Adherence and HIV Protection Thresholds for Emtricitabine and Tenofovir Disoproxil Fumarate Preexposure Prophylaxis among Cisgender Women: A Systematic Review.

PURPOSE OF REVIEW: Adherence-concentration-efficacy benchmarks have not been fully characterized for cisgender women using emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) oral daily pre-exposure prophylaxis (PrEP) for HIV prevention. RECENT FINDINGS: We conducted a systematic review to investigate current evidence on the adherence-concentration-efficacy relationship of tenofovir-diphosphate (TFV-DP) derived from FTC/TDF PrEP in dried blood spots (DBS) and peripheral mononuclear cells (PBMC) in cisgender women without HIV, including during pregnancy. We searched for completed and ongoing studies published before May 2024 in PubMed, Embase, Cochrane Library, CINAHL, and clinicaltrial.gov.  Overall, 11 studies assessing adherence benchmarks focusing on (n = 5) or involving (n = 6) cisgender women were included. Women-specific median steady-state TFV-DP concentration for daily dosing ranged from 17 to 51 fmol/106 in PBMC and 1389 to 1685 fmol/punch in DBS in non-pregnant women; 50 to 71 fmol/106 in PBMC and 583 to 965 fmol/punch in DBS in pregnant women; and 618 to 1406 fmol/punch in DBS in postpartum women. DBS TFV-DP levels were 14-43% lower in pregnancy versus postpartum or non-pregnant periods, but PBMC TFV-DP levels appear to be comparable. Clinical and modeling studies demonstrate effective HIV protection for women taking at least four doses/week of oral TDF-based PrEP, and emerging evidence suggests that systemic drug levels are more likely to be predictive of efficacy than local tissue levels at the site of exposure. The preponderance of emerging evidence points to comparable efficacy and similar adherence requirement for women as men among those with detectable drug levels, although there was an indication that the highest achievable efficacy may be reached at a lower adherence level in men than women. In this review, we found evidence that women-specific TFV-DP adherence benchmarks in DBS and PBMC are within range of US-based historical thresholds derived from healthy men and women. Emerging evidence suggests that imperfect but adequate adherence to oral FTC/TDF PrEP with at least four doses/week provides sufficient HIV protection in cisgender women as it does in MSM, but more data are still needed to refine intrinsic achievable efficacy estimates for cisgender women.

"Now that PrEP is reducing the risk of transmission of HIV, why then do you still insist that we use condoms?" the condom quandary among PrEP users and health care providers in Kenya.

Communication around condom use in the context of PrEP services presents a potential conundrum for patients and providers. Within the Partners Scale-Up Project, which supports integration of PrEP delivery in HIV care clinics, we interviewed 41 providers and 61 PrEP users and identified themes relating to condom messaging and use. Most providers counselled PrEP initiators to always use both PrEP and condoms, except when trying to conceive. However, others reported contexts and rationales for not emphasizing condom use. Providers reported that PrEP users were sometimes confused, even frustrated, with their insistence on using condoms in addition to PrEP. PrEP users generally regarded PrEP as a more feasible and desirable HIV prevention method than condoms, enabling increased sexual pleasure and conception, and reducing the conflict and stigma associated with condom use. Innovative approaches to condom counselling in PrEP programs are needed.

Low costs and opportunities for efficiency: a cost analysis of the first year of programmatic PrEP delivery in Kenya's public sector.

BACKGROUND: In 2017, the Kenyan Ministry of Health integrated provision of pre-exposure prophylaxis (PrEP) into public HIV-1 care clinics as a key component of the national HIV-1 prevention strategy. Estimates of the cost of PrEP provision are needed to inform the affordability and cost-effectiveness of PrEP in Kenya. METHODS: We conducted activity-based micro-costing from the payer perspective to estimate both the financial and economic costs of all resources and activities required to provide PrEP in Kenya's public sector. We estimated total and unit costs in 2019 United States dollars from a combination of project expense reports, Ministry of Health training reports, clinic staff interviews, time-and-motion observations, and routinely collected data from PrEP recipient files from 25 high-volume HIV-1 care clinics. RESULTS: In the first year of programmatic PrEP delivery in 25 HIV-1 care clinics, 2,567 persons initiated PrEP and accrued 8,847 total months of PrEP coverage, accounting for 2 % of total outpatient clinic visits. The total financial cost to the Ministry of Health was $91,175, translating to an average of $10.31 per person per month. The majority (69 %) of financial costs were attributable to PrEP medication, followed by administrative supplies (17 %) and training (9 %). Economic costs were higher ($188,584 total; $21.32 per person per month) due to the inclusion of the opportunity cost of staff time re-allocated to provide PrEP and a proportional fraction of facility overhead. The vast majority (88 %) of the annual $80,811 economic cost of personnel time was incurred during activities to recruit new clients (e.g., discussion of PrEP within HIV-1 testing and counselling services), while the remaining 12 % was for activities related to both initiation and maintenance of PrEP provision (e.g., client consultations, technical advising, support groups). CONCLUSIONS: Integration of PrEP provision into existing public health HIV-1 care service delivery platforms resulted in minimal additional staff burden and low incremental costs. Efforts to improve the efficiency of PrEP provision should focus on reductions in the cost of PrEP medication and extra-clinic demand creation and community sensitization to reduce personnel time dedicated to recruitment-related activities. TRIAL REGISTRATION: ClinicalTrials.gov registration NCT03052010 . Retrospectively registered on February 14, 2017.

