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.

The potential benefits of long-acting injectable cabotegravir in pregnant and breastfeeding women and their infants.

BACKGROUND: Pregnant and breastfeeding women (PBW) in sub-Saharan Africa have high HIV incidence rates and associated risk of vertical transmission to their infants. Oral preexposure prophylaxis (PrEP) and injectable PrEP (long-acting cabotegravir, or CAB-LA) can potentially reduce this HIV transmission, but population-level impacts are uncertain. METHODS: We extended a previously developed model of HIV and PrEP in South Africa to allow for variable PrEP duration and preference in PBW. We considered three potential scenarios for PrEP provision to PBW: oral PrEP only, CAB-LA only, and allowing oral/CAB-LA choice, with uptake and retention assumptions informed by South African data, each compared with a 'base' scenario without PrEP for PBW. RESULTS: Without PrEP for PBW, the model estimates 1.31 million new infections will occur between 2025 and 2035 in South African adults and children, including 100 000 in PBW, 16 800 in infants at/before birth, and 35 200 in children through breastmilk. In the oral PrEP-only scenario, these numbers would reduce by 1.2% (95% CI: 0.7-1.7%), 8.6% (4.8-12.9%), 4.0% (2.1-5.8%), and 5.3% (3.0-8.2%) respectively. In the CAB-LA-only scenario, the corresponding reductions would be 6.1% (2.9-9.6%), 41.2% (19.8-65.0%), 12.6% (6.0-19.4%), and 29.5% (13.9-46.8%), respectively, and in the oral/CAB-LA choice scenario, similar reductions would be achieved [5.6% (3.4-8.0%), 39% (23.4-55.9%), 12.4% (7.4-16.8%) and 27.6% (16.5-39.9%) respectively]. CONCLUSION: CAB-LA has the potential to be substantially more effective than oral PrEP in preventing HIV acquisition in PBW and vertical transmission, and can also modestly reduce HIV incidence at a population level.

Association of naturally acquired type-specific HPV antibodies and subsequent HPV re-detection: systematic review and meta-analysis.

BACKGROUND: Understanding the role of naturally acquired (i.e., infection-induced) human papillomavirus (HPV) antibodies against reinfection is important given the high incidence of this sexually transmitted infection. However, the protective effect of naturally acquired antibodies in terms of the level of protection, duration, and differential effect by sex remains incompletely understood. We conducted a systematic review and a meta-analysis to (1) strengthen the evidence on the association between HPV antibodies acquired through past infection and subsequent type-specific HPV detection, (2) investigate the potential influence of type-specific HPV antibody levels, and (3) assess differential effects by HIV status. METHODS: We searched Embase and Medline databases to identify studies which prospectively assessed the risk of type-specific HPV detection by baseline homologous HPV serostatus among unvaccinated individuals. Random-effect models were used to pool the measures of association of naturally acquired HPV antibodies against subsequent incident detection and persistent HPV positivity. Sources of heterogeneity for each type were assessed through subgroup analyses stratified by sex, anatomical site of infection, male sexual orientation, age group, and length of follow-up period. Evidence of a dose-response relationship of the association between levels of baseline HPV antibodies and type-specific HPV detection was assessed. Finally, we pooled estimates from publications reporting associations between HPV serostatus and type-specific HPV detection by baseline HIV status. RESULTS: We identified 26 publications (16 independent studies, with 62,363 participants) reporting associations between baseline HPV serostatus and incident HPV detection, mainly for HPV-16 and HPV-18, the most detected HPV type. We found evidence of protective effects of baseline HPV seropositivity and subsequent detection of HPV DNA (0.70, 95% CI 0.61-0.80, NE = 11) and persistent HPV positivity (0.65, 95% CI 0.42-1.01, NE = 5) mainly for HPV-16 among females, but not among males, nor for HPV-18. Estimates from 8 studies suggested a negative dose-response relationship between HPV antibody level and subsequent detection among females. Finally, we did not observe any differential effect by baseline HIV status due to the limited number of studies available. CONCLUSION: We did not find evidence that naturally acquired HPV antibodies protect against subsequent HPV positivity in males and provide only modest protection among females for HPV-16. One potential limitation to the interpretation of these findings is potential misclassification biases due to different causes.

Efficacy estimates of oral pre-exposure prophylaxis for HIV prevention in cisgender women with partial adherence.

