The pathway to delivering injectable CAB for HIV prevention: strategies from global PrEP leaders leveraging an adapted version of the Intervention Scalability Assessment Tool (ISAT).

BACKGROUND: Longer-acting cabotegravir (CAB) is a novel, safe, and efficacious pre-exposure prophylaxis (PrEP) for HIV prevention. As we near a time for CAB scale-up, the experience of global leaders in PrEP research and implementation can be leveraged to identify optimal strategies for scaling and integrating CAB into existing PrEP infrastructure worldwide. METHODS: We recruited leaders of HIV prevention clinical trials and large PrEP programs through a combination of purposive and snowball sampling for participation in individual interviews. We conducted interviews using a semi-structured guide that compared CAB to oral PrEP and sought perspectives on barriers and strategies for CAB scale-up. Interviews were conducted virtually, audio recorded, and transcribed. We used thematic analysis, grounded in an adapted version of the Intervention Scalability Assessment Tool (ISAT), to identify critical elements for optimizing delivery of CAB. RESULTS: From October 2021 to April 2022, we interviewed 30 participants with extensive experience in PrEP research, care, and programming. Participants worked in all seven WHO regions and reported a median of 20 years working in HIV and 10 years in PrEP. Participants agreed that CAB was efficacious and discrete, therefore having the potential to address current concerns about oral PrEP adherence and stigma. Participants indicated direct and indirect costs for provider training, expansion of existing medical infrastructure, and the current medication cost of CAB as major concerns for roll out. The true cost to the end-user and health system were unknown. There were some conflicting strategies on how to best address product targeting, presentation of efficacy, and timing of product availability with scale-up. Some thought that targeting CAB for the general population could normalize PrEP and decrease stigma, while others thought that prioritizing key populations could optimize impact by targeting those with highest risk. Overall, participants emphasized that to ensure successful CAB scale-up, communities and stakeholders must be involved at every stage of planning and implementation. CONCLUSIONS: Our evaluation found that although there is a clear and urgent need for additional HIV PrEP options beyond daily oral PrEP, CAB scale-up must be thoughtful, flexible, and based in lessons learned from oral PrEP rollout.

Efficacy of the Dapivirine Vaginal Ring Accounting for Imperfect Adherence.

Product adherence is critical to obtaining objective estimates of efficacy of pre-exposure prophylactic interventions against HIV-1 infection. With imperfect adherence, intention-to-treat analyses assess the collective effects of complete, sub-optimal and non-adherence, providing a biased and attenuated estimate of the average causal effect of an intervention. Using data from the MTN-020/ASPIRE phase III trial evaluating HIV-1 efficacy of the dapivirine vaginal ring, we conducted per-protocol, and adherence-adjusted causal inference analyses using principal stratification and marginal structural models. We constructed two adherence cut offs of ≥ 0.9 mg (low cutoff) and > 4.0 mg (high cutoff) that represent drug released from the ring over a 28-day period. The HIV-1 efficacy estimate (95% CI) was 30.8% (3.6%, 50.3%) (P = 0.03) from the per-protocol analysis, and 53.6% (16.5%, 74.3%) (P = 0.01) among the highest predicted adherers from principal stratification analyses using the low cutoff. Marginal structural models produced efficacy estimates (95% CIs) ranging from 48.8 (21.8, 66.4) (P = 0.0019) to 56.5% (32.8%, 71.9%) (P = 0.0002). Application of adherence-adjusted causal inference methods are useful in interpreting HIV-1 efficacy in secondary analyses of PrEP clinical trials.

A point-of-care tenofovir urine test improves accuracy of self-reported preexposure prophylaxis adherence and increases condomless sex reporting among young women.

