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Depot medroxyprogesterone acetate (DMPA) is a widely used contraceptive method. HIV pre-exposure prophylaxis with emtricitabine and tenofovir disoproxil fumarate (F/TDF) is highly effective in reducing HIV acquisition in women. We sought to determine the impact of DMPA on F/TDF pharmacokinetics and pharmacodynamics.Twelve healthy premenopausal cisgender women were enrolled and each completed 4 sequential conditions: (1) baseline, (2) steady-state F/TDF alone, (3) steady-state F/TDF + DMPA, and (4) DMPA alone. Assessments included clinical, pharmacokinetic, viral infectivity (ex vivo challenge of peripheral blood mononuclear cells by X4- and R5-tropic green fluorescent protein pseudoviruses and cervical tissue by HIV BaL ), endocrine, immune cell phenotyping, and renal function.Compared with baseline, F/TDF (± DMPA) significantly decreased both %R5- and X4-infected CD4 T cells and F/TDF + DMPA decreased cervical explant p24 (all P0.05). The %R5- and X4-infected CD4 T cells were higher during DMPA alone than during F/TDF periods and lower than baseline (not statistically significant). Cervical explant p24 fell between baseline and F/TDF values (not statistically significant). There were neither statistically significant differences in F/TDF pharmacokinetics, including total or renal clearance of either antiviral drug, nor changes in glomerular filtration rate with the addition of DMPA. There were few immune cell phenotypic differences across conditions.F/TDF decreased HIV infection in both challenge assays, whereas DMPA alone did not enhance HIV infection in either challenge assay. DMPA did not alter F/TDF pharmacokinetics or renal function.

Data to inform behaviorally congruent delivery of rectal microbicides as lubricants are scant. Dapivirine (DPV) is a nonnucleoside reverse transcriptase inhibitor which has been demonstrated to be well-tolerated and efficacious in multiple clinical trials when used in a vaginal ring formulation. DPV gel administered rectally with an applicator was found to be well-tolerated in a phase 1 clinical trial. MTN-033, a single site, open label, sequence randomized, crossover study, enrolled HIV-negative men to receive 0.05% DPV gel intrarectally using an applicator (2.5 g) and self-administered on an artificial phallus as lubricant (up to 10 g). The study evaluated the pharmacokinetics (in plasma, rectal fluid, and mucosal rectal tissue), safety, acceptability, and pharmacodynamics of DPV gel when applied rectally. Statistical comparisons between methods of application were performed using mixed effects models or Wilcoxon’s signed rank tests. Sixteen participants used DPV gel by applicator and 15/16 participants used gel as lubricant (mean, 1.8 g; SD, 0.8). DPV plasma AUC(0–24h) after use as lubricant was estimated to be 0.41 times the AUC(0–24h) (95% CI 0.24, 0.88) after use with applicator. While DPV was quantifiable in plasma and luminal fluid, it was not quantifiable in tissue for both applicator and as lubricant administration. No related adverse events (AE) were reported, and 15/15 participants felt the gel was easy to use. Evidence of local delivery and systemic absorption of DPV when dosed as an anal lubricant supports the feasibility and potential for development of lubricant-delivered rectal microbicides. There were no safety concerns associated with use of DPV gel and participants reported finding it easy to use. However, lower DPV exposure in plasma and lack of quantifiable DPV in rectal tissue indicate that higher potency, concentration, and longer half-life antiretrovirals with optimized formulations will be needed to achieve protective tissue concentrations.

Introduction Dapivirine (DPV), formulated as vaginal ring, demonstrated HIV risk reduction. MTN-026 explored DPV, formulated as rectal gel, for safety, pharmacokinetics, and acceptability. Methods HIV-uninfected men and women aged 18-45 years were enrolled at United States and Thailand sites and randomized 2:1 to receive DPV 0.05% or placebo gel via rectal applicator. A single dose phase was followed by 7 observed daily doses. Plasma, and fluid and tissue from both rectum and cervix were collected at baseline and after the final dose over 72 hours for pharmacokinetics, ex-vivo HIV-1 biopsy challenge, histology, and flow cytometry. Results 28 participants were randomized; 2 terminated early; 9 were female and 19 male; 12 were white, 11 Asian, 4 black and 1 other race/ethnicity. Mean age was 28.5 and 34.2 years in the DPV and placebo arms, respectively. Thirty adverse events occurred (all Grade 1 or 2, except one unrelated Grade 3) without study arm differences. DPV rectal tissue concentrations (median [interquartile range]) 0.5-1 and 2 hours after a single dose were 256 ng/gm (below limit of quantitation [BLQ], 666) and BLQ (BLQ, 600), respectively, then BLQ (BLQ, BLQ) from 24-72 hours; concentrations following multiple doses were similar. The largest median DPV plasma concentrations were 0.33 ng/mL (0.15, 0.48) after one dose and 0.40 (0.33, 0.49) after seven doses. Conclusions The DPV rectal gel was acceptable and without safety concerns. While DPV plasma concentrations were similar to the vaginal ring, rectal tissue concentrations were well below vaginal ring tissue concentrations, suggesting need for reformulation.

The Combination HIV Antiretroviral Rectal Microbicide-3 (CHARM-03) study was a randomized, open-label, crossover Phase 1 safety and pharmacokinetic (PK) study of oral maraviroc (MVC) and MVC 1% gel. At a single site, healthy HIV-uninfected men and women were enrolled and randomized to an open label crossover sequence of eight consecutive daily exposures to MVC 300 mg dosed orally, MCV 1% gel dosed rectally, and MVC 1% gel dosed vaginally. Male participants received oral and rectal dosing and female participants received oral, rectal, and vaginal dosing. Assessments were undertaken at baseline and following each 8-day period and included collection of plasma, rectal/cervical tissue (CT), and rectal/endocervical/vaginal fluids. Eleven men and nine women were enrolled. Two participants withdrew from the study before receiving study product. There were 25 adverse events, of which 24 were Grade 1 (G1) and one was G2 (unrelated). After eight doses, MVC was quantifiable in all samples following oral, rectal, or vaginal product administration. The highest drug concentrations in plasma, rectal tissue (RT), and CT were associated with oral, rectal, and vaginal drug delivery, respectively. There were significant reductions in tissue drug concentrations when rectal and cervical biopsies were incubated in media before tissue processing for PK (p

The Microbicide Trials Network-017 study was undertaken to characterize the safety, acceptability, pharmacokinetic (PK), and pharmacodynamic profile of the reduced-glycerin (RG) 1% tenofovir (RG-TFV) gel compared to oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF). The study was a Phase 2, three-period, randomized sequence, open-label, expanded safety and acceptability crossover study. In each 8-week study period, HIV-1-uninfected participants were randomized to RG-TFV rectal gel daily or RG-TFV rectal gel before and after receptive anal intercourse (RAI) (or at least twice weekly in the event of no RAI), or daily oral FTC/TDF. A mucosal substudy was conducted at sites in the United States and Thailand. Samples were collected to evaluate PK and ex vivo biopsy challenge with HIV-1. A total of 195 men who have sex with men and transgender women were enrolled in the parent study and 37 in the mucosal substudy. As previously reported, both products were found to be safe and acceptable. Systemic TFV concentrations were significantly higher following oral exposure and daily rectal administration compared to RAI-associated product use (p