Pre-exposure prophylaxis (PrEP) with tenofovir (TFV) disoproxil fumarate and emtricitabine administered orally daily is effective in preventing human immunodeficiency virus (HIV) acquisition in both men and women with sufficient adherence; however, the adherence-efficacy relationship in cisgender women has not been well established. We calculated the adherence-efficacy curve for cisgender women by using HIV incidence and plasma TFV concentration data from three trials (FEM-PrEP, VOICE and Partners PrEP). We imputed TFV diphosphate (TFV-DP) concentrations, a measure of long-term adherence, from TFV quantification by using data from the HIV Prevention Trials Network 082 study, which measured both TFV-DP and TFV concentrations. Two, four and seven pills per week reduced HIV incidence by 59.3% (95% credible interval (CrI) 29.9-95.8%), 83.8% (95% CI 51.7-99.8%) and 95.9% (95% CI 72.6-100%), respectively. Our adherence-efficacy curve can be validated and updated by HIV prevention studies that directly measure TFV-DP concentrations. The curve suggests that high adherence confers high protection in cisgender women. However, the lower efficacy with partial adherence highlights the need for new PrEP products and interventions to increase adherence.

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.

HIV infection.

The AIDS epidemic has been a global public health issue for more than 40 years and has resulted in ~40 million deaths. AIDS is caused by the retrovirus, HIV-1, which is transmitted via body fluids and secretions. After infection, the virus invades host cells by attaching to CD4 receptors and thereafter one of two major chemokine coreceptors, CCR5 or CXCR4, destroying the host cell, most often a T lymphocyte, as it replicates. If unchecked this can lead to an immune-deficient state and demise over a period of ~2-10 years. The discovery and global roll-out of rapid diagnostics and effective antiretroviral therapy led to a large reduction in mortality and morbidity and to an expanding group of individuals requiring lifelong viral suppressive therapy. Viral suppression eliminates sexual transmission of the virus and greatly improves health outcomes. HIV infection, although still stigmatized, is now a chronic and manageable condition. Ultimate epidemic control will require prevention and treatment to be made available, affordable and accessible for all. Furthermore, the focus should be heavily oriented towards long-term well-being, care for multimorbidity and good quality of life. Intense research efforts continue for therapeutic and/or preventive vaccines, novel immunotherapies and a cure.

A decision support tool has similar high PrEP uptake and increases early PrEP persistence in adolescent girls and young women in South Africa: results from a randomized controlled trial.

INTRODUCTION: African adolescent girls and young women (AGYW) have high rates of HIV acquisition and are a priority population for HIV pre-exposure prophylaxis (PrEP). PrEP implementation has been limited by AGYW's low perceived HIV risk and provider demands. A decision support tool (DST) with information about PrEP could improve clients' risk perception, knowledge about PrEP, informed decision-making and motivation to use PrEP based on their risk, facilitating PrEP delivery in primary healthcare (PHC) clinics. METHODS: We designed MyPrEP, a client-facing DST about PrEP and HIV prevention, with youth-friendly information and images. The impact of the MyPrEP tool was assessed among HIV-negative women aged 18-25 years presenting to a PHC clinic in Johannesburg, South Africa from March 2019 to 2020. AGYW were randomized by day to the DST or a general health website as the control condition. A clinician blinded to DST versus control allocation provided standard of care counselling about PrEP, offered PrEP, administered a questionnaire and conducted sexually transmitted infection testing. The primary outcome was PrEP initiation and the secondary outcome was PrEP persistence at 1 month, determined by pharmacy dispensation records. RESULTS: Of 386 AGYW screened, 353 were randomized (DST n = 172, control n = 181) with a median age of 21 years (interquartile range [IQR] 20, 23) and 56% (199/353) attending the clinic for HIV testing, 46% (164/353) using contraception, 15% (53/353) using condoms consistently and 37% (108/353) with a curable sexually transmitted infection. PrEP was initiated by 97% in the DST group and 94% in the control group (OR 1.79; 95% confidence interval, CI = 0.79-1.53), of whom two-thirds planned to continue PrEP until they decided if they liked PrEP. At 1 month, PrEP persistence was 19% in the DST and 10% in the control group (OR 1.97, 95% CI 1.08-3.69). Ninety-nine percent randomized to the DST reported satisfaction with MyPrEP. CONCLUSIONS: Among AGYW attending a South African PHC clinic, PrEP uptake was >90% with two-fold higher PrEP persistence at 1 month in those randomized to use the MyPrEP DST. Given the need for strategies to support PrEP implementation and improve low PrEP persistence among African AGYW, a PrEP DST warrants further evaluation.