Integrating preexposure prophylaxis delivery in routine family planning clinics: A feasibility programmatic evaluation in Kenya.

BACKGROUND: Young women account for a disproportionate fraction of new HIV infections in Africa and are a priority population for HIV prevention, including implementation of preexposure prophylaxis (PrEP). The overarching goal of this project was to demonstrate the feasibility of integrating PrEP delivery within routine family planning (FP) clinics to serve as a platform to efficiently reach at-risk adolescent girls and young women (AGYW) for PrEP in HIV high-burden settings. METHODS AND FINDINGS: The PrEP Implementation in Young Women and Adolescents (PrIYA) program is a real-world implementation program to demonstrate integration of PrEP delivery for at-risk AGYW in FP clinics in Kisumu, Kenya. Between November 2017 and June 2018, women aged 15 to 45 from the general population seeking FP services at 8 public health clinics were universally screened for HIV behavioral risk factors and offered PrEP following national PrEP guidelines. We evaluated PrEP uptake and continuation, and robust Poisson regression methods were used to identify correlates of uptake and early continuation of PrEP, with age included as a one-knot linear spline. Overall, 1,271 HIV-uninfected women accessing routine FP clinics were screened for PrEP; the median age was 25 years (interquartile range [IQR]: 22-29), 627 (49%) were <24 years old, 1,026 (82%) were married, more than one-third (34%) had partners of unknown HIV status, and the vast majority (n = 1,200 [94%]) reported recent condom-less sex. Of 1,271 women screened, 278 (22%) initiated PrEP, and 114 (41%) returned for at least one refill visit after initiation. PrEP uptake was independently associated with reported male-partner HIV status (HIV-positive 94%, unknown 35%, HIV-negative 8%; p < 0.001) and marital status (28% unmarried versus married 21%; p = 0.04), and a higher proportion of women ≥24 years (26%; 191/740) initiated PrEP compared to 16% (87/531) of young women <24 years (p < 0.001). There was a moderate and statistically non-significant unadjusted increase in PrEP uptake among women using oral contraception pills (OCPs) compared to women using injectable or long-acting reversible contraception methods (OCP 28% versus injectable/implants/intrauterine devices [IUDs] 18%; p = 0.06). Among women with at least one post-PrEP initiation follow-up visit (n = 278), no HIV infection was documented during the project period. Overall, continuation of PrEP use at 1, 3, and 6 months post initiation was 41%, 24%, and 15%, respectively. The likelihood for early continuation of PrEP use (i.e., return for at least one PrEP refill within 45 days post initiation) was strongly associated with reported male-partner HIV status (HIV-positive 67%, -negative 39%, unknown 31%; overall effect p = 0.001), and a higher proportion of women ≥24 years old continued PrEP at 1 month compared with young women <24 years old (47% versus 29%; p = 0.002). For women ≥24 years old, the likelihood to continue PrEP use at 1 month post initiation increased by 3% for each additional year of a woman's age (adjusted prevalence ratio [PR]: 1.03; 95% confidence interval [CI]: 1.01-1.05; p = 0.01). In contrast, for women <24 years old, the likelihood of continuing PrEP for each additional year of a woman's age was high in magnitude (approximately 6%) but statistically non-significant (adjusted PR: 1.06; 95% CI: 0.97-1.16; p = 0.18). Frequently reported reasons for discontinuing PrEP were low perceived risk of HIV (25%), knowledge that partner was HIV negative (24%), experiencing side effects (20%), and pill burden (17%). Study limitations include lack of qualitative work to provide insights into women's decision-making on PrEP uptake and continuation, the small number of measured covariates imposed by the program data, and a nonrandomized design limiting definitive ascertainment of the robustness of a PrEP-dedicated nurse-led implementation strategy. CONCLUSIONS: In this real-world PrEP implementation program in Kenya, integration of universal screening and counseling for PrEP in FP clinics was feasible, making this platform a potential "one-stop" location for FP and PrEP. There was a high drop-off in PrEP continuation, but a subset of women continued PrEP use at least through 1 month, possibly indicating further reflection or decision-making on PrEP use. Greater efforts to support PrEP normalization and persistence for African women are needed to help women navigate their decisions about HIV prevention preferences as their reproductive goals and HIV vulnerability evolve.

Pre-exposure Prophylaxis Use by Breastfeeding HIV-Uninfected Women: A Prospective Short-Term Study of Antiretroviral Excretion in Breast Milk and Infant Absorption.

