5%) and lowest among HC2 baseline screen-negative women (0.5%, 95% CI 0.1%-1.8%). Limitations of our study are that WLHIV included in the study may not reflect a contemporary cohort of WLHIV initiating ART in the universal ART era and that we did not evaluate HPV tests available in study settings today. CONCLUSIONS: In this cohort study among WLHIV in Africa, a human papillomavirus (HPV) test targeting 14 high-risk (HR) types had higher sensitivity to detect CIN2+ compared to visual inspection but had low specificity, although a restricted genotype approach targeting 8 HR types decreased the number of unnecessary colposcopy referrals. Cytology HSIL+ had optimal performance for CIN2+/CIN3+ detection in SA. Triage of HPV-positive women with HSIL+ maintained high specificity but with some loss in sensitivity compared to HC2 alone.

PrEP uptake, persistence, adherence, and effect of retrospective drug level feedback on PrEP adherence among young women in southern Africa: Results from HPTN 082, a randomized controlled trial.

BACKGROUND: Pre-exposure prophylaxis (PrEP) is highly effective and an important prevention tool for African adolescent girls and young women (AGYW), but adherence and persistence are challenging. PrEP adherence support strategies for African AGYW were studied in an implementation study. METHODS AND FINDINGS: HIV Prevention Trials Network (HPTN) 082 was conducted in Cape Town, Johannesburg (South Africa) and Harare (Zimbabwe) from October 2016 to October 2018 to evaluate PrEP uptake, persistence, and the effect of drug level feedback on adherence. Sexually active HIV-negative women ages 16-25 were offered PrEP and followed for 12 months; women who accepted PrEP were randomized to standard adherence support (counseling, 2-way SMS, and adherence clubs) or enhanced adherence support with adherence feedback from intracellular tenofovir-diphosphate (TFV-DP) levels in dried blood spots (DBS). PrEP uptake, persistence through 12 months (no PrEP hold or missed visits), and adherence were assessed. The primary outcome was high adherence (TFV-DP ≥700 fmol/punch) at 6 months, compared by study arm. Of 451 women enrolled, median age was 21 years, and 39% had curable sexually transmitted infections (STIs). Most (95%) started PrEP, of whom 55% had uninterrupted PrEP refills through 12 months. Of those with DBS, 84% had detectable TFV-DP levels at month 3, 57% at month 6, and 31% at month 12. At 6 months, 36/179 (21%) of AGYW in the enhanced arm had high adherence and 40/184 (22%) in the standard adherence support arm (adjusted odds ratio [OR] of 0.92; 95% confidence interval [CI] 0.55, 1.34; p = 0.76). Four women acquired HIV (incidence 1.0/100 person-years), with low or undetectable TFV-DP levels at or prior to seroconversion, and none of whom had tenofovir or emtricitabine resistance mutations. The study had limited power to detect a modest effect of drug level feedback on adherence, and there was limited awareness of PrEP at the time the study was conducted. CONCLUSIONS: In this study, PrEP initiation was high, over half of study participants persisted with PrEP through month 12, and the majority of young African women had detectable TFV-DP levels through month 6 with one-fifth having high adherence. Drug level feedback in the first 3 months of PrEP use did not increase the proportion with high adherence at month 6. HIV incidence was 1% in this cohort with 39% prevalence of curable STIs and moderate PrEP adherence. Strategies to support PrEP use and less adherence-dependent formulations are needed for this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT02732730.

Exploring the feasibility and acceptability of integrating screening for gender-based violence into HIV counselling and testing for adolescent girls and young women in Tanzania and South Africa.