Rectal microbicide (RM) researchers have increasingly been interested in using antiretroviral (ARV) drugs in the form of a sexual lubricant as a form of HIV prevention. We triangulated quantitative and qualitative assessments to evaluate participants’ acceptability of 0.05% dapivirine gel administered via two separate modalities (a rectal applicator and an artificial phallus for use as a coital simulation device) in two different randomization groups: Sequence A (Applicator/Coital Simulation Device) or Sequence B (Coital Simulation Device/Applicator) as part of a Phase I trial (N=14) among a group of men who have sex with men (MSM) randomized using a 1:1 ratio from the Microbicide Trials Network (MTN)-033 trial. Overall, participants reported favorable acceptability of the gel (n=11; 78.6%) the same or more at the end of the study compared to when they started the study. Additionally, when discussing their preferred administration modality, they noted that both methods have positive qualities but also potential areas of improvement. Our findings underscore the need to create multiple delivery methods for a future microbicide gel (i.e., with and without the need for an applicator) and highlight the importance of offering MSM choices in how biomedical HIV prevention strategies are delivered.

Multipurpose prevention technologies (MPT) have been increasingly researched for their dual-purpose preventative properties against HIV and other STIs. The acceptability of PC-1005, a topical MPT candidate, was explored among men and women participating in the MTN-037 Phase I trial at two U.S. sites (Pittsburgh, PA, and Birmingham, AL). We triangulated quantitative and qualitative assessments of the acceptability of three volumes (4 mL, 16 mL, 32 mL) of PC-1005 administered rectally (N = 12; 6 males, 6 females). Participants rated overall gel acceptability on a scale of 1–10, with a median of 7.17 (SD = 2.04) and had positive feelings about all three dose volumes, citing them to be very comfortable or comfortable (dose 1 = 91.7%; dose 2 = 91.7%; dose 3 = 83.3%). High acceptability of and comfort with all three dose volumes shows promise for PC-1005 as an MPT to prevent HIV and STIs, warranting future clinical development.

BACKGROUND: Cabotegravir delivered as a long-acting intramuscular injection has shown superior efficacy to oral tenofovir-emtricitabine as pre-exposure prophylaxis (PrEP) for HIV. Cabotegravir pharmacokinetics (PK), like those of other long-acting depot preparations, exhibit variability between individuals and between injection occasions. AIM: To describe the population pharmacokinetics of long-acting cabotegravir (CAB-LA). METHODS: Using available PK measurements from 133 participants in the HIV Prevention Trials Network (HPTN) 077 trial, we analyzed CAB-LA PK data using nonlinear mixed-effects modeling to develop a population PK model. RESULTS: A two-compartment model with first order absorption best described the CAB-LA PK. The analysis identified between-occasional variability (BOV, i.e., differences in PK within one individual from one injection to the next) as a significant covariate affecting the absorption rate, with an estimated contribution of BOV to PK variability on the absorption rate (Ka) of 38.5%. Sex and body weight were identified as significant covariates influencing the absorption rate and apparent clearance of CAB-LA after intramuscular injection at various doses and frequencies. Male participants had 67% higher Ka than female participants. Serially adding to the model body weight on clearance, Sex on Ka, and BOV on Ka led to a decrease in the objective function value (OFV) of 24.4, 36, and 321.4, respectively. CONCLUSION: The public availability of this model will facilitate and enable a wide variety of future clinically relevant simulations to inform the optimal use of CAB-LA.

In spite of the rollout of oral pre-exposure prophylaxis (PrEP), the rate of new HIV infections remains a major health crisis. In the United States, new infections occur predominantly in men having sex with men (MSM) in rural settings where access to PrEP can be limited. As an alternative congruent with MSM sexual behavior, we have optimized and tested tenofovir (TFV) and analog-based iso-osmolar and hypo-osmolar (HOsm) rectal douches for efficacy against rectal simian/human immunodeficiency virus (SHIV) infection of macaques. Single TFV HOsm high-dose douches achieved peak plasma TFV levels similar to daily oral PrEP, while other formulations yielded lower concentrations. Rectal tissue TFV-diphosphate (TFV-DP) concentrations at the portal of virus entry, however, were markedly higher after HOsm douching than daily oral PrEP. Repeated douches led to significantly higher plasma TFV and higher TFV-DP concentrations in rectal tissue at 24 hours compared with single douches, without detectable mucosal or systemic toxicity. Using stringent repeated intrarectal SHIV exposures, single HOsm high-dose douches delivered greater protection from virus acquisition for more than 24 hours compared with oral PrEP. Our results demonstrate a rapid delivery of protective TFV doses to the rectal portal of virus entry as a potential low-cost and safe PrEP alternative.

A long-acting injectable formulation of rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor, is currently under investigation for use in human immunodeficiency virus (HIV) maintenance therapy. We previously characterized RPV metabolism after oral dosing and identified seven metabolites: four metabolites resulting from mono- or dioxygenation of the 2,6-dimethylphenyl ring itself or either of the two methyl groups located on that ring, one N-linked RPV glucuronide conjugate, and two O-linked RPV glucuronides produced via glucuronidation of mono- and dihydroxymethyl metabolites. However, as is true for most drugs, the metabolism of RPV after injection has yet to be reported. The phase II clinical trial HPTN 076 enrolled 136 HIV-uninfected women and investigated the safety and acceptability of long-acting injectable RPV for use in HIV pre-exposure prophylaxis. Through the analysis of plasma samples from 80 of these participants in the active product arm of the study, we were able to detect 2 metabolites after intramuscular injection of long-acting RPV, 2-hydroxymethyl-RPV, and RPV N-glucuronide. Of the total of 80 individuals, 72 participants exhibited detectable levels of 2-hydroxymethyl-RPV in plasma samples whereas RPV N-glucuronide was detectable in plasma samples of 78 participants. In addition, RPV N-glucuronide was detectable in rectal fluid, cervicovaginal fluid, and vaginal tissue. To investigate potential genetic variation in genes encoding enzymes relevant to RPV metabolism, we isolated genomic DNA and performed next-generation sequencing of CYP3A4, CYP3A5, UGT1A1 and UGT1A4. From these analyses, four missense variants were detected for CYP3A4 whereas one missense variant and one frameshift variant were detected for CYP3A5. A total of eight missense variants of UGT1A4 were detected, whereas two variants were detected for UGT1A1; however, these variants did not appear to account for the observed interindividual variability in metabolite levels. These findings provide insight into the metabolism of long-acting RPV and contribute to an overall understanding of metabolism after oral dosing versus injection. ClinicalTrials.gov Identifier: NCT02165202

Defining tissue and plasma‐specific prophylactic drug concentrations is central to pre‐exposure prophylaxis product development for sexual transmission of HIV‐1. Pharmacokinetic (PK) data from study RMP‐02/MTN‐006 comparing single dose oral tenofovir disoproxil fumarate with single and multiple dose rectal tenofovir (TFV) gel administration in HIV‐1 seronegative adults was used to construct a multicompartment plasma‐rectal tissue population PK model for TFV and tenofovir‐diphosphate (TFVdp) in plasma and rectal tissue. PK data were collected in five matrices: TFV (plasma, rectal tissue homogenate), TFVdp (peripheral blood mononuclear cells, rectal mononuclear cells (MMCs), rectal tissue homogenate). A viral growth compartment and a delayed effect compartment for p24 antigen expression measured from an ex vivo explant assay described HIV‐1 infection and replication. Using a linear PK/pharmacodynamic model, MMC TFVdp levels over 9,000 fmol/million cells in the explant assay provided apparent viral replication suppression down to 1%. Parameters were estimated using NONMEM version 7.4.