OBJECTIVES: We evaluated a recently developed and validated point-of-care urine tenofovir (POC TFV) test to determine whether its use improves the accuracy of self-reported adherence to preexposure prophylaxis (PrEP) and sexual behavior. DESIGN: We enrolled sexually active HIV-negative women ages 16 to 25 years in Kampala, Uganda. METHODS: Women were followed quarterly for 24 months with HIV prevention counseling, PrEP dispensation, and adherence counseling. Midway through the study, the POC TFV test was introduced as part of routine study procedures. We examined changes in self-reported PrEP adherence, sexual behavior, and accuracy of self-reported PrEP adherence before and after the introduction of the POC TFV test. RESULTS: A total of 146 women receiving PrEP refills had at least one visit with a POC TFV test administered before the study exit. At baseline, the median age was 19 years [interquartile range (IQR): 18-21] and the majority (76%) reported having condomless sex within the last 3 months. Participants more frequently self-reported low PrEP adherence [odds ratio (OR): 2.96, 95% confidence interval (CI): 1.89-4.67, P  = 0.001] and condomless sex (OR: 1.47, 95% CI: 1.04-2.06, P  = 0.03) during visits using the test compared with visits without the test. The accuracy of self-reported PrEP adherence (determined by concordance with TFV-diphosphate levels) was greater when the test was used (61 versus 24%, OR: 4.86, 95% CI: 2.85-8.30, P  < 0.001). CONCLUSION: When the POC TFV test was used, we observed greater reporting of condomless sex, low PrEP adherence, and more accurate reports of PrEP adherence. The test could facilitate honest conversations between clients and providers and warrant further investigation.

Differentiated Service Delivery Models for Maintaining HIV Treatment and Prevention Services During Crisis and Disease Outbreaks: Lessons from the COVID-19 Pandemic.

PURPOSE OF REVIEW: This review summarizes differentiated service delivery (DSD) models for HIV treatment and prevention that have been adapted for maintaining continuity of services during the COVID-19 pandemic and proposes strategies for sustaining their benefits now and during future disruptions. RECENT FINDINGS: The COVID-19 pandemic resulted in an overburdened and disrupted health system, forcing countries to adopt and/or scale up DSD models for HIV services. While initially implemented as emergency measures, these models evolved and were refined over time to fit recipient needs ensuring continued HIV treatment and prevention services with minimal health system impact. Successful models employed task shifting, community-based delivery models, multimonth scripting and dispensing, and telehealth for remote consultation. DSD models enabled HIV services globally to be maintained during the COVID-19 pandemic. Though these models and adaptations were critical in addressing health gaps and disruptions caused by the pandemic, they were beneficial in improving efficiency and access to client-centered services and should be sustained.

Implementation of gender-based violence screening guidelines in public HIV treatment programs: A mixed methods evaluation in Uganda.

BACKGROUND: HIV and gender-based violence (GBV) intersect to threaten population health. The Uganda Ministry of Health recommends routine GBV screening alongside HIV care but evidence detailing its implementation in HIV care settings is limited. We evaluated screening practices in public HIV clinics to generate evidence supporting GBV screening optimization. METHODS: To evaluate GBV screening implementation in antiretroviral therapy (ART) clinics, we extracted client data from GBV registers at 12 public ART clinics in Uganda (January 2019-December 2021). We concurrently evaluated perceptions of GBV screening/referral practices by conducting in-depth qualitative interviews with providers (N = 30) and referral partners (N = 10). We contextualized quantitative findings with interview data which were analyzed using a thematic analysis approach. RESULTS: During the evaluation period, >90% of providers in participating health facilities implemented GBV screening. Among 107,767 clients served in public ART clinics, providers identified 9,290 (8.6%) clients who experienced past-year physical, sexual and/or emotional GBV of whom 86% received counseling and 19% were referred to support services-most commonly to legal services. Key factors influencing GBV screening implementation included awareness of screening guidelines; client volume; and client's level of engagement in HIV care. Providers and referral partners identified important benefits to clients (e.g., pursuit of justice and removal from violent environments) when referrals were successful. Key factors influencing referrals included financial constraints that limited referral partners' ability to provide services at no cost to clients and socio-cultural norms that inhibited client willingness to pursue support services. CONCLUSIONS: GBV screening implementation in ART clinics supports identification and referral of clients exposed to violence. The effectiveness of GBV screening may be limited by socio-cultural factors that inhibit client capacity to pursue referrals and fragmented and resource-constrained referral networks. Providers and referral partners identified allocating funds to support referrals and collaborative networking meetings as important opportunities for strengthening GBV referrals.