BACKGROUND: As pre-exposure prophylaxis (PrEP) becomes more widely used in heterosexual populations, an important consideration is its safety in infants who are breastfed by women taking PrEP. We investigated whether tenofovir and emtricitabine are excreted into breast milk and then absorbed by the breastfeeding infant in clinically significant concentrations when used as PrEP by lactating women. METHODS AND FINDINGS: We conducted a prospective short-term, open-label study of daily oral emtricitabine-tenofovir disoproxil fumarate PrEP among 50 HIV-uninfected breastfeeding African mother-infant pairs between 1-24 wk postpartum (ClinicalTrials.gov Identifier: NCT02776748). The primary goal was to quantify the steady-state concentrations of tenofovir and emtricitabine in infant plasma ingested via breastfeeding. PrEP was administered to women through daily directly observed therapy (DOT) for ten consecutive days and then discontinued thereafter. Non-fasting peak and trough samples of maternal plasma and breast milk were obtained at drug concentration steady states on days 7 and 10, and a single infant plasma sample was obtained on day 7. Peak blood and breast milk samples were obtained 1-2 h after the maternal DOT PrEP dose, while maternal trough samples were obtained at the end of the PrEP dosing interval (i.e., 23 to 24 h) after maternal DOT PrEP dose. Tenofovir and emtricitabine concentrations were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays. Of the 50 mother-infant pairs enrolled, 48% were ≤12 wk and 52% were 13-24 wk postpartum, and median maternal age was 25 y (interquartile range [IQR] 22-28). During study follow-up, the median (IQR) daily reported frequency of infant breastfeeding was 15 times (12 to 18) overall, 16 (14 to 19) for the ≤12 weeks, and 14 (12 to 17) for the 13-24 wk infant age groups. Overall, median (IQR) time-averaged peak concentrations in breast milk were 3.2 ng/mL (2.3 to 4.7) for tenofovir and 212.5 ng/mL (140.0 to 405.0) for emtricitabine. Similarly, median (IQR) time-averaged trough concentrations in breast milk were 3.3 ng/mL (2.3 to 4.4) for tenofovir and 183.0 ng/mL (113.0 to 250.0) for emtricitabine, reflecting trough-to-peak breast milk concentration ratios of 1.0 for tenofovir and 0.8 for emtricitabine, respectively. In infant plasma, tenofovir was unquantifiable in 46/49 samples (94%), but emtricitabine was detectable in 47/49 (96%) (median [IQR] concentration: 13.2 ng/mL [9.3 to 16.7]). The estimated equivalent doses an infant would ingest daily from breastfeeding were 0.47 µg/kg (IQR 0.35 to 0.71) for tenofovir and 31.9 µg/kg (IQR 21.0 to 60.8) for emtricitabine, translating into a <0.01% and 0.5% relative dose when compared to the 6 mg/kg dose that is proposed for therapeutic treatment of infant HIV infection and for prevention of infant postnatal HIV infection; a dose that has not shown safety concerns. No serious adverse effects were recorded during study follow-up. The key study limitation was that only a single infant sample was collected to minimize venipunctures for the children. However, maternal daily DOT and specimen collection at drug concentration steady state provided an adequate approach to address the key research question. Importantly, there was minimal variation in breast milk concentrations of tenofovir and emtricitabine (respective median trough-to-peak concentration ratio ~1), demonstrating that infants were exposed to consistent drug dosing via breast milk. CONCLUSION: In this short-term study of daily directly observed oral PrEP in HIV-uninfected breastfeeding women, the estimated infant doses from breast milk and resultant infant plasma concentrations for tenofovir and emtricitabine were 12,500 and >200-fold lower than the respective proposed infant therapeutic doses, and tenofovir was not detected in 94% of infant plasma samples. These data suggest that PrEP can be safely used during breastfeeding with minimal infant drug exposure. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: NCT02776748.

Estimating the Effect of COVID-19 Pandemic Restrictions on Self-reported Antiretroviral Therapy Use and Late Refill Visits Among People Living With HIV in Rural South Africa.