A study of demographic and behavioral factors found that older age, high intention, and shorter duration of preexposure prophylaxis use were associated with higher preexposure prophylaxis adherence among Beninese female sex workers., Background HIV preexposure prophylaxis (PrEP) efficacy is closely linked to adherence, and factors associated with PrEP adherence are not well understood and may differ across populations. As PrEP demonstration projects and implementation are ongoing, it is essential to understand factors associated with adherence to oral PrEP to design effective adherence interventions and maximize the public health impact of PrEP. We thus aimed to assess demographic and behavioral factors associated with optimal PrEP adherence (100%) among female sex workers (FSWs) participating in a demonstration project in Cotonou, Benin. Methods Female sex workers were provided with daily Truvada and followed quarterly for 1 to 2 years. Sociodemographics, partners, and behaviors were collected through face-to-face questionnaires. Another questionnaire based on sexual the theory of planned behavior and the theory of interpersonal behavior was also administered. Generalized estimating equations were used to identify factors associated with optimal daily adherence. Results At baseline, 255 FSWs were followed up. One-year increase in age of FSWs was associated with a 3% increase in optimal adherence (prevalence ratio, 1.03; 95% confidence interval, 1.01–1.05; P for trend = 0.0003), and optimal adherence decreased by 31% for every 6 months of follow-up (prevalence ratio, 0.69; 95% confidence interval, 0.59–0.79; P for trend < 0.0001). For the participants who have completed the behavioral questionnaires, high intention to adhere to the treatment was also a predictor of optimal adherence. Conclusions Efforts should be geared toward FSWs intending to use PrEP to help them reach adequate adherence levels for effective HIV protection.

Background Daily dosing of tenofovir disoproxil fumarate, with or without emtricitabine, has high efficacy in preventing human immunodeficiency virus (HIV) infection when individuals are adherent. The target protective plasma concentration of tenofovir (TFV), however, is not fully understood. The aim of this study is to estimate the protective TFV plasma concentration. Methods Participant data from TFV-based daily oral and topical active arms of phase 3 trials (iPrEx, VOICE, and Partners PrEP) were pooled (n = 2950). Individual specific risk scores (low and high risk) of acquiring HIV, based on an earlier placebo analysis, were created. Longitudinal TFV pharmacokinetics (PK), HIV outcome, individual risk scores and the effect of sex at birth data were integrated and analyzed using non-linear mixed effects models. Results Around 50% of the individuals were estimated to be adherent, which differed from self-reported adherence (∼90%) and large variation between longitudinal adherence patterns were identified. Following oral administration, the estimated protective TFV trough concentration was substantially higher in high-risk females (45.8 ng/mL) compared with high-risk males (16.1 ng/mL) and to low-risk individuals (∼7.5 ng/mL). Dosing simulations indicated that high-risk women require full adherence to maintain protective levels. Conclusions Using the largest PK-HIV outcome database to date, we developed a population adherence-PK-risk-outcome model. Our results indicate that high-risk females need higher levels of plasma TFV to achieve HIV protection compared with males. HIV protection exceeds 90% in all populations if daily adherence is achieved.

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

Transgender women (TGW) have been underrepresented in trials and use gender-affirming hormonal therapies (GAHT) that may alter renal function by significantly increasing creatinine clearance. Population pharmacokinetic (popPK) models and simulations would aid in understanding potential differences in emtricitabine/tenofovir disproxil fumarate (F/TDF) parent-metabolite concentrations in TGW on GAHT when compared to cisgender men (CGM) not exposed to GAHT.Pharmacokinetic (PK) data from a Phase 1, open-label clinical trial with directly observed therapy of daily F/TDF consisting of 8 TGW and 8 CGM was utilized for model building. PopPK analysis was performed using nonlinear mixed effects modelling (NONMEM 7.5.0). Covariates of body weight, creatinine clearance, and gender were evaluated. Final models were subjected to Monte Carlo simulations to compare drug exposure following once daily and on-demand (IPERGAY 2 + 1 + 1) dosing of F/TDF.Tenofovir (TFV) and emtricitabine PK were best described by a 2-compartment model, first-order absorption/elimination with absorption lag time. Parent models were linked to their metabolites by first order formation and elimination. Creatinine clearance was a significant covariate influencing clearance in both models. Simulations demonstrated that at least 2, weekly 2 + 1 + 1 cycles of on-demand dosing in TGW on GAHT is necessary for TFV-diphosphate to reach similar exposure after the initial week of on-demand dosing in CGM not on GAHT.PopPK models of TFV, emtricitabine and intracellular metabolites in TGW were established. Dose simulations revealed that TGW should be treated for at least 2 weeks to have comparable exposures to CGM.

Background Depot medroxyprogesterone acetate (DMPA) is a commonly used contraceptive in areas where use of tenofovir disoproxil fumarate and emtricitabine for HIV pre-exposure prophylaxis (PrEP) is increasing. Objectives We aimed to investigate the impact of DMPA on PrEP drug pharmacokinetics and pharmacodynamics in women using PrEP before and after DMPA administration. Methods In this pilot study, twelve HIV-negative women ages 18-45 underwent biological sample collection at three time points: before study drug, after 2 weeks of daily PrEP use alone, and after 2 weeks of daily PrEP and concomitant DMPA use. We measured drug and drug metabolites in plasma, peripheral blood mononuclear cells, cervicovaginal fluid, cervical tissue, and rectal fluid after each 2-week course of PrEP. We measured HIV replication ex vivo in genital tissue biopsies and innate anti-HIV activity in cervicovaginal fluid before PrEP and after both courses. We compared drug concentrations after PrEP alone to after PrEP and DMPA in the same participant using Wilcoxon signed-rank tests. We used mixed effects linear regression models to compare pharmacodynamic measures for each participant at pre-drug baseline, after PrEP alone, and after PrEP and DMPA. Results We found no significant differences in PrEP drug and drug metabolite concentrations in any compartment during concomitant DMPA use compared to use of PrEP alone, except for a reduction in emtricitabine concentration in cervical tissue. We found no difference in HIV replication in cervical tissue or anti-HIV activity in cervicovaginal fluid during concomitant DMPA and PrEP use compared to during PrEP use alone. Conclusions Concomitant use of DMPA does not clinically alter pharmacokinetics or pharmacodynamics of PrEP in women. These data support the safety of DMPA use in women using PrEP.