Exploring adolescent girls and young women's PrEP-user profiles: qualitative insights into differentiated PrEP delivery platform selection and engagement in Cape Town, South Africa.

INTRODUCTION: Adolescent girls and young women (AGYW), a priority population for HIV prevention in Africa, show high interest but difficulty in sustained effective use of pre-exposure prophylaxis (PrEP). With ongoing PrEP scale-up focused on increasing access, it is important to understand what influences AGYW's choice of PrEP delivery platforms. METHODS: The POWER implementation study in Cape Town provided PrEP between 2017 and 2020 to AGYW (16-25 years) from four differentiated delivery platforms: mobile clinic, government facility, courier delivery or community-based youth club. Healthcare providers at government and mobile clinics provided PrEP (initiation and refills) as part of comprehensive, integrated sexual and reproductive health services. Courier and youth club platforms provided light-touch PrEP refill services incorporating rapid HIV self-testing. We conducted in-depth interviews with a purposive sample of AGYW who had ≥3 months of PrEP-use and accessed ≥2 PrEP delivery platforms. The thematic analysis explored AGYW's preferences, decision-making and habits related to PrEP access to inform market segmentation. RESULTS: We interviewed 26 AGYW (median age 20) PrEP-users between November 2020 and March 2021. AGYW PrEP-users reported accessing different services with, 24 accessing mobile clinics, 17 courier delivery, 9 government health facilities and 6 youth clubs for their PrEP refills. Qualitative findings highlighted four potential behavioural profiles. The "Social PrEP-user" preferred PrEP delivery in peer spaces, such as youth clubs or adolescent-friendly mobile clinics, seeking affirmation and social support for continued PrEP use. The "Convenient PrEP-user" favoured PrEP delivery at easily accessible locations, providing quick (courier) or integrated contraception-PrEP refill visits (mobile and government clinic). The "Independent PrEP-user" preferred PrEP delivery that offered control over delivery times that fit into their schedule, such as the courier service. The "Discreet PrEP-user" highly valued privacy regarding their PrEP use (courier delivery) and avoided delivery options where unintentional disclosure was evident (youth club). Comfort with HIV self-testing had minimal influence on PrEP delivery choice. CONCLUSIONS: Market segmentation of AGYW characterizes different types of PrEP-users and has the potential to enhance tailored messaging and campaigns to reach specific segments, with the aim of improving sustained PrEP use and HIV prevention benefits.

The Effect of Stigma on Family Planning and HIV Pre-exposure Prophylaxis Decisions of Young Women Accessing Post-Abortion Care in Kenya.

Adolescent girls and young women (AGYW) in Eastern and Southern Africa face parallel epidemics of unintended pregnancy and HIV. Their sexual health decisions are often dominated by intersecting stigmas. In an implementation science project integrating delivery of daily, oral pre-exposure prophylaxis (PrEP) for HIV prevention into 14 post-abortion care (PAC) clinics in Kenya, we enrolled a subset of PrEP initiating AGYW (aged 15 to 30 years) into a research cohort. Utilizing log binomial models, we estimated the effect of PrEP stigma on PrEP continuation (measured via self-report and urine assay for tenofovir) and abortion stigma on contraceptive initiation. Between April 2022 and February 2023, 401 AGYW were enrolled after initiating PrEP through their PAC provider, of which 120 (29.9%) initiated highly-effective contraception. Overall, abortion and PrEP stigmas were high in this cohort. Abortion stigma was more prevalent among those that were adolescents, unmarried, and reported social harm. Among 114 AGYW returning for the month 1 follow-up visit, 83.5% reported continuing PrEP and 52.5% had tenofovir detected. In this subset, higher levels of PrEP stigma were significantly associated with greater likelihood of PrEP adherence, but not PrEP continuation. For abortion stigma, greater scores in the subdomain of isolation were significantly associated with greater likelihood of initiating a highly-effective contraception, while greater scores in the subdomain of community condemnation were significantly associated with reduced likelihood of initiating a highly-effective contraception. Given the burden of stigma documented by our work, PAC settings are a pivotal space to integrate stigma-informed counseling and to empower young women to optimize contraceptive and PrEP decisions.