BACKGROUND: Gender-based violence (GBV) undermines HIV prevention and treatment cascades, particularly among women who report partner violence. Screening for violence during HIV testing, and prior to offering pre-exposure prophylaxis (PrEP) to HIV uninfected women, provides an opportunity to identify those at heightened HIV risk and greater potential for non-adherence or early discontinuation of PrEP. The paper describes our experience with offering integrated GBV screening and referral as part of HIV counselling and testing. This component was implemented within EMPOWER, a demonstration project offering combination HIV prevention, including daily oral PrEP, to young women in South Africa and Tanzania. METHODS: Between February 2017 and March 2018, a process evaluation was conducted to explore views, experiences and practices of stakeholders (study participants and study clinical staff) during implementation of the GBV screening component. This article assesses the feasibility and acceptability of the approach from multiple stakeholder perspectives, drawing on counselling session observations (n = 10), in-depth interviews with participants aged 16-24 (n = 39) and clinical staff (n = 13), and notes from debriefings with counsellors. Study process data were also collected (e.g. number of women screened and referred). Following a thematic inductive approach, qualitative data were analysed using qualitative software (NVivo 11). RESULTS: Findings show that 31% of young women screened positive for GBV and only 10% requested referrals. Overall, study participants accessing PrEP were amenable to being asked about violence during HIV risk assessment, as this offered the opportunity to find emotional relief and seek help, although a few found this traumatic. In both sites, the sensitive and empathetic approach of the staff helped mitigate distress of GBV disclosure. In general, the delivery of GBV screening in HCT proved to be feasible, provided that the basic principles of confidentiality, staff empathy, and absence of judgment were observed. However, uptake of linkage to further care remained low in both sites. CONCLUSION: Most stakeholders found GBV screening acceptable and feasible. Key principles that should be in place for young women to be asked safely about GBV during HIV counselling and testing included respect for confidentiality, a youth-friendly and non-judgmental environment, and a functioning referral network.

Disclosure of PrEP use by young women in South Africa and Tanzania: qualitative findings from a demonstration project.

Investigating how young women disclose oral pre-exposure prophylaxis (PrEP) use is important given evidence that disclosure is associated with higher adherence. We report qualitative results on PrEP disclosure among young women in South Africa and Tanzania who participated in a PrEP demonstration project (EMPOWER). In total, 81 in-depth interviews were conducted with 39 young women aged 16-24 years-25 from Johannesburg and 14 from Mwanza-at approximately 3, 6 and/or 9 months post-enrolment. Analysis of data was thematic and inductive. Most Johannesburg participants were students in the inner-city; in Mwanza, all worked in recreational venues, occasionally engaging in sexual transactions with customers. A continuum of approaches was evident. Partner disclosure was common in Johannesburg but less so in Mwanza, where many partners were feared as judgemental and potentially violent. In both sites, participants commonly disclosed to family to secure support, and to friends and work colleagues to advocate about PrEP and encourage uptake among at-risk peers. Adherence clubs appeared helpful in building participants' skills and confidence to disclose, particularly in gender-inequitable sexual relationships. PrEP counselling for young women should focus on strengthening communication skills and helping develop strategies for safe disclosure.

"You talk about problems until you feel free": South African adolescent girls' and young women's narratives on the value of HIV prevention peer support clubs.

BACKGROUND: Daily oral pre-exposure prophylaxis (PrEP) can reduce HIV infection in adolescent girls and young women if used consistently during periods of risk. The EMPOWER study evaluated peer-based clubs incorporating an empowerment curriculum offered to adolescent girls and young women (16-24 years) in South Africa and Tanzania for adherence support. METHODS: Using serial in-depth interviews (n = 33), we assessed the benefits and challenges of club attendance among 13 EMPOWER participants in the Johannesburg site who were randomised to clubs. We used a summary matrix of coded data to support a narrative, case-based analysis. Four case studies are presented. RESULTS: Club participants reported benefits such as increased self-esteem and self-efficacy, reduced isolation, and greater insight into gender-based violence and strategies to address it. Day-to-day PrEP adherence was not the only topic discussed in clubs; participants also appreciated the safe space for sharing problems (such as relationship conflict and PrEP stigma) and found interactive exercises helpful in improving partner communication. CONCLUSIONS: Findings support the use of peer-based clubs using a structured empowerment approach, which may offer valuable PrEP initiation support to adolescent girls and young women in settings with high HIV and gender-based violence prevalence. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR202006754762723 , 5 April  2020, retrospectively registered.

Prevalence and Antimicrobial Resistance of Mycoplasma genitalium Infection Among Women Living With Human Immunodeficiency Virus in South Africa: A Prospective Cohort Study.

This prospective cohort study of 622 women living with human immunodeficiency virus (HIV) from Johannesburg (2012) detected Mycoplasma genitalium in 7.4% (95% confidence interval [CI]: 5.5-9.7, 46/622), with detection more likely with lower CD4 counts(adjusted odds ratio [AOR] 1.02 per 10 cells/µL decrease, 95% CI: 1.00-1.03) and higher plasma HIV-1 RNA (AOR 1.15 per log copies/mL increase, 95% CI: 1.03-1.27). No mutations for macrolide/quinolone resistance was detected.