BACKGROUND: People living with HIV require reliable access to and adequate supply of antiretroviral therapy (ART) for viral suppression. The Deliver Health Study, a randomized trial conducted during the COVID-19 pandemic, found that home-delivered ART significantly increased viral suppression compared with clinic-based care. The effect of changing COVID-19 alert levels on self-reported ART use has not been quantified. SETTING: KwaZulu-Natal, South Africa. METHODS: Adults living with HIV were followed in the Deliver Health Study during October 2019-December 2020. We used difference-in-differences (DiD) to estimate the effect of changing COVID-19 alert levels during 3 distinct periods on self-reported missed ART doses (missed 0 vs. ≥1 doses in past week) for participants receiving home-delivered vs. clinic-based refills. We additionally estimated the effect of changing COVID-19 alert levels on late clinic ART refill visits (late vs. on-time). We used relative risk regression for both binary outcomes. RESULTS: Of 155 participants, 46% were women and the median age was 36 years. The mean number of missed weekly doses was 0.11, 0, and 0.12 in the home-delivery group and 0.09, 0.08, and 0.18 in the clinic group during periods 1, 2, and 3, respectively. There were no differences in relative risk of self-reported daily ART use between refill groups when comparing across periods [DiDperiod 2 vs. 1 = 1.05; 95% confidence interval: 0.97, 1.13 and DiDperiod 3 vs. 2 = 0.99; 95% confidence interval (CI): 0.91, 1.08]. In the clinic group, the risk of late refill visits was significantly higher during COVID-19 restrictions (vs. before alert level 5 implementation) and even after the COVID-19 alert level was downgraded to level 1 (RRperiod 2 vs. 1 = 1.83, 95% CI: 1.34, 2.51 and RRperiod 3 vs. 2 = 1.71; 95% CI: 1.43, 2.04). CONCLUSION: The COVID-19 pandemic did not differentially impact self-reported ART adherence by the method of ART refills, but the risk of late clinic refill visits was significantly higher during COVID-19 restrictions and sustained after restrictions were loosened.

Effect of differentiated direct-to-pharmacy PrEP refill visits supported with client HIV self-testing on clinic visit time and early PrEP continuation.

INTRODUCTION: Delivery of oral pre-exposure prophylaxis (PrEP) is being scaled up in Africa, but clinic-level barriers including lengthy clinic visits may threaten client continuation on PrEP. METHODS: Between January 2020 and January 2022, we conducted a quasi-experimental evaluation of differentiated direct-to-pharmacy PrEP refill visits at four public health HIV clinics in Kenya. Two clinics implemented the intervention package, which included direct-to-pharmacy for PrEP refill, client HIV self-testing (HIVST), client navigator, and pharmacist-led rapid risk assessment and dispensing. Two other clinics with comparable size and client volume served as contemporaneous controls with the usual clinic flow. PrEP continuation was evaluated by visit attendance and pharmacy refill records, and time and motion studies were conducted to determine time spent in the clinics. Dried blood spots were collected to test for tenofovir-diphosphate (TFV-DP) at random visits. We used logistic regression to assess the intervention effect on PrEP continuation and the Wilcoxon rank sum test to assess the effect on clinic time. RESULTS: Overall, 746 clients were enrolled, 366 at control clinics (76 during pre-implementation and 290 during implementation phase), and 380 at direct-to-pharmacy clinics (116 during pre-implementation and 264 during implementation phase). Prior to implementation, the intervention and control clinics were comparable on client characteristics (female: 51% vs. 47%; median age: 33 vs. 33 years) and PrEP continuation (35% vs. 37% at 1 month, and 37% vs. 39% at 3 months). The intervention reduced total time spent at the clinic by 35% (median of 51 minutes at control vs. 33 minutes at intervention clinics; p<0.001), while time spent on HIV testing (20 vs. 20 minutes; p = 0.50) and pharmacy (8 vs. 8 minutes; p = 0.8) was unchanged. PrEP continuation was higher at intervention versus the control clinics: 45% versus 33% at month 1, 34% versus 25% at month 3 and 23% versus 16% at month 6. TFV-DP was detected in 85% (61/72) of samples, similar by the study group (83% vs. 85%). CONCLUSIONS: A client-centred PrEP delivery approach with direct-to-pharmacy PrEP refill visits plus client HIVST significantly reduced clinic visit time by more than one-third and improved PrEP continuation in public health HIV clinics in Kenya.

Establishing adherence-concentration-efficacy thresholds of TDF-FTC pre-exposure prophylaxis for HIV prevention in African women: a protocol for the Women TDF-FTC Benchmark Study.

Background: Oral pre-exposure prophylaxis (PrEP) using co-formulated emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) is a potent HIV prevention method for men and women, with its efficacy highly dependent on adherence. A pivotal HIV efficacy study combined with a directly observed pharmacological study defined the thresholds for HIV protection in men who have sex with men (MSM), which are the keys to PrEP promotion and development of new PrEP agents. For African women at risk for HIV and belonging to a priority group considered due to disproportionately high incident HIV infections, the variable adherence in PrEP clinical trials and the limited pharmacologic data have resulted in a lack of clarity about the PrEP adherence required for HIV protection. We propose a study to quantify the adherence-concentration-efficacy thresholds of TDF/FTC PrEP among African cisgender women to inform decisions about optimal PrEP dosing and adherence for HIV protection. Methods: We randomized 45 low-risk HIV-uninfected African women, aged 18-30 years old, to directly observe the TDF/FTC PrEP of two, four, or seven doses per week for 8 weeks. A complementary age-matched pregnant women cohort at high risk of HIV, who will receive seven doses per week, was recruited (N = 15) with the primary aim of establishing benchmark concentrations in dried blood spots and peripheral blood mononuclear cells. Plasma, whole blood (WB), urine, hair, vaginal fluid, and vaginal tissue (non-pregnant women only) were archived for future testing. Drug concentrations were measured using methods validated for each biological matrix. Pharmacokinetic models were fitted to drug concentrations to quantify concentration-adherence thresholds. To define the drug concentrations associated with HIV protection, we applied the newly defined thresholds from the primary pharmacologic trial to the subset of women randomized to TDF/FTC or TDF in the Partners PrEP Study with the drug concentration assessed in plasma and WB samples. Multiple imputation was used to construct a data set with drug concentrations at each visit when an HIV test was performed for the entire cohort, replicating the work for MSM. Discussion: The proposed study generated the first African women-specific TDF-PrEP adherence-concentration-efficacy thresholds essential for guiding the accurate interpretation of TDF/FTC PrEP programs and clinical trials of novel HIV prevention products using TDF/FTC as an active control. Clinical Trial Registration: ClinicalTrials.gov, identifier (NCT05057858).