How PrEP delivery was integrated into public ART clinics in central Uganda: A qualitative analysis of implementation processes.

Tailored delivery strategies are important for optimizing the benefit and overall reach of PrEP in sub-Saharan Africa. An integrated approach of delivering time-limited PrEP in combination with ART to serodifferent couples encourages PrEP use in the HIV-negative partner as a bridge to sustained ART use. Although PrEP has been delivered in ART clinics for many years, the processes involved in integrating PrEP into ART services are not well understood. The Partners PrEP Program was a stepped-wedge cluster randomized trial of integrated PrEP and ART delivery for HIV serodifferent couples in 12 public health facilities in central Uganda (Clinicaltrials.gov NCT03586128). Using qualitative data, we identified and characterized key implementation processes that explain how PrEP delivery was integrated into existing ART services in the Partners PrEP Program. In-depth interviews were conducted with a purposefully-selected sub-sample of 83 members of 42 participating serodifferent couples, and with 36 health care providers implementing integrated delivery. High quality training, technical supervision, and teamwork were identified as key processes supporting providers to implement PrEP delivery. Interest in the PrEP program was promoted through the numerous ways health care providers made integrated ART and PrEP meaningful for serodifferent couples, including tailored counseling messages, efforts to build confidence in integrated delivery, and strategies to create demand for PrEP. Couples in the qualitative sample responded positively to providers' efforts to promote the integrated strategy. HIV-negative partners initiated PrEP to preserve their relationships, which inspired their partners living with HIV to recommit to ART adherence. Lack of disclosure among couples and poor retention on PrEP were identified as barriers to implementation of the PrEP program. A greater emphasis on understanding the meaning of PrEP for users and its contribution to implementation promises to strengthen future research on PrEP scale up in sub-Saharan Africa.

"Take services to the people": strategies to optimize uptake of PrEP and harm reduction services among people who inject drugs in Uganda.

BACKGROUND: People who inject drugs (PWID) are at increased risk of HIV acquisition and often encounter barriers to accessing healthcare services. Uganda has high HIV prevalence among PWID and lacks integrated pre-exposure prophylaxis (PrEP) and harm reduction services. Understanding PWID experiences accessing and using harm reduction services and PrEP will inform strategies to optimize integration that align with PWID needs and priorities. METHODS: Between May 2021 and March 2023, we conducted semi-structured interviews with PWID in Kampala, Uganda. We recruited participants with and without previous experience accessing harm reduction services and/or PrEP using purposive and snowball sampling. Interviews were audio recorded, translated, and transcribed. We used thematic analysis to characterize motivations for uptake of harm reduction and HIV prevention services, and strategies to optimize delivery of needle and syringe programs (NSP), medications for opioid use disorder (MOUD), and PrEP. RESULTS: We conducted interviews with 41 PWID. Most participants were relatively aware of their personal HIV risk and accurately identified situations that increased risk, including sharing needles and engaging in transactional sex. Despite risk awareness, participants described engaging in known HIV risk behaviors to satisfy immediate drug use needs. All reported knowledge of harm reduction services, especially distribution of sterile needles and syringes, and many reported having experience with MOUD. Participants who had accessed MOUD followed two primary trajectories; limited resources and relationships with other PWID caused them to discontinue treatment while desire to regain something they believed was lost to their drug use motivated them to continue. Overall, PrEP knowledge among participants was limited and few reported ever taking PrEP. However, participants supported integrating PrEP into harm reduction service delivery and advocated for changes in how these services are accessed. Stigma experienced in healthcare facilities and challenges acquiring money for transportation presented barriers to accessing current facility-based harm reduction and HIV prevention services. CONCLUSIONS: Meeting the HIV prevention needs of PWID in Uganda will require lowering barriers to access, including integrated delivery of PrEP and harm reduction services and bringing services directly to communities. Additional training in providing patient-centered care for healthcare providers may improve uptake of facility-based services.