Incidence, Persistence, Clearance, and Correlates of Genital Human Papillomavirus Infection and Anogenital Warts in a Cohort of Men Living With Human Immunodeficiency Virus in South Africa.

OBJECTIVE: To estimate the incidence; persistence and correlates of human papillomavirus (HPV) infection and anogenital warts (AGW) among men living with human immunodeficiency virus (MLHIV). METHODS: Overall, 304 MLHIV 18 years or older were enrolled and attended follow-up visits at 6, 12, and 18 months. Clinicians examined for AGW, collected blood, and penile swabs for HPV testing (Roche Linear Array) at each visit. Time to AGW incidence or clearance was estimated by Kaplan-Meier method. Factors associated with persistent HPV infection and AGW clearance were evaluated with generalized estimating equations and Cox regression, respectively. RESULTS: Mean age of participants was 38 years (standard deviation, 8 years); 25% reported more than 1 sexual partner in the past 3 months. Most (65%) participants were on antiretroviral treatment (ART) with a median CD4 count of 445 cells/µL (interquartile range, 328-567). Prevalence of HPV infection and AGW at enrolment were 79% (224 of 283) and 12% (36 of 304), respectively. Two hundred fifty-nine men were followed up for a median (interquartile range) 1.4 years (0.5-1.7 years). Incidence of any-genital HPV infection was 2.9 (95% confidence interval, 1.5-5.5) per 100 person-years. Persistence of any-genital HPV infection was 35% (68 of 192) and was higher among MLHIV with low CD4 count (adjusted odds ratio, 3.54; 95% confidence interval, 2.07-6.05). Incidence of AGW was 1.4 per 100 person-years. Men living with human immunodeficiency virus with high CD4 count were more likely to clear AGW than those with low CD4 count (adjusted hazard ratio, 3.69; 95% confidence interval, 1.44-9.47). No associations were observed between persistent genital HPV infection, AGW clearance with enrolment ART status or duration. CONCLUSIONS: Human immunodeficiency virus-positive men have a high burden of genital HPV infection and AGW. The ART and HPV vaccine could reduce this burden.

Clinical Characteristics of Mycoplasma genitalium and the Usefulness of Syndromic Management Among Women Living With Human Immunodeficiency Virus.

We report the clinical symptoms and examination findings of Mycoplasma genitalium (MG) in women living with human immunodeficiency virus in South Africa. If we relied on syndromic management alone to treat MG, only 15 of 46 MG-infected women would have received. appropriate treatment: sensitivity of 32.6% (95% confidence interval, 19.5-48.0) and specificity of 67.4% (95% confidence interval, 63.4-71.2).

Advancing vaccine development for gonorrhoea and the Global STI Vaccine Roadmap.

Efforts to develop vaccines against Neisseria gonorrhoeae have become increasingly important, given the rising threat of gonococcal antimicrobial resistance (AMR). Recent data suggest vaccines for gonorrhoea are biologically feasible; in particular, epidemiological evidence shows that vaccines against a closely related pathogen, serogroup B Neisseria meningitidis outer membrane vesicle (OMV) vaccines, may reduce gonorrhoea incidence. Vaccine candidates using several approaches are currently in preclinical development, including meningococcal and gonococcal OMV vaccines, a lipooligosaccharide epitope and purified protein subunit vaccines. The Global STI Vaccine Roadmap provides action steps to build on this technical momentum and advance gonococcal vaccine development. Better quantifying the magnitude of gonorrhoea-associated disease burden, for outcomes like infertility, and modelling the predicted role of gonococcal vaccines in addressing AMR will be essential for building a full public health value proposition, which can justify investment and help with decision making about future vaccine policy and programs. Efforts are underway to gain consensus on gonorrhoea vaccine target populations, implementation strategies and other preferred product characteristics that would make these vaccines suitable for use in low- and middle-income, as well as high-income, contexts. Addressing these epidemiological, programmatic and policy considerations in parallel to advancing research and development, including direct assessment of the ability of meningococcal B OMV vaccines to prevent gonorrhoea, can help bring about the development of viable gonococcal vaccines.