Summary Background Long-acting injectable cabotegravir is a novel integrase inhibitor currently in advanced clinical development for HIV prevention and treatment. We aimed to assess the terminal phase pharmacokinetics and safety of long-acting injectable cabotegravir in participants included in the HPTN 077 trial. Methods HPTN 077 was a multicentre, double-blind, randomised, placebo-controlled phase 2a trial done at eight sites in Brazil, Malawi, South Africa, and the USA. Participants (aged 18–65 years), who were HIV-uninfected and at low-risk for HIV, were randomly assigned (3:1) to long-acting injectable cabotegravir (800 mg given three times at 12 week intervals or 600 mg given five times, administered at one 4 week interval, and every 8 weeks thereafter) or placebo. Participants were followed up to 76 weeks after final injection. In a prespecified analysis of secondary and exploratory outcomes, we assessed the safety, measured by the proportion of participants with grade 2 or worse adverse events, and pharmacokinetics, measured by apparent terminal phase half-life (t1/2app) and estimated time to lower limit of quantification (LLOQ) of long-acting injectable cabotegravir during the injection phase (defined as the time between first injection and 12 weeks or 8 weeks after the last injection in cohort 1 or cohort 2 respectively) and tail phase (defined as the time between final injection and 52–76 weeks post-final injection). Safety was analysed in all participants who received at least one injection. Pharmacokinetic analyses included all participants who had received at least one injection and had at least three cabotegravir measurements higher than the LLOQ after the final injection. Pharmacokinetic outcomes were estimated using non-compartmental methods. The trial is completed, and was registered with ClinicalTrials.gov , NCT02178800 . Findings Between Feb 9, 2015, and May 27, 2016, 177 participants (134 participants in the cabotegravir group [74 participants in cohort 1; 60 participants in cohort 2] and 43 participants in the placebo group [25 participants in cohort 1; 18 participants in cohort 2) were enrolled and received at least one injection and thus were included in the safety analysis. The incidence of grade 2 or worse adverse events was significantly lower during the tail phase than the injection phase (p Interpretation The clinical significance of the long pharmacokinetic tail of cabotegravir observed in female participants compared with male participants, and those with higher BMI compared with a lower BMI, need to be addressed in future trials. Funding National Institute of Allergy and Infectious Diseases.

OBJECTIVES. To describe receptive anal intercourse (RAI) behaviors and correlates in a cohort of sub-Saharan African women, evaluate the association of RAI with HIV-1 risk, and evaluate whether the HIV-1 prevention efficacy of a dapivirine-containing vaginal ring differs among women who reported RAI. DESIGN. Secondary analysis of the MTN-020/ASPIRE trial, a randomized, double-blind, placebo-controlled trial evaluating a dapivirine-containing vaginal ring for HIV-1 prevention. METHODS. At enrollment and month three, women reported RAI in the prior three months in audio computer-assisted self-interviews. We evaluated associations between RAI and participant characteristics with chi-square and t-tests adjusted for study site. Cox proportional hazards models stratified by study site tested the association of RAI with HIV-1 acquisition and effect modification by RAI. RESULTS. Nineteen percent of women reported any RAI at enrollment and/or month 3, with a median of 2 (IQR: 1, 4) RAI acts in the prior three months, accounting for 1.5% of total sex acts. RAI prevalence was higher among women with lower educational attainment and those reporting transactional sex. In adjusted models, RAI was not associated with HIV-1 acquisition (aHR: 0.93, 95% CI: 0.57, 1.54). The ring reduced HIV-1 risk by 27% (95% CI: -5, 49) among women reporting no RAI and by 18% (95% CI: -57, 57) among women reporting any RAI (interaction p-value=0.77). CONCLUSIONS. RAI was modestly infrequent and was not associated with reduced HIV-1 protection from the ring, suggesting that, in populations with rates of RAI similar to this cohort, RAI may not appreciably reduce the population-level impact of the dapivirine vaginal ring.

Global efforts aimed at preventing human immunodeficiency virus type one (HIV-1) infection in vulnerable populations appear to be stalling, limiting our ability to control the epidemic. Long-acting, controlled drug administration from subdermal implants holds significant potential by reducing the compliance burden associated with frequent dosing. We, and others, are exploring the development of complementary subdermal implant technologies delivering the potent prodrug, tenofovir alafenamide (TAF). The current report addresses knowledge gaps in the preclinical pharmacology of long-acting, subdermal TAF delivery using several mouse models. Systemic drug disposition during TAF implant dosing was explained by a multi-compartment pharmacokinetic (PK) model. Imaging mass spectrometry was employed to characterize the spatial distribution of TAF and its principal five metabolites in local tissues surrounding the implant. Humanized mouse studies determined the effective TAF dose for preventing vaginal and rectal HIV-1 acquisition. Our results represent an important step in the development of a safe and effective TAF implant for HIV-1 prevention.

This study describes the acceptability of a rectal microbicide gel formulation using dapivirine (DPV) among men and women from two countries (United States and Thailand) participating in the Microbicide Trials Network-026 trial. We evaluated participants' acceptability of a rectal DPV/placebo gel as part of a Phase I trial (N = 26; 18 male, 8 female). Participants reported favorable acceptability of the study gel, with most participants reporting that they liked the gel the same (n = 14; 53.8%) or more (n = 11; 42.4%) than when they started the trial. Over half of participants noted that they would prefer the gel over condoms (n = 13; 50%) or that they liked condoms and the gel equally (n = 8; 30.8%). Side effects across products included leakage (n = 8; 30.8%), diarrhea (n = 4; 15.4%), or soiling (n = 1; 3.8%). The high acceptability of a rectal gel underscores its promise as a short-acting biomedical prevention, warranting future research for HIV prevention.Trial Registration: NCT03239483.Este estudio describe la aceptabilidad de un microbicida rectal (RM) con dapivirina (DPV) formulado como un gel por hombres y mujeres de dos países (Estados Unidos y Tailandia) que participaron como parte del Microbicide Trials Network (MTN)-026. Evaluamos la aceptabilidad de un gel rectal de DPV y un placebo como parte de un estudio de Fase I (N = 26; 18 hombres, 8 mujeres). Los participants informaron una aceptabilidad favorable sobre el gel del estudio; la mayoría de los participantes informaron que les gustó el gel igual (n = 14; 53.8%) o más (n = 11; 42.4%) que cuando comenzaron el estudio. Más de la mitad de los participantes señalaron que preferirían el gel sobre los condones (n = 13; 50%) o que les gustaban los condones y el gel por igual (n = 8; 30,8%). Los efectos de los productos incluyeron fugas (n = 8; 30,8%), diarrea (n = 4; 15,4%) o ensuciamiento (n = 1; 3,8%). La alta aceptabilidad de un gel rectal enfatiza su promesa para la prevención biomédica de acción corta y justifica futuras investigaciones para la prevención del VIH.