Behavioral Modeling and its Association with PrEP and ART Use in Ugandan HIV-Serodifferent Couples.

Integrating Pre-Exposure Prophylaxis (PrEP) delivery into Antiretroviral Therapy (ART) programs bridges the Human Immunodeficiency Virus (HIV) prevention gap for HIV-serodifferent couples prior to the partner living with HIV achieving viral suppression. Behavioral modeling is one mechanism that could explain health-related behavior among couples, including those using antiretroviral medications, but few tools exist to measure the extent to which behavior is modeled. Using a longitudinal observational design nested within a cluster randomized trial, this study examined the factor structure and assessed the internal consistency of a novel 24-item, four-point Likert-type scale to measure behavioral modeling and the association of behavioral modeling with medication-taking behaviors among heterosexual, cis-gender HIV-serodifferent couples. In 149 couples enrolled for research, a five-factor model provided the best statistical and conceptual fit, including attention to partner behavior, collective action, role modeling, motivation, and relationship quality. Behavioral modeling was associated with medication-taking behaviors among members of serodifferent couples. Partner modeling of ART/PrEP taking could be an important target for assessment and intervention in HIV prevention programs for HIV serodifferent couples.

Structural influences on delivery and use of oral HIV PrEP among adolescent girls and young women seeking post abortion care in Kenya.

Background: Adolescent girls and young women (AGYW) in East and southern Africa experience a disproportionate burden of HIV incidence. Integrating HIV pre-exposure prophylaxis (PrEP) within existing programs is a key component of addressing this disparity. Methods: We evaluated an oral PrEP program integrated into post-abortion care (PAC) in Kenya from March 2021 to November 2022. Technical advisors trained staff at PAC clinics on PrEP delivery, abstracted program data from each clinic, and collected data on structural characteristics. Utilizing a modified Poisson regression, we estimated the effect of structural factors on the probability of PrEP offer and uptake. Findings: We abstracted data on 6877 AGYW, aged 15-30 years, across 14 PAC clinics. PrEP offers were made to 57.4% of PAC clients and 14.1% initiated PrEP. Offers were associated with an increased probability at clinics that had consistent supply of PrEP (relative risk (RR):1.81, 95% CI: 1.1-2.95), inconsistent HIV testing commodities (RR: 1.89, 95% CI: 1.29-2.78), had all providers trained (RR: 1.65, 95% CI: 1.01, 2.68), and were public (RR: 1.89, 95% CI: 1.29-2.78). These same factors were associated with PrEP uptake: consistent supply of PrEP (RR: 2.71, 95% CI: 1.44-5.09), inconsistent HIV testing commodities (RR: 2.55, 95% CI: 1.39-4.67), all providers trained (RR: 2.61, 95% CI: 1.38-4.92), and were public (RR: 2.55, 95% CI: 1.39-4.67). Interpretation: Greater success with integration of HIV prevention into reproductive health services will likely require investments in systems, such as human resources and PrEP and HIV testing commodities, to create stable availability and ensure consistent access. Funding: PrEDIRA 2 was supported by funding from Children's Investment Fund Foundation (R-2001-04433). Ms. Zia was funded by the NIH Ruth L. Kirchstein pre-doctoral award (5F31HD105494-02) and Dr. Heffron was funded by National Institute of Mental Health (K24MH123371).

Intimate Partner Violence and Adherence to PrEP and ART Among Ugandan HIV Serodifferent Couples.