Mixed-methods protocol for the WiSSPr study: Women in Sex work, Stigma and psychosocial barriers to Pre-exposure prophylaxis in Zambia.

INTRODUCTION: Women engaging in sex work (WESW) have 21 times the risk of HIV acquisition compared with the general population. However, accessing HIV pre-exposure prophylaxis (PrEP) remains challenging, and PrEP initiation and persistence are low due to stigma and related psychosocial factors. The WiSSPr (Women in Sex work, Stigma and PrEP) study aims to (1) estimate the effect of multiple stigmas on PrEP initiation and persistence and (2) qualitatively explore the enablers and barriers to PrEP use for WESW in Lusaka, Zambia. METHODS AND ANALYSIS: WiSSPr is a prospective observational cohort study grounded in community-based participatory research principles with a community advisory board (CAB) of key population (KP) civil society organi sations (KP-CSOs) and the Ministry of Health (MoH). We will administer a one-time psychosocial survey vetted by the CAB and follow 300 WESW in the electronic medical record for three months to measure PrEP initiation (#/% ever taking PrEP) and persistence (immediate discontinuation and a medication possession ratio). We will conduct in-depth interviews with a purposive sample of 18 women, including 12 WESW and 6 peer navigators who support routine HIV screening and PrEP delivery, in two community hubs serving KPs since October 2021. We seek to value KP communities as equal contributors to the knowledge production process by actively engaging KP-CSOs throughout the research process. Expected outcomes include quantitative measures of PrEP initiation and persistence among WESW, and qualitative insights into the enablers and barriers to PrEP use informed by participants' lived experiences. ETHICS AND DISSEMINATION: WiSSPr was approved by the Institutional Review Boards of the University of Zambia (#3650-2023) and University of North Carolina (#22-3147). Participants must give written informed consent. Findings will be disseminated to the CAB, who will determine how to relay them to the community and stakeholders.

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.

Patterns of PrEP continuation and coverage in the first year of use: a latent class analysis of a programmatic PrEP trial in Kenya.

INTRODUCTION: Effective PrEP use is critical for impact, but data are limited on common patterns of continuation and coverage among persons using PrEP in real-world settings. METHODS: Data are from the Partners Scale-Up Project, a programmatic stepped-wedge cluster-randomized trial to integrate PrEP delivery in 25 Kenyan public health facilities conducted between February 2017 and December 2021. We evaluated PrEP continuation using visit attendance and pharmacy refill records, and computed medication possession ratio to define coverage during the first year of use. Latent class mixture models were used to identify and characterize membership to different PrEP continuation patterns. Multinomial logistic regression was used to examine the association between group trajectories and demographic and behaviour characteristics. RESULTS: Overall, 4898 persons initiated PrEP, 54% (2640) were female, mean age was 33 years (standard deviation 11) and 84% (4092) had partners living with HIV. PrEP continuation was 57%, 44%, and 34% at 1, 3, and 6 months, respectively. Four unique trajectories of PrEP coverage were identified: (1) one-fourth (1154) exhibited consistent high coverage throughout the year with 93%, 94%, 96%, and 67% continuing PrEP at months 1, 3, 6, and 12, respectively; (2) 13% (682) showed high coverage trajectory throughout 6 months but coverage rapidly declined thereafter (94%, 93%, 63%, and 10% continued at months 1, 3, 6, and 12, respectively); (3) 18.9% (918) exhibited moderate coverage trajectory with 91% of clients refilling PrEP at month 1 but nearly all dropped-off thereafter (37%, 5%, and 4% continued at months 3, 6, and 12, respectively); and (4) 43.8% (2144) exhibited immediate discontinuation trajectory, in which nearly all did not have any subsequent PrEP refill. Overall, being female, older age, having partners living with HIV or of unknown HIV status were statistically associated with better PrEP continuation trajectories compared to the immediate discontinuation trajectory (p <0.05 for all). CONCLUSIONS: In this analysis of a real-world PrEP implementation programme in Kenya, we found four distinct patterns of PrEP continuation, with one-third of users exhibiting consistent high continuation throughout 12 months and two-fifths with immediate discontinuation patterns. These data may help guide tailored interventions to support PrEP continuation in this setting.