BackgroundSafe and effective long-acting injectable agents for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection are needed to increase the options for preventing HIV infection.MethodsWe conducted a randomized, double-blind, double-dummy, noninferiority trial to compare long-acting injectable cabotegravir (CAB-LA, an integrase strand-transfer inhibitor [INSTI]) at a dose of 600 mg, given intramuscularly every 8 weeks, with daily oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) for the prevention of HIV infection in at-risk cisgender men who have sex with men (MSM) and in at-risk transgender women who have sex with men. Participants were randomly assigned (1:1) to receive one of the two regimens and were followed for 153 weeks. HIV testing and safety evaluations were performed. The primary end point was incident HIV infection.ResultsThe intention-to-treat population included 4566 participants who underwent randomization; 570 (12.5%) identified as transgender women, and the median age was 26 years (interquartile range, 22 to 32). The trial was stopped early for efficacy on review of the results of the first preplanned interim end-point analysis. Among 1698 participants from the United States, 845 (49.8%) identified as Black. Incident HIV infection occurred in 52 participants: 13 in the cabotegravir group (incidence, 0.41 per 100 person-years) and 39 in the TDF-FTC group (incidence, 1.22 per 100 person-years) (hazard ratio, 0.34; 95% confidence interval, 0.18 to 0.62). The effect was consistent across prespecified subgroups. Injection-site reactions were reported in 81.4% of the participants in the cabotegravir group and in 31.3% of those in the TDF-FTC group. In the participants in whom HIV infection was diagnosed after exposure to CAB-LA, INSTI resistance and delays in the detection of HIV infection were noted. No safety concerns were identified.ConclusionsCAB-LA was superior to daily oral TDF-FTC in preventing HIV infection among MSM and transgender women. Strategies are needed to prevent INSTI resistance in cases of CAB-LA PrEP failure. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 083 ClinicalTrials.gov number, NCT02720094.).

Two phase 3 clinical trials showed that use of a monthly vaginal ring containing 25 mg dapivirine was well tolerated and reduced HIV-1 incidence in women by approximately 30% compared with placebo. We aimed to evaluate use and safety of the dapivirine vaginal ring (DVR) in open-label settings with high background rates of HIV-1 infection, an important step for future implementation.We did a phase 3B open-label extension trial of the DVR (MTN-025/HIV Open-label Prevention Extension [HOPE]). Women who were HIV-1-negative and had participated in the MTN-020/ASPIRE phase 3 trial were offered 12 months of access to the DVR at 14 clinical research centres in Malawi, South Africa, Uganda, and Zimbabwe. At each visit (monthly for 3 months, then once every 3 months), women chose whether or not to accept the offer of the ring. Used, returned rings were tested for residual amounts of dapivirine as a surrogate marker for adherence. HIV-1 serological testing was done at each visit. Dapivirine amounts in returned rings and HIV-1 incidence were compared with data from the ASPIRE trial, and safety was assessed. This study is registered with ClinicalTrials.gov, NCT02858037.Between July 16, 2016, and Oct 10, 2018, of 1756 women assessed for eligibility, 1456 were enrolled and participated in the study. Median age was 31 years (IQR 27-37). At baseline, 1342 (92·2%) women chose to take the DVR; ring acceptance was more than 79% at each visit up until 12 months and 936 (73·2%) of 1279 chose to take the ring at all visits. 12 530 (89·3%) of 14 034 returned rings had residual dapivirine amounts consistent with some use during the previous month (0·9 mg released) and the mean dapivirine amount released was greater than in the ASPIRE trial (by 0·21 mg; p0·0001). HIV-1 incidence was 2·7 per 100 person-years (95% CI 1·9-3·8, 35 infections), compared with an expected incidence of 4·4 per 100 person-years (3·2-5·8) among a population matched on age, site, and presence of a sexually transmitted infection from the placebo group of ASPIRE. No serious adverse events or grade 3 or higher adverse events observed were assessed as related to the DVR.High uptake and persistent use in this open-label extension study support the DVR as an HIV-1 prevention option for women. With an increasing number of HIV-1 prophylaxis choices on the horizon, these results suggest that the DVR will be an acceptable and practical option for women in Africa.The Microbicide Trials Network and the National Institute of Allergy and Infectious Diseases, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health, all components of the US National Institutes of Health.

A lubricating microbicide gel designed for rectal and vaginal use would provide a behaviorally congruent strategy to enhance pre-exposure prophylaxis adherence and reduce HIV infection risk. In this study, we report the first-in-human evaluation of such a gel containing 1% IQP-0528, an investigational antiretroviral. Seven HIV-1-negative participants received one 10 mL rectal dose of radiolabeled 1% IQP-0528 gel. We assessed safety; IQP-0528 pharmacokinetics in plasma, and rectal and vaginal tissue; ex vivo local pharmacodynamics (PD); and colorectal distribution. The 1% gel was determined to be safe with one mild event attributed to study product and no effects on rectal tissue histology. All concentrations measured in plasma and vaginal tissue were below the limit of quantitation. Median IQP-0528 concentrations in rectal tissue exceeded the in vitro EC(95) against HIV-1 (0.07 ng/mg) by 3–5 h of dosing and remained above this concentration for at least 24 h, despite a 3-log reduction in concentration over this duration of time. Rectal tissue PD—assessed by ex vivo HIV challenge—demonstrated significant p24 antigen reduction 3–5 h postdose compared with baseline (p = .05), but not 24–26 h postdose (p = .75). Single-photon emission computed tomography/computed tomography imaging revealed that product distribution was localized to the rectosigmoid. The IQP-0528 gel possesses desirable features for a topical microbicide including: local safety with no systemic absorption, delivery of locally high IQP-0528 concentrations, and significant reductions in ex vivo HIV infectivity. However, the gel is limited by its rapid clearance and inability to penetrate vaginal tissues following rectal dosing. Clinical Trial Registration number: NCT03082690.

Introduction Vaginal rings are a promising approach to provide a woman‐centred, long‐acting HIV prevention strategy. Prior trials of a 25 mg dapivirine (DPV) ring have shown a favourable safety profile and approximately 30% risk reduction of HIV‐1 infection. Extended duration rings replaced every three months may encourage user adherence, improve health service efficiency and reduce cost overall. We evaluated safety, pharmacokinetics, adherence and acceptability of two three‐month rings with different DPV dosages, compared with the monthly DPV ring. Methods From December 2017 to October 2018, MTN‐036/IPM‐047 enrolled 49 HIV‐negative participant in Birmingham, Alabama and San Francisco, California into a phase 1, randomized trial comparing two extended duration (three‐month) rings (100 or 200 mg DPV) to a monthly 25 mg DPV ring, each used over 13 weeks, with follow‐up completed in January 2019. Safety was assessed by recording adverse events (AEs). DPV concentrations were quantified in plasma, cervicovaginal fluid (CVF) and cervical tissue, at nominal timepoints. Geometric mean ratios (GMRs) relative to the comparator ring were estimated from a regression model. Results There were no differences in the proportion of participants with grade ≥2 genitourinary AEs or grade ≥3 AEs in the extended duration versus monthly ring arms (p = 1.0). Plasma and CVF DPV concentrations were higher in the extended duration rings compared to the monthly ring. Plasma GMRs were 1.31 to 1.85 and 1.41 to 1.86 and CVF GMRs were 1.45 to 2.87 and 1.74 to 2.60 for the 100 and 200 mg ring respectively. Cervical tissue concentrations were consistently higher in the 200 mg ring (GMRs 2.36 to 3.97). The majority of participants (82%) were fully adherent (ring inserted at all times, with no product discontinuations/outages) with no differences between the monthly versus three‐month rings. Most participants found the ring acceptable (median = 8 on 10‐point Likert scale), with a greater proportion of participants reporting high acceptability (9 or 10) in the 25 mg arm (73%) compared with the 100 mg (25%) and 200 mg (44%) arms (p = 0.01 and p = 0.15 respectively). Conclusions The extended duration DPV rings were well‐tolerated and achieved higher DPV concentrations compared with the monthly DPV ring. These findings support further evaluation of three‐month DPV rings for HIV prevention.