BACKGROUND: Intimate partner violence (IPV) is associated with increased risk of HIV acquisition and reduced engagement in HIV care. There is limited understanding of the ways in which IPV exposure and other maladaptive relationship dynamics may influence adherence to antiretroviral treatment (ART) and pre-exposure prophylaxis (PrEP) for individuals in committed, HIV serodifferent partnerships. METHODS: We used binomial generalized linear mixed-effect regression models to evaluate the association between IPV exposure and ART/PrEP adherence among members of serodifferent couples in Uganda. Secondarily, we assessed the association between relationship powerlessness and ART/PrEP adherence. RESULTS: We enrolled and followed both partners in 149 heterosexual serodifferent couples. The partner living with HIV was female in 64% of couples. IPV exposure was associated with low ART adherence (15% vs. 5% in quarters with no IPV, odds ratio: 4.78, 95% confidence interval: 1.48 to 15.42), but not low PrEP adherence (33% vs. 36%, P = 0.69). Among HIV-negative individuals, those reporting moderate relationship powerlessness were less likely to have poor PrEP adherence compared with those with low relationship powerlessness (20% vs. 30%, odds ratio: 0.57, 95% confidence interval: 0.36 to 0.90). We observed no association between relationship powerlessness and ART adherence. CONCLUSIONS: We found that IPV exposure was associated with low adherence to ART and that relationship powerlessness was associated with good adherence to PrEP. These findings contribute to the evidence base outlining the influence of IPV and relationship power on ART/PrEP adherence for individuals in HIV serodifferent unions.

Awareness of Heightened Sexual and Behavioral Vulnerability as a Trigger for PrEP Resumption Among Adolescent Girls and Young Women in East and Southern Africa.

PURPOSE OF REVIEW: East and Southern Africa are the epicenter of the HIV epidemic. High HIV incidence rates among adolescent girls and young women (AGYW) remain stable over the last decade despite access to daily oral PrEP. Some settings have experienced high PrEP uptake among AGYW; however, discontinuation has been high. This review sought to understand drivers of PrEP discontinuation in this population in order to identify potential mechanisms to facilitate PrEP restart and optimize PrEP use. RECENT FINDINGS: Drivers of PrEP discontinuation included low perceived HIV acquisition risk, PrEP-associated side effects, pill burden, family/sexual partner disapproval, lack of/intermittent sexual activity, PrEP use stigma, fear of intimate partner violence, misinformation about long-term PrEP use, and limited/inconsistent access to PrEP. The most frequently reported driver of PrEP discontinuation was low perceived HIV acquisition risk. This indicates that innovative interventions to help AGYW recognize their HIV risk and make informed decisions about PrEP use are urgently needed.

"Gender-based Violence (GBV) and HIV, they are like sister and brother": barriers and facilitators to GBV screening and referral in public HIV treatment settings in Uganda.

BACKGROUND: People living with HIV are vulnerable to gender-based violence (GBV), which can negatively impact HIV treatment outcomes. National guidelines in Uganda recommend GBV screening alongside HIV treatment services. We explored barriers and facilitators to providers implementing GBV screening and referral in public antiretroviral therapy (ART) clinics in Uganda. METHODS: We conducted qualitative in-depth interviews. Providers were purposively sampled from 12 ART clinics to represent variation in clinical specialty and gender. We used the Theoretical Domains Framework to structure our deductive analysis. RESULTS: We conducted 30 in-depth interviews with providers implementing GBV screening and/or referral. Respondents had a median age of 36 (IQR: 30, 43) years and had been offering post-GBV care to clients for a median duration of 5 (4, 7) years. 67% of respondents identified as female and 57% were counselors. Facilitators of GBV screening and referral included providers having access to post-GBV standard operating procedures and screening tools, trainings offered by the Ministry of Health, facility-sponsored continuing medical education units and support from colleagues. Respondents indicated that referrals were uncommon, citing the following barriers: negative expectations regarding the quality and quantity of referral services; lack of financial resources to support clients, facilities, and referral partners throughout the referral process; and sociocultural factors that threatened client willingness to pursue post-GBV support services. CONCLUSIONS: Findings from this evaluation support the refinement of GBV screening and referral implementation strategies that leverage facilitators and address barriers to better support individuals living with HIV and who may have heightened vulnerability to GBV.

Contraceptive effects on the cervicovaginal microbiome: Recent evidence including randomized trials.