The importance of the "how": the case for differentiated service delivery of long-acting and extended delivery regimens for HIV prevention and treatment.

INTRODUCTION: Long-acting and extended delivery (LAED) regimens for HIV treatment and prevention offer unique benefits to expand uptake, effective use and adherence. To date, research has focused on basic and clinical science around the safety and efficacy of these products. This commentary outlines opportunities in HIV prevention and treatment programmes, both for the health system and clients, that could be addressed through the inclusion of LAED regimens and the vital role of differentiated service delivery (DSD) in ensuring efficient and equitable access. DISCUSSION: The realities and challenges within HIV treatment and prevention programmes are different. Globally, more than 28 million people are accessing HIV treatment-the vast majority on a daily fixed-dose combination oral pill that is largely available, affordable and well-tolerated. Many people collect extended refills outside of health facilities with clinical consultations once or twice a year. Conversely, uptake of daily oral pre-exposure prophylaxis (PrEP) has consistently missed global targets due to limited access with high individual cost and lack of choice contributing to substantial unmet PrEP need. Recent trends in demedicalization, simplification, additional method options and DSD for PrEP have led to accelerated uptake as its availability has become more aligned with user preferences. How people currently receive HIV treatment and prevention services and their barriers to adherence must be considered for the introduction of LAED regimens to achieve the expected improvements in access and outcomes. Important considerations include the building blocks of DSD: who (provider), where (location), when (frequency) and what (package of services). Ideally, all LAED regimens will leverage DSD models that emphasize access at the community level and self-management. For treatment, LAED regimens may address challenges with adherence but their delivery should provide clear advantages over existing oral products to be scaled. For prevention, LAED regimens expand a potential PrEP user's choice of methods, but like other methods, need to be delivered in a manner that can facilitate frequent re-initiation. CONCLUSIONS: To ensure that innovative LAED HIV treatment and prevention products reach those who most stand to benefit, service delivery and client considerations during development, trial and early implementation are critical.

Counterfactual estimation of efficacy against placebo for novel PrEP agents using external trial data: example of injectable cabotegravir and oral PrEP in women.

INTRODUCTION: Multiple antiretroviral agents have demonstrated efficacy for human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP). As a result, clinical trials of novel agents have transitioned from placebo- to active-controlled designs; however, active-controlled trials do not provide an estimate of efficacy versus no use of PrEP. Counterfactual placebo comparisons using other data sources could be employed to provide this information. METHODS: We compared the active-controlled study (HPTN 084) of injectable cabotegravir (CAB-LA) versus daily oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) among women from seven countries in Africa to three external, contemporaneous randomized HIV prevention trials from which we constructed counterfactual placebo estimates. We used direct standardization via analysis weights to achieve the same distribution of person-years between the external study and HPTN 084, across strata predictive of HIV risk (country and selected risk covariates). We estimated prevention efficacy against a counterfactual placebo to provide information on the use of CAB-LA and FTC/TDF compared to no intervention. We compared the counterfactual placebo findings for FTC/TDF to previous placebo-controlled trials, adjusted for observed adherence to daily pills. RESULTS: Distribution of age and baseline prevalence of gonorrhoea and chlamydia were similar among matched counterfactual placebo and observed HPTN 084 arms after standardization. Counterfactual estimates of CAB-LA versus placebo in all three settings showed a consistent risk reduction of 93%-94%, with lower bounds of the confidence intervals above 72%. Observed adherence (quantifiable tenofovir in plasma) in HPTN 084 was 54%-56%, and estimated efficacy of daily oral FTC/TDF against a counterfactual placebo was consistent with a predicted risk reduction of 39%-40% for this level of daily pill use. CONCLUSIONS: Counterfactual placebo rates of HIV acquisition derived from external trial data in similar locations and time can be used to support estimates of placebo-based efficacy of a novel HIV prevention agent. External trial data must be standardized to be representative of the clinical trial cohort testing the novel HIV prevention agent, accounting for confounders.

Association of sexual relationship power with PrEP persistence and other sexual health outcomes among adolescent and young women in Kenya and South Africa.