Aims Cabotegravir is an integrase strand transfer inhibitor in clinical development as long-acting (LA) injectable HIV preexposure prophylaxis. Methods This phase I study assessed pharmacokinetics of cabotegravir in plasma and anatomical sites associated with sexual HIV-1 transmission after repeated oral and single intramuscular (IM) LA dosing in healthy adults. Following a 28-day oral lead-in period of cabotegravir 30 mg and a washout period of 14-42 days, participants were administered a single ultrasound-guided gluteal IM cabotegravir LA 600-mg injection. The study objective was to characterize cabotegravir concentrations in plasma, cervical, vaginal and rectal tissues, and cervicovaginal and rectal fluids and up to Week 12 after IM injection. Results Nineteen participants enrolled and 16 completed the study through Week 52. Cabotegravir was detected in plasma and all tissues and fluids. Median plasma cabotegravir concentrations exceeded the in vitro protein-adjusted 90% maximal inhibitory concentration through Week 12. Median tissue- and fluid-to-plasma cabotegravir concentration ratios across all visits were 0.32 for rectal fluid and 0.08-0.16 for other tissues and fluids. Adjusted R2 coefficients between cabotegravir concentrations in plasma and cervical, vaginal and rectal tissues were 0.78, 0.79 and 0.90, respectively. Injection-site reactions were common (88% of participants) and were mostly grade 1 in intensity (82%). Two participants reported 11 non-drug-related serious adverse events. Conclusion Concentrations of cabotegravir in tissues and fluids were proportional to plasma over time, with strong correlations between tissue and plasma concentrations. Cabotegravir LA tissue-to-plasma ratios may be important for understanding its use as preexposure prophylaxis.

We evaluated the relationship between 2 types of social relationships, ie, (1) external support for use of HIV pre-exposure prophylaxis (PrEP) and related study supplies and (2) participants' disclosure of PrEP use and condom use and HIV PrEP adherence among daily-dosing regimen participants in HIV Prevention Trials Network (HPTN) 067, an open-label trial of oral tenofovir (TFV) disoproxil fumarate (TDF) 300 mg/emtricitabine (FTC) 200 mg.Using HPTN 067 survey data, we developed scales examining (1) Low Perceived External Support for PrEP: low perceived support by others for PrEP use or perceived negative reactions to the pill case (scoring ranges from 0 to 2) and (2) Participant-Staff Disclosure Challenges Scale, which identifies challenges to sharing nonuse of PrEP or condoms to study staff (scoring ranges from 0 to 4); these scales are the primary independent variables. Adherence, the dependent variable, was determined using log-transformed plasma TFV concentrations. generalized estimating equation (GEE) linear regression was used to assess the association between both scales and adherence.Participants (n = 161) included HIV-uninfected women in South Africa, and men who have sex with men and transgender women, in Thailand and the United States. In multivariable analyses, higher scores in the Participant-Staff Disclosure Challenges Scale were significantly associated with lower PrEP adherence [exp(β) = 0.62, 95% CI: (0.46 to 0.84); P = 0.002] as were increased days since the last PrEP dose [exp(β) = 0.73, 95% CI: (0.65 to 0.83); P ≤ 0.001].Given the association with adherence, study staff-participant interactions and participants' disclosure of PrEP challenges may be worthwhile intervention targets for improving PrEP adherence in confirmatory studies.

Author(s): Velloza, Jennifer; Bacchetti, Peter; Hendrix, Craig W; Murnane, Pamela; Hughes, James P; Li, Maoji; Curlin, Marcel E; Holtz, Timothy H; Mannheimer, Sharon; Marzinke, Mark A; Amico, K Rivet; Liu, Albert; Piwowar-Manning, Estelle; Eshleman, Susan H; Dye, Bonnie J; Gandhi, Monica; Grant, Robert M; HPTN 067/ADAPT Study Team | Abstract: BackgroundThe effectiveness of oral emtricitabine (FTC)/tenofovir (TFV) disoproxil fumarate-based HIV pre-exposure prophylaxis (PrEP) depends on adherence. Pharmacologic measures help interpret patterns and predictors of PrEP adherence.SettingWe analyzed data from the subsample of men who have sex with men enrolled in HPTN 067/ADAPT in Bangkok, Thailand, and Harlem, NY, U.S.MethodsAfter a 5-week directly observed therapy period, participants were randomized to daily, time-driven, or event-driven PrEP. Follow-up occurred at weeks 4, 12, and 24 after randomization. Plasma and hair FTC/TFV levels indicated short- and long-term PrEP use, respectively. Electronic pill bottle data (Wisepill) were collected weekly. Pearson correlation coefficients between PrEP use measures were calculated; linear mixed models assessed predictors of plasma and hair drug concentrations.ResultsAmong 350 participants (median age: 31 years, interquartile range: 25-38), 49.7% were from Harlem, half had less than college education, and 21% reported heavy alcohol use. In multivariable models, being enrolled in Harlem, being in non-daily arms, and having less than college education were associated with lower hair FTC/TFV concentrations; heavy alcohol use was associated with higher concentrations. Similar results were found for plasma concentrations by site and arm, but older age and greater number of sex partners were associated with higher concentrations. Hair and plasma FTC/TFV concentrations were moderately correlated with Wisepill data (r ≥ 0.29) across visits.ConclusionsIn HPTN067, plasma, hair, and Wisepill data correlated with one another and served as complementary adherence measures. Site, arm, education, age, alcohol, and sexual behavior influenced patterns of adherence.

Background Genital infection with herpes simplex virus type 2 (HSV-2) is common and increases risk of human immunodeficiency virus (HIV) transmission and acquisition. Pericoital use of tenofovir (TFV) gel provided protection from HSV-2 acquisition in the CAPRISA 004 study. Methods We measured estimate of effect of vaginal TFV 1% gel in preventing HSV-2 acquisition among women in VOICE, randomized, double-blinded, placebo-controlled trial assessing daily use of oral and vaginal TFV for HIV-1 preexposure prophylaxis. The TFV level in plasma at the first quarterly visit was used as a measure of gel use. Results Of 566 participants at risk for HSV-2 acquisition, 532 (94%) had first-quarter plasma TFV and end-of-study HSV-2 serologic data available. Over a follow-up period of 501 person-years, 92 incident cases of HSV-2 acquisition occurred: 77 were in women with no TFV detected in plasma, and 15 occurred in women with TFV detected in plasma (incidence, 20.6 cases/100 person-years [95% confidence interval [CI], 16.2-25.7] vs 11.9 cases/100 person-years [95% CI, 6.6-19.6], respectively). TFV detection in plasma was associated with a trend toward a reduced risk of HSV-2 seroconversion, with an unadjusted hazard ratio (HR) of 0.59 (95% CI, .34-1.02; P = .060) and a HR adjusted for site, age, having ≥2 male sex partners in the past 3 months, use of hormonal contraception, having anal sex in the past 3 months, and HIV status of 0.60 (95% CI, .33-1.08; P = .086). Conclusions Detection of TFV in plasma among TFV gel users was associated with a trend toward a reduced risk of HSV-2 acquisition, after controlling for sexual behavior and HIV-1 acquisition.