BACKGROUND: Until recently, most data regarding the effects of non-barrier contraceptives on the mucosal microbiome have derived from observational studies, which are potentially biased due to behavioral confounders that may mask their true biological effects. METHOD OF STUDY: This narrative review summarises recent evidence of the effect of contraceptives on the cervicovaginal microbiome, emphasising data obtained through randomized trials. RESULTS: Good quality data describe that initiation of long-acting progestin-only contraceptives, including levonorgestrel (LNG)-implant and the injectables depot-medroxyprogesterone acetate (DMPA-IM) and norethisterone enanthate (NET-EN) do not alter the mucosal microbial environment. Likewise, no strong evidence exists that the use of oral contraceptive pills (OCPs) is associated with alterations of the vaginal microbiome or increased risk of bacterial sexually transmitted infections (STIs). Limited data on the effect of intravaginal rings (IVRs) on the mucosal environment exist and show conflicting effects on the vaginal microbiota. Copper intrauterine device (Cu-IUD) initiation has been associated with bacterial vaginosis (BV) acquisition, including in a randomized trial. LNG-IUDs may have similar affects but need to be evaluated further. CONCLUSION: Different synthetic hormones have divergent effects on the microbiome and therefore novel hormonal methods need to be rigorously evaluated. Furthermore, the addition of antiretrovirals into multipurpose technologies may alter the effects of the hormonal component. There is thus a critical need to improve our understanding of the biological effects of contraceptive hormones and delivery methods with different pharmacokinetic and chemical properties on the mucosal microbiome in rigorous trials, to inform the development of novel contraceptives and improve individual family planning guidance.

Systems analysis reveals differential expression of endocervical genes in African women randomized to DMPA-IM, LNG implant or cu-IUD.

Although effective contraceptives are crucial for preventing unintended pregnancies, evidence suggests that their use may perturb the female genital tract (FGT). A comparative analysis of the effects of the most common contraceptives on the FGT have not been evaluated in a randomized clinical trial setting. Here, we evaluated the effect of three long-acting contraceptive methods: depot medroxyprogesterone acetate(DMPA-IM), levonorgestrel(LNG) implant, and a copper intrauterine device (Cu-IUD), on the endocervical host transcriptome in 188 women from the Evidence for Contraceptive Options and HIV Outcomes Trial (ECHO) trial. Cu-IUD usage showed the most extensive transcriptomic changes, and was associated with inflammatory and anti-viral host responses. DMPA-IM usage was enriched for pathways associated with T cell responses. LNG implant had the mildest effect on endocervical gene expression, and was associated with growth factor signaling. These data provide a mechanistic basis for the diverse influence that varying contraceptives have on the FGT.

How Central Ugandan HIV Clinics Adapted During COVID-19 Lockdown Restrictions to Promote Continuous Access to Care: A Qualitative Analysis.

We used qualitative data from the Partners PrEP Program (PPP) to address the question: How did Central Ugandan HIV clinics adapt to COVID-19 lockdown restrictions to promote continuous access to HIV care? PPP was a stepped-wedge cluster randomized trial of integrated PrEP and ART delivery for HIV serodifferent couples at Central Ugandan HIV clinics (NCT03586128). Individual interviews with purposefully selected PPP couples (N = 42) and clinicians, coordinators, and counselors providing HIV care (N = 36) were carried out. Sixty-four interviews were completed after lockdown and included questions about accessing and providing ART/PrEP refills during lockdown restrictions. We used an inductive, content-focused approach to analyze these interview data. Barriers to continuous access identified by interviewees included loss of income with increased cost of transport, reduced staff at clinics, and physical distancing at clinics. Interviewees pointed to multi-month refills, visits to clinics "close to home," transport to clinics for providers, and delivery of refills in neighborhoods as factors promoting continuous access to antiretroviral medications. Access barriers appeared somewhat different for ART and PrEP. Fewer resources for community delivery and pre-refill HIV testing requirements were identified as PrEP-specific access challenges. Participants emphasized their success in continuing ART/PrEP adherence during the lockdown, while providers emphasized missed refill visits. These results highlight the contributions of providers and ART/PrEP users to adaptation of HIV services during COVID-19 lockdown restrictions in Uganda. The roles of direct care providers and service users as drivers of adaptation should be recognized in future efforts to conceptualize and investigate health system resiliency.