Introduction: Gendered power inequalities impact adolescent girls' and young women's (AGYW) sexual and reproductive health (SRH) outcomes. We investigated the influence of sexual relationship power on AGYW's SRH outcomes, including HIV pre-exposure prophylaxis (PrEP) persistence. Methods: The POWER study in Kisumu, Kenya, and Cape Town and Johannesburg, South Africa provided PrEP to 2,550 AGYW (aged 16-25). AGYW's perceived power in their primary sexual relationship was measured among the first 596 participants enrolled using the Sexual Relationship Power Scale's (SRPS) relationship control sub-scale. Multivariable regression was used to test for (1) key sociodemographic and relationship characteristics associated with relationship power; and (2) the association of relationship power with SRH outcomes including PrEP persistence. Results: In this cohort, the mean SRPS score was 2.56 (0.49), 542 (90.9%) initiated PrEP; 192 (35.4%) persisted with PrEP at 1 month of which 46 (24.0% of 192) persisted at 6 months. SRPS were significantly lower among AGYW who cohabited with their sex partner (-0.14, 95% CI: -0.24 to -0.04, p = 0.01), or had ≥1 sex partner (-0.10, 95% CI: -0.19 to -0.00, p = 0.05). AGYW with lower SRPS were more likely to not know their partner's HIV status (aOR 2.05, 95% CI: 1.27 to 3.33, p < 0.01), but SRPS was not associated with PrEP persistence, STI infection, condom, or hormonal contraception use. Discussion: AGYW's reasons for initiating PrEP and reasons for continuously using PrEP may be different. While low relationship power was associated with perceived HIV vulnerability, AGYW's PrEP persistence may be influenced by more than relationship power.

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.

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.

Development of a tool to assess HIV prevention readiness of adolescent girls and young women in HPTN 082 study.

BACKGROUND: African adolescent girls and young women (AGYW) represent a large proportion of new HIV infections, a priority population for pre-exposure prophylaxis (PrEP), but adherence remains a challenge. A reliable, valid readiness tool would help identify AGYW motivated to take PrEP who need adherence support. METHODS: In the HPTN 082 open-label PrEP study (2016-2019), South African and Zimbabwean women ages 16-25 were administered an HIV prevention readiness measure (HPRM). The 25 items in the HPRM included medication beliefs, connection with care, disclosure of PrEP use, social support, and housing stability using a 5-point Likert scale. Exploratory factor analysis (EFA) using polychoric correlations, scale reliability, and predictive validity were performed on data from 315 participants who responded to all items. We assessed the predictive value of HPRM scores with PrEP adherence, defined as tenofovir-diphosphate (TFV-DP) concentrations in dried blood spots, as a continuous measure and dichotomized as high PrEP adherence (≥700 fmol/punch). RESULTS: EFA yielded 23 items with three subscales: self-efficacy (16 items), PrEP disclosure (4 items), and social support (3 items). Cronbach's α ranged from 0.71 to 0.92 for the overall scale and the subscales. The average overall scale and the subscales were predictive of 3-month PrEP adherence for TFV-DP concentrations: for each unit increase of the HPRM score, TFV-DP concentration increased by 103 fmol/punch (95% CI: 16, 189, p = 0.02); the highest HPRM score equated with 608 fmol/punch on average. For the self-efficacy subscale, TFV-DP increased by 90 fmol/punch (95% CI: 7, 172, p = 0.03); PrEP disclosure, 68 fmol/punch (95% CI: 19, 117 p = 0.01); and social support, 58fmol/punch (95% CI: 2, 113, p = 0.04). Higher PrEP disclosure suggests high adherence (OR 1.36, 95% CI: 1.00, 1.86, p = 0.05) and predicted persistent high adherence at both months three and six (OR: 1.50, 95% CI: 1.03, 2.21, p = 0.04). CONCLUSIONS: The HPRM scale overall and the subscales individually demonstrated good internal consistency among African young women. PrEP disclosure subscale exhibiting significant association with persistent high PrEP adherence is an important finding for PrEP adherence support programs. Future work will assess replicability and expand self-efficacy and social-support subscales after item revision. TRIAL REGISTRATION: ClinicalTrials.gov NCT02732730.

Predicted effects of the introduction of long-acting injectable cabotegravir pre-exposure prophylaxis in sub-Saharan Africa: a modelling study.