OBJECTIVE:HIV Prevention Trials Network 069/AIDS Clinical Trials Group A5305 was a study of 48-week oral pre-exposure prophylaxis (PrEP) regimens in MSM and transgender women. A rectal substudy was included to evaluate drug concentrations in rectal compartment vs. blood, gut-associated lymphoid tissue (GALT) responses to four antiretroviral PrEP regimens [maraviroc (MVC), MVC + emtricitabine (FTC), MVC + tenofovir (TFV) disoproxil fumarate, and TFV disoproxil fumarate + FTC], and to determine whether ARV exposure was associated with ex-vivo suppression of HIV infection in colorectal explants. METHODS:C-C chemokine receptor type 5 (CCR5) genotype was characterized using PCR. At baseline and at Weeks 24, 48, and 49, GALT phenotype was characterized by flow cytometry, rectal biopsies were challenged with HIV-1BaL, and tissue and plasma pharmacokinetics were measured via mass spectrometry. RESULTS:Exposure to MVC was not associated with increased expression of CD4+/CCR5+ HIV target T cells. Significant ex-vivo viral suppression compared with baseline was seen at Weeks 24 and 48, ranging from 1.4 to 1.8 log10 for all study regimens except the MVC-alone arm which did not show statistically significant viral suppression at Week 48. Tissue concentrations of TFV, TFV-diphosphate, and FTC were correlated with viral suppression. CONCLUSION:MVC-containing HIV PrEP regimens did not increase GALT CD4+ T-cell activation or the CD4+/CCR5+ phenotype. No virologic suppression was seen with MVC-alone at Week 48 compared with combination regimens, suggesting MVC monotherapy might be less effective than combination antiretroviral PrEP regimens.

Background Tenofovir disoproxil fumarate-containing pre-exposure prophylaxis (PrEP) has been associated with decreases in bone mineral density (BMD), but the bone effects of other non-tenofovir disoproxil fumarate candidate PrEP regimens are not well described. Methods The HPTN 069/ACTG A5305 study randomized 406 US cisgender men and transgender women, and 188 cisgender women at risk for HIV infection to one of four double-blinded regimens: (i) maraviroc; (ii) maraviroc + emtricitabine; (iii) maraviroc + tenofovir disoproxil fumarate; or (iv) tenofovir disoproxil fumarate + emtricitabine. BMD was measured in a subset of participants at the lumbar spine (LS) and hip by dual-energy X-ray absorptiometry (DXA) at baseline and 48 weeks. Percentage change in LS and hip BMD was compared between the tenofovir disoproxil fumarate- and non-tenofovir disoproxil fumarate-containing arms by Wilcoxon rank-sum tests and multiple linear regression adjusting for sex, race and baseline BMI. Results At baseline (n = 307), the median age was 33 years, 56% male and 43% black. At the hip, the median percentage change in BMD at 48 weeks was –1.05% in the tenofovir disoproxil fumarate arms and 0.0% in the non-tenofovir disoproxil fumarate arms (between group P = 0.001). No interaction by sex was observed. The median percentage change in LS BMD was not different between arms. Conclusions Tenofovir disoproxil fumarate-containing PrEP was associated with significantly greater bone loss compared with maraviroc ± emtricitabine PrEP at the hip, but not the LS. The BMD changes at the hip were similar in magnitude in men and women.

Despite clinicians consistently advising against vaginal douching, 29–92% of women worldwide report douching. This review documents women’s douching practices, motivations for douching, and specific associations (or absence of associations) between vaginal douche use and vaginal outcomes thought to be associated with douching. Understanding women’s existing douching behaviors and vaginal health outcomes is critical for developing a safe vaginal microbicide douche that can be used as HIV pre-exposure prophylaxis (PrEP). A vaginal douche as PrEP could help prevent new HIV infections, since emerging evidence shows some women discontinue oral PrEP. We performed a systematic review of the literature using the guidelines for Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA). Articles included in the analysis (N = 48) were published 2009–2019 in English and focused on women’s experiences with douching. Two trained independent reviewers assessed these articles for content on vaginal douching, including racial/ethnic focus of studies, study design, sampling, women’s reasons for douching, contents of douche solutions, and associations between vaginal douching and vaginal health outcomes. Several studies focused on Black women (N = 12 studies) or had no racial/ethnic focus (N = 12). Just over half of all studies (N = 24) were cross-sectional and involved a self-reported questionnaire and lab samples. Studies sampled women from health clinics where they were (N = 13) or were not (N = 14) presenting for vaginal health complaints. Women’s primary motivation for douching was for “general cleanliness” (N = 13), and most douche solutions contained water (N = 12). There was little empirical agreement between vaginal douche use and most vaginal health outcomes. Future studies of PrEP vaginal douches should be well controlled and prioritize safety to ensure positive vaginal health outcomes.

Aim Cabotegravir long-acting (LA) intramuscular (IM) injection is being investigated for HIV preexposure prophylaxis due to its potent antiretroviral activity and infrequent dosing requirement. A subset of healthy adult volunteers participating in a phase I study assessing cabotegravir tissue pharmacokinetics underwent serial magnetic resonance imaging (MRI) to assess drug depot localization and kinetics following a single cabotegravir LA IM targeted injection. Methods Eight participants (four men, four women) were administered cabotegravir LA 600 mg under ultrasonographic-guided injection targeting the gluteal muscles. MRI was performed to determine injection-site location in gluteal muscle (IM), subcutaneous (SC) adipose tissue, and combined IM/SC compartments and to quantify drug depot characteristics, including volume and surface area, on Days 1 (≤2 hours postinjection), 3, and 8. Linear regression analysis examined correlations between MRI-derived parameters and plasma cabotegravir exposure metrics, including maximum observed concentration (Cmax ) and partial area under the concentration-time curve (AUC) through Weeks 4 and 8. Results Cabotegravir LA depot locations varied by participant and were identified in the IM compartment (n=2), combined IM/SC compartments (n=4), SC compartment (n=1), and retroperitoneal cavity (n=1). Although several MRI parameter and exposure metric correlations were determined, total depot surface area on Day 1 strongly correlated with plasma cabotegravir concentration at Days 3 and 8, Cmax , and partial AUC through Weeks 4 and 8. Conclusion MRI clearly delineated cabotegravir LA injection-site location and depot kinetics in healthy adults. Although injection-site variability was observed, drug depot surface area correlated with both plasma Cmax and partial AUC independently of anatomical distribution.