Provider perspectives on service delivery modifications to maintain access to HIV pre-exposure prophylaxis during the COVID-19 pandemic: qualitative results from a PrEP implementation project in Kenya.

INTRODUCTION: HIV pre-exposure prophylaxis (PrEP) is an essential prevention strategy being scaled up for priority populations in Kenya, including for HIV serodiscordant couples. The COVID-19 pandemic posed challenges to PrEP rollout. We conducted a qualitative study of PrEP providers to understand how clinics adjusted PrEP delivery during the COVID-19 pandemic. METHODS: Since 2017, the Partners Scale-Up Project has integrated PrEP into 25 HIV clinics in Central and Western Kenya. We conducted qualitative interviews with 40 purposively sampled clinic personnel. We interviewed personnel once during the first pandemic wave (May-Aug 2020) and again after some decline in COVID-19 rates (Nov-Jan 2021). We analysed data using inductive memo-writing and summarized data by themes along the PrEP delivery cascade, guided by the Framework for Reporting Adaptation and Modifications (FRAME). RESULTS: We interviewed 27 clinical officers, five nurses, four health records and information officers, and four counsellors from Central (n = 20) and Western (n = 20) Kenya. About half (n = 19) were female, with a median age of 32 (IQR: 29-34) and 2.3 years of experience delivering PrEP (IQR: 2-3). All participants reported clinic changes in PrEP demand creation and service delivery during the pandemic. Modifications occurred during PrEP implementation and sustainment phases, were partly reactive to the pandemic and also facilitated by interim Ministry of Health guidance on PrEP delivery during COVID, and were made by PrEP delivery teams, clients and clinic managers. Commonly reported modifications included dispensing multiple-month PrEP refills, intensifying phone-based client engagement and collaborating with other HIV clinics to ensure that clients with prolonged stays in other regions could continue to access PrEP. Some clinics also adopted practices to streamline visits, such as within clinical-room PrEP dispensing, pre-packing PrEP and task-shifting. Most providers liked these changes and hoped they would continue after the pandemic subsides. CONCLUSIONS: COVID-19 served as a catalyst for PrEP delivery innovations in Kenya. HIV clinics successfully and rapidly adapted their PrEP demand creation, refill and retention strategies to promote PrEP uptake and effective use. These modified implementation strategies highlight opportunities to streamline the delivery of PrEP, as well as other HIV and chronic care services, and strengthen engagement with populations post-pandemic.

The effect of daily oral PrEP use during pregnancy on bone mineral density among adolescent girls and young women in Uganda.

Introduction: Oral pre-exposure prophylaxis (PrEP) is recommended during pregnancy for at-risk cisgender women. Pregnancy is known to impede bone growth and tenofovir-based PrEP may also yield detrimental changes to bone health. Thus, we evaluated the effect of PrEP use during pregnancy on bone mineral density (BMD). Methods: We used data from a cohort of women who were sexually active, HIV-negative, ages 16-25 years, initiating DMPA or choosing condoms for contraception and enrolled in the Kampala Women's Bone Study. Women were followed quarterly with rapid testing for HIV and pregnancy, PrEP dispensation, and adherence counseling. Those who became pregnant were counseled on PrEP use during pregnancy per national guidelines. BMD of the neck of the hip, total hip, and lumbar spine was measured using dual-energy x-ray absorptiometry at baseline and annually. We compared the mean percent change in BMD from baseline to month 24. Results: Among 499 women enrolled in the study, 105 pregnancies occurred in 90 women. At enrollment, the median age was 20 years (IQR: 19-21) and 89% initiated PrEP. During pregnancy, 67% of women continued using PrEP and PrEP was dispensed in 64% of visits. BMD declined significantly in women using PrEP during pregnancy compared to women who were not pregnant nor used PrEP: relative BMD change was -2.26% (95% CI: -4.63 to 0.11, p = 0.06) in the femoral neck, -2.57% (95% CI: -4.48 to -0.66, p = 0.01) in total hip, -3.06% (95% CI: -5.49 to -0.63, p = 0.001) lumbar spine. There was no significant difference in BMD loss when comparing PrEP-exposed pregnant women to pregnant women who never used PrEP. Women who became pregnant were less likely to continue PrEP at subsequent study visits than women who did not become pregnant (adjOR: 0.25, 95% CI: 0.16-0.37, p < 0.001). Based on pill counts, there was a 62% reduction in the odds of high PrEP adherence during pregnancy (adjOR = 0.38, 95% CI: 0.27-0.58, p < 0.001). Conclusion: Women who used PrEP during pregnancy experienced a similar reduction in BMD as pregnant women with no PrEP exposure, indicating that BMD loss in PrEP-using pregnant women is largely driven by pregnancy and not PrEP.