BACKGROUND: Long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) is recommended by WHO as an additional option for HIV prevention in sub-Saharan Africa, but there is concern that its introduction could lead to an increase in integrase-inhibitor resistance undermining treatment programmes that rely on dolutegravir. We aimed to project the health benefits and risks of cabotegravir-PrEP introduction in settings in sub-Saharan Africa. METHODS: With HIV Synthesis, an individual-based HIV model, we simulated 1000 setting-scenarios reflecting both variability and uncertainty about HIV epidemics in sub-Saharan Africa and compared outcomes for each with and without cabotegravir-PrEP introduction. PrEP use is assumed to be risk-informed and to be used only in 3-month periods (the time step for the model) when having condomless sex. We consider three groups at risk of integrase-inhibitor resistance emergence: people who start cabotegravir-PrEP after (unknowingly) being infected with HIV, those who seroconvert while on PrEP, and those with HIV who have residual cabotegravir drugs concentrations during the early tail period after recently stopping PrEP. We projected the outcomes of policies of cabotegravir-PrEP introduction and of no introduction in 2022 across 50 years. In 50% of setting-scenarios we considered that more sensitive nucleic-acid-based HIV diagnostic testing (NAT), rather than regular antibody-based HIV rapid testing, might be used to reduce resistance risk. For cost-effectiveness analysis we assumed in our base case a cost of cabotegravir-PrEP drug to be similar to oral PrEP, resulting in a total annual cost of USD$144 per year ($114 per year and $264 per year considered in sensitivity analyses), a cost-effectiveness threshold of $500 per disability-adjusted life years averted, and a discount rate of 3% per year. FINDINGS: Reflecting our assumptions on the appeal of cabotegravir-PrEP, its introduction is predicted to lead to a substantial increase in PrEP use with approximately 2·6% of the adult population (and 46% of those with a current indication for PrEP) receiving PrEP compared with 1·5% (28%) without cabotegravir-PrEP introduction across 20 years. As a result, HIV incidence is expected to be lower by 29% (90% range across setting-scenarios 6-52%) across the same period compared with no introduction of cabotegravir-PrEP. In people initiating antiretroviral therapy, the proportion with integrase-inhibitor resistance after 20 years is projected to be 1·7% (0-6·4%) without cabotegravir-PrEP introduction but 13·1% (4·1-30·9%) with. Cabotegravir-PrEP introduction is predicted to lower the proportion of all people on antiretroviral therapy with viral loads less than 1000 copies per mL by 0·9% (-2·5% to 0·3%) at 20 years. For an adult population of 10 million an overall decrease in number of AIDS deaths of about 4540 per year (-13 000 to -300) across 50 years is predicted, with little discernible benefit with NAT when compared with standard antibody-based rapid testing. AIDS deaths are predicted to be averted with cabotegravir-PrEP introduction in 99% of setting-scenarios. Across the 50-year time horizon, overall HIV programme costs are predicted to be similar regardless of whether cabotegravir-PrEP is introduced (total mean discounted annual HIV programme costs per year across 50 years is $151·3 million vs $150·7 million), assuming the use of standard antibody testing. With antibody-based rapid HIV testing, the introduction of cabotegravir-PrEP is predicted to be cost-effective under an assumed threshold of $500 per disability-adjusted life year averted in 82% of setting-scenarios at the cost of $144 per year, in 52% at $264, and in 87% at $114. INTERPRETATION: Despite leading to increases in integrase-inhibitor drug resistance, cabotegravir-PrEP introduction is likely to reduce AIDS deaths in addition to HIV incidence. Long-acting cabotegravir-PrEP is predicted to be cost-effective if delivered at similar cost to oral PrEP with antibody-based rapid HIV testing. FUNDING: Bill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases of the National Institutes of Health.

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.

Qualitative Analysis Using Social Maps to Explore Young Women's Experiences With Social Support of their Oral PrEP Use in Kenya and South Africa.

ABSTRACT: Daily oral pre-exposure prophylaxis (PrEP) adherence is challenging. We explored African adolescent girls and young women's (AGYW) perceptions of the social influencers of their PrEP use and the social influencers' PrEP knowledge and support (six focus group discussions; 33 South African and Kenyan AGYW) in the Prevention Options for Women Evaluation Research demonstration project. Participants completed a social mapping exercise indicating strength and direction of influence of members in their social networks. Mothers and counselors were identified as positive influencers and most influential by >50% of participants, sex partners were labeled negative influencers or both positive and negative, and best friends were mostly positive influencers. HIV- and PrEP-related stigma were the major reasons influencers were identified as negative. Participants wanted their social networks to be better educated about PrEP by someone other than the AGYW themselves (e.g., clinic staff) and to support their PrEP use. To improve PrEP adherence, community- and peer-based PrEP sensitization and delivery interventions should be evaluated.

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.