Author(s): Sekabira, Rogers; McGowan, Ian; Yuhas, Krista; Brand, Rhonda M; Marzinke, Mark A; Manabe, Yukari C; Frank, Ian; Eron, Joseph; Landovitz, Raphael J; Anton, Peter; Cranston, Ross D; Anderson, Peter; Mayer, Kenneth H; Amico, K Rivet; Wilkin, Timothy J; Chege, Wairimu; Kekitiinwa, Adeodata R; McCauley, Marybeth; Gulick, Roy M; Hendrix, Craig W | Abstract: ObjectiveThe objective of this study was to compare HIV-negative cisgender women (CGW) with MSM for mucosal tissue differences in pharmacokinetics, HIV infectivity and cell phenotype.DesignA substudy of HPTN 069/ACTG A5305, 48-week study of three oral candidate preexposure prophylaxis regimens: maraviroc, maraviroc/emtricitabine and maraviroc/tenofovir disoproxil fumarate (TDF) compared with a TDF/emtricitabine control group.MethodsPlasma, peripheral blood mononuclear cells and cervical and colorectal tissue biopsies were collected at Baseline (no drug), Week 24 and 48 (on drug), and Week 49 (1-week postdrug). Drug concentrations were assessed in all matrices. HIV infectivity was assessed using tissue biopsy 'explants' challenged with HIV ex vivo followed by HIV p24 measurement. Flow cytometry evaluated colorectal cell phenotype.ResultsThirty-seven CGW and 54 MSM participated. CGW's colorectal explant p24 was higher than MSM before (0.31 log10, P = 0.046), during (1.01-1.19 log10, P = 0.016) and one week after (0.61 log10, P = 0.011) study drug dosing. Pooling regimens, cervical explant p24 did not differ among visits. CGW had higher plasma maraviroc and colorectal tissue tenofovir diphosphate and lower colorectal tissue emtricitabine (all P l 0.005) compared with MSM. Each study drug's cervical tissue concentrations were more than 10-fold below paired colorectal concentrations (P l 0.001). Cell phenotype sex differences included 4% higher CD38+/CD8+ cells at baseline and 3-7% higher CD69+/CD8+ cells throughout Weeks 24-49 in CGW compared with MSM (P l 0.05).ConclusionColorectal explants in CGW demonstrated greater HIV infectivity than MSM with and without study drugs. Small differences in adherence, drug concentration and colorectal tissue flow cytometry cannot fully explain this difference.

Background The HIV Prevention Trials Network (HPTN) 083 trial demonstrated that long-acting cabotegravir (CAB-LA) was more effective than tenofovir disoproxil fumarate–emtricitabine (TDF/FTC) in preventing human immunodeficiency virus (HIV) in cisgender men and transgender women who have sex with men. We characterized HIV infections that occurred in the blinded phase of HPTN 083. Methods Retrospective testing included HIV testing, viral load testing, quantification of study drugs, and HIV drug resistance testing. Results Fifty-eight infections were evaluated, including 51 incident infections (12 in CAB arm and 39 in TDF/FTC arm). In many cases (5 in CAB arm and 37 in TDF/FTC arm), infection was associated with low or unquantifiable study drug concentrations. In 4 cases, infection occurred with on-time CAB-LA injections and expected plasma CAB concentrations. CAB exposure was associated with prolonged viral suppression and delayed antibody expression. In some cases, delayed HIV diagnosis resulted in CAB provision to participants with undetected infection, delayed antiretroviral therapy, and emergence of drug resistance; most of these infections would have been detected earlier with viral load testing. Conclusions Early detection of HIV infection and prompt antiretroviral therapy initiation could improve clinical outcomes in persons who become infected despite CAB-LA prophylaxis. Further studies are needed to elucidate the correlates of HIV protection in persons receiving CAB-LA.

Author(s): Okafor, Chukwuemeka N; Hucks-Ortiz, Christopher; Hightow-Weidman, Lisa B; Magnus, Manya; Emel, Lynda; Beauchamp, Geetha; Kuo, Irene; Hendrix, Craig; Mayer, Kenneth H; Shoptaw, Steven J | Abstract: BackgroundPre-exposure prophylaxis (PrEP) is efficacious for HIV prevention. Black men who have sex with men (MSM) accounted for the largest proportion of new HIV diagnoses in the United States relative to other racial/ethnic groups. Black MSM who use substances are at an increased risk for HIV infection and are ideal candidates for PrEP, but barriers to maintaining PrEP adherence remain a concern. We assessed whether substance use behaviors are associated with initiation and adherence to PrEP among a sample of black MSM in the United States.MethodsData for this analysis come from the HIV Prevention Trails Network Study 073 (HPTN 073). Substance use behaviors-including alcohol, marijuana, poppers (ie, alkyl nitrites), and stimulants (ie, methamphetamine/cocaine use) including use of these substances before/during condomless anal intercourse (CAI)-were assessed longitudinally through self-report. PrEP adherence was assessed by pharmacological testing in blood. Generalized estimating equations were used to evaluate association between substance use behaviors and PrEP initiation and adherence.ResultsAmong 226 HIV-negative black MSM, the majority (60%) were 25+ years of age. Most of the substance use behaviors were not significantly associated with PrEP initiation or adherence. However, stimulant use before/during CAI was significantly associated with lower odds of PrEP adherence (adjusted odds ratio = 0.21, 95% confidence interval = 0.07 to 0.61; P = l0.01).ConclusionsThese findings suggest that PrEP adherence is feasible among black MSM who use substances. However, black MSM who engage in stimulant use before/during CAI may present a unique group for additional study and support with enhanced behavioral health and support services.

Background Pre-exposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate is efficacious in reducing HIV acquisition. For some gay, bisexual, and other men who have sex with men (MSM), daily ongoing PrEP may be unsuitable for use as a long-term prevention strategy because of episodic risk, cost issues, or concerns about the biological consequences of medication. Setting This study evaluated the feasibility of short-term, fixed-interval episodic PrEP (Epi-PrEP) for use among vacationing MSM. We describe the feasibility of implementing a clinic-based Epi-PrEP pilot program for 48 MSM who reported occasional condomless sex and anticipated a defined high-risk time. Methods This was a nonrandomized naturalistic study of an observational clinical intervention. The primary outcome assessed was adherence, as measured by self-report and plasma tenofovir levels. Results Of 54 MSM who enrolled in the study, 48 completed the 3-month visit. The majority (93.7%) had tenofovir concentrations consistent with daily use on returning from vacation. Almost 3/4 reported condomless sex during vacation, and about 1/3 reported recreational drug use. During the 3-month follow-up, 1 participant had become HIV-infected because of a lapse in continued access to the PrEP after study. Although adverse events were common, none were serious. More than 70% of participants indicated an interest in daily ongoing PrEP use. Conclusions Epi-PrEP was well tolerated by at risk MSM in this study, with high levels of medication adherence. Many participants felt the experience of initiating PrEP while on vacation could be a means for transition to long-term PrEP use.

Author(s): Blair, Cherie S; Li, Sue; Chau, Gordon; Cottle, Leslie; Richardson, Paul; Marzinke, Mark A; Eshleman, Susan H; Adeyeye, Adeola; Rinehart, Alex R; Margolis, David; McCauley