Targeted Implementation of HIV Self-Testing Increases Testing Uptake Among Partners of Index Persons Known to Have HIV in Kenya.

BACKGROUND: Partners of persons living with HIV (PLHIV) are at a high risk of HIV acquisition, particularly if PLHIV are newly diagnosed or not virally suppressed. A focused partner HIV testing strategy could stimulate efficient identification of persons for pre-exposure prophylaxis (PrEP) or antiretroviral therapy (ART) programs. METHODS: We sequentially implemented 2 partner testing strategies at 2 Kenyan HIV clinics: (1) an invitation for clinic-based testing and (2) HIV self-testing (HIVST) kits distribution to index PLHIV. For each testing strategy, we enrolled approximately 150 consecutive index PLHIV with partners of unknown HIV status, not on ART, <6 months on ART, or who had detectable viral load. We compared partner engagement, testing uptake, and linkage for ART or PrEP between the 2 testing strategies. RESULTS: Of 313 index PLHIV enrolled (160 in invitation, 153 in HIVST), the median age was 32 years (interquartile range 26-40) and 76% were women. Overall, 73% of participants (229) discussed HIV testing with their partners: 76% (121) in the invitation strategy vs 71% (108) in the HIVST strategy [adjusted odds ratio (adjOR): 0.54, 95% confidence interval (CI): 0.31 to 0.97]. Overall, 52% (79) partners in the HIVST strategy tested vs 38% (60) in the invitation strategy (adjOR: 1.78, 95% CI: 1.13 to 2.78). Among partners engaged, 73% in the HIVST strategy vs 50% in the invitation tested (adjOR: 2.68, 95% CI: 1.46 to 4.96); 25% (35/139) tested positive for HIV. Eighty-nine percentage (31/35) who tested positive initiated treatment, but only 21% (20/93) who tested negative initiated PrEP. CONCLUSIONS: HIVST kit distribution to PLHIV with partners of unknown HIV status effectively increased partner testing. Only one-fifth of partners who tested negative initiated PrEP-thus innovations to link to prevention services are urgently needed.

Bone mineral density, nutrient intake, and physical activity among young women from Uganda.

Few studies have characterized bone mineral density (BMD) among health young African women. In our study of 496 Ugandan women age ≤25 years, we found that women had healthy BMD that were lower on average than the standard reference ranges. Reference ranges available for BMD measurements need greater precision. PURPOSE: Data describing bone mineral density (BMD), nutrient intake, and body composition among healthy, young women in sub-Saharan Africa are limited. Using baseline data from a cohort of young, healthy Ugandan women, we summarize bone health and associated risk factors for reduced bone mass. METHODS: Using baseline data from Ugandan women ages 16-25 years who enrolled in an ongoing cohort study of bone health with concurrent use of injectable contraception and oral HIV pre-exposure prophylaxis, we describe the distribution of BMD, nutrient intake, physical activity, and body composition. The association of low BMD (1 or more standard deviations below the age, sex, and race-matched reference range from the USA) and calcium intake, vitamin D intake, physical activity, and body composition was estimated using multivariable logistic regression. RESULTS: In 496 healthy, Ugandan women with median age of 20 years (interquartile range [IQR] 19-21) and median fat:lean mass ratio of 0.55 (IQR 0.46-0.64), median lumbar spine and total hip BMD was 0.9g/cm2 (IQR 0.9-1.0) each. For lumbar spine, Z-score distributions were lower overall than the reference population and 9.3% and 36.3% of women had Z-score >2 and >1 standard deviations below the reference range, respectively. For total hip, Z-scores were similar to the reference population and 1.0% and 12.3% of women had Z-score >2 and >1 standard deviations below the reference range, respectively. In the week prior to enrollment, 41.1% of women consumed >7 servings of calcium, 56.5% had >7 servings of vitamin D, and 98.6% reported ≥2.5 h of physical activity. Having greater body fat was associated with greater frequency of low lumbar spine BMD (p<0.01 for fat:lean mass ratio, total body fat percentage, waist circumference, and BMI). CONCLUSION: Young Ugandan women exhibited healthy levels of BMD that were lower than the reference range population.

Integrating Pre-Exposure Prophylaxis Delivery in Public Health Family Planning Clinics: Lessons Learned From a Programmatic Implementation Project in Kenya.