Randomized controlled phase IIa clinical trial of safety, pharmacokinetics and pharmacodynamics of tenofovir and tenofovir plus levonorgestrel releasing intravaginal rings used by women in Kenya.

Introduction: Globally, many young women face the overlapping burden of HIV infection and unintended pregnancy. Protection against both may benefit from safe and effective multipurpose prevention technologies. Methods: Healthy women ages 18-34 years, not pregnant, seronegative for HIV and hepatitis B surface antigen, not using hormonal contraception, and at low risk for HIV were randomized 2:2:1 to continuous use of a tenofovir/levonorgestrel (TFV/LNG), TFV, or placebo intravaginal ring (IVR). In addition to assessing genital and systemic safety, we determined TFV concentrations in plasma and cervicovaginal fluid (CVF) and LNG levels in serum using tandem liquid chromatography-mass spectrometry. We further evaluated TFV pharmacodynamics (PD) through ex vivo CVF activity against both human immunodeficiency virus (HIV)-1 and herpes simplex virus (HSV)-2, and LNG PD using cervical mucus quality markers and serum progesterone for ovulation inhibition. Results: Among 312 women screened, 27 were randomized to use one of the following IVRs: TFV/LNG (n = 11); TFV-only (n = 11); or placebo (n = 5). Most screening failures were due to vaginal infections. The median days of IVR use was 68 [interquartile range (IQR), 36-90]. Adverse events (AEs) were distributed similarly among the three arms. There were two non-product related AEs graded >2. No visible genital lesions were observed. Steady state geometric mean amount (ssGMA) of vaginal TFV was comparable in the TFV/LNG and TFV IVR groups, 43,988 ng/swab (95% CI, 31,232, 61,954) and 30337 ng/swab (95% CI, 18,152, 50,702), respectively. Plasma TFV steady state geometric mean concentration (ssGMC) was <10 ng/ml for both TFV IVRs. In vitro, CVF anti-HIV-1 activity showed increased HIV inhibition over baseline following TFV-eluting IVR use, from a median of 7.1% to 84.4% in TFV/LNG, 15.0% to 89.5% in TFV-only, and -27.1% to -20.1% in placebo participants. Similarly, anti-HSV-2 activity in CVF increased >50 fold after use of TFV-containing IVRs. LNG serum ssGMC was 241 pg/ml (95% CI 185, 314) with rapid rise after TFV/LNG IVR insertion and decline 24-hours post-removal (586 pg/ml [95% CI 473, 726] and 87 pg/ml [95% CI 64, 119], respectively). Conclusion: TFV/LNG and TFV-only IVRs were safe and well tolerated among Kenyan women. Pharmacokinetics and markers of protection against HIV-1, HSV-2, and unintended pregnancy suggest the potential for clinical efficacy of the multipurpose TFV/LNG IVR. Clinical Trial Registration: NCT03762382 [https://clinicaltrials.gov/ct2/show/NCT03762382].

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.

Update on the Impact of Depot Medroxyprogesterone Acetate on Vaginal Mucosal Endpoints and Relevance to Sexually Transmitted Infections.

PURPOSE OF REVIEW: The long-acting reversible intramuscularly-injected contraceptive depot medroxyprogesterone acetate (DMPA-IM) is widely used by cisgender women in Africa. Although DMPA-IM provides reliable contraception, potential effects on the female genital tract (FGT) mucosa have raised concern, including risk of HIV infection. This review summarises and compares evidence from observational cohort studies and the randomised Evidence for Contraceptive Options in HIV Outcomes (ECHO) Trial. RECENT FINDINGS: Although previous observational studies found women using DMPA-IM had higher abundance of bacterial vaginosis (BV)-associated bacteria, increased inflammation, increased cervicovaginal HIV target cell density, and epithelial barrier damage, sub-studies of the ECHO Trial found no adverse changes in vaginal microbiome, inflammation, proteome, transcriptome, and risk of viral and bacterial STIs, other than an increase in Th17-like cells. Randomised data suggest that DMPA-IM use does not adversely change mucosal endpoints associated with acquisition of infections. These findings support the safe use of DMPA-IM in women at high risk of acquiring STIs, including HIV.