Sexually active African women are a priority population for HIV prevention due to the disproportionately high frequency of new HIV infections. Family planning (FP) clinics offer an already trusted platform that can be used to reach women for HIV prevention services, including pre-exposure prophylaxis (PrEP). In the recent PrEP Implementation in Young Women and Adolescent (PrIYA program), we piloted PrEP implementation in FP clinics in Kisumu, Kenya, and demonstrated that it was possible to integrate PrEP provision in FP systems with a program-dedicated staff. In this perspective, we describe experiences and strategies employed to introduce PrEP implementation in FP clinics and lessons learned. We identified the following lessons for PrEP introduction in FP clinics in Kenya: (1) possible to integrate and generate high enthusiasm for PrEP delivery in FP clinics but persistence on PrEP is a challenge, (2) involvement of national and regional stakeholders is critical for buy-in, contextualization, and sustainability, (3) delivery models that do not integrate fully with existing staff and systems are less sustainable, (4) creatinine testing at PrEP initiation may not be necessary, (5) fully integrated HIV and FP data systems need to be developed, and (6) incorporating implementation science evaluation is important to understand and document effective implementation strategies. In summary, integration of HIV prevention and FP services provides an opportunity to promote one-stop women-centered care efficiently. However, a broader focus on delivery models that utilize existing staff and novel strategies to help women identify their own risk for HIV are needed to ensure greater success and sustainability.

Safety review of tenofovir disoproxil fumarate/emtricitabine pre-exposure prophylaxis for pregnant women at risk of HIV infection.

Introduction: Pregnancy is a period of elevated HIV risk in high-burden settings, motivating the need for prevention tools that are both safe for use and effective during pregnancy. Oral pre-exposure prophylaxis (PrEP) containing tenofovir disoproxil fumarate (TDF) is recommended by the World Health Organization, including for pregnant and postpartum women at substantial risk of HIV infection. Although TDF use during pregnancy appears generally safe, data on PrEP use during pregnancy remain limited.Areas covered: We provide an overview of the clinical pharmacology and efficacy of daily TDF-based PrEP and summarize current evidence on the safety of PrEP use by pregnant HIV-uninfected women. We synthesize relevant studies assessing pregnancy outcomes among pregnant women who are living with HIV (WLHIV) and using TDF-based therapy. Finally, we make comparison to the safety profiles of other emerging HIV prevention options.Expert opinion: The current evidence indicates that TDF/FTC PrEP use is not associated with increased risk of adverse pregnancy and early infant growth outcomes. While safety data are generally reassuring, there is need for continued accrual of data on growth and pregnancy outcomes in PrEP research, implementation projects, and controlled pharmacokinetic studies to support current evidence and to understand concentration-efficacy relationship in pregnant women.

A one-stop shop model for improved efficiency of pre-exposure prophylaxis delivery in public clinics in western Kenya: a mixed methods implementation science study.

INTRODUCTION: In public clinics in Kenya, separate, sequential delivery of the component services of pre-exposure prophylaxis (PrEP) (e.g. HIV testing, counselling, and dispensing) creates long wait times that hinder clients' ability and desire to access and continue PrEP. We conducted a mixed methods study in four public clinics in western Kenya to identify strategies for operationalizing a one-stop shop (OSS) model and evaluate whether this model could improve client wait time and care acceptability among clients and providers without negatively impacting uptake or continuation. METHODS: From January 2020 through November 2020, we collected and analysed 47 time-and-motion observations using Mann-Whitney U tests, 29 provider and client interviews, 68 technical assistance reports, and clinic flow maps from intervention clinics. We used controlled interrupted time series (cITS) to compare trends in PrEP initiation and on-time returns from a 12-month pre-intervention period (January-December 2019) to an 8-month post-period (January-November 2020, excluding a 3-month COVID-19 wash-out period) at intervention and control clinics. RESULTS: From the pre- to post-period, median client wait time at intervention clinics dropped significantly from 31 to 6 minutes (p = 0.02), while median provider contact time remained around 23 minutes (p = 0.4). Intervention clinics achieved efficiency gains by moving PrEP delivery to lower volume departments, moving steps closer together (e.g. relocating supplies; cross-training and task-shifting), and differentiating clients based on the subset of services needed. Clients and providers found the OSS model highly acceptable and additionally identified increased privacy, reduced stigma, and higher quality client-provider interactions as benefits of the model. From the pre- to post-period, average monthly initiations at intervention and control clinics increased by 6 and 2.3, respectively, and percent of expected follow-up visits occurring on time decreased by 18% and 26%, respectively; cITS analysis of PrEP initiations (n = 1227) and follow-up visits (n = 2696) revealed no significant difference between intervention and control clinics in terms of trends in PrEP initiation and on-time returns (all p>0.05). CONCLUSIONS: An OSS model significantly improved client wait time and care acceptability without negatively impacting initiations or continuations, thus highlighting opportunities to improve the efficiency of PrEP delivery efficiency and client-centredness.

Kidney injury biomarkers during exposure to tenofovir-based preexposure prophylaxis.

We previously reported a higher incidence of non-albumin proteinuria and a small but significant decline in estimated glomerular filtration rate (eGFR) among HIV-negative adults randomized to emtricitabine/tenofovir disoproxil fumarate preexposure prophylaxis (FTC/TDF PrEP) versus placebo. In a nested case--control study among participants randomized to FTC/TDF PrEP, established kidney injury biomarkers measured at 12 months were not significantly different between participants who subsequently experienced one of these kidney endpoints and randomly selected controls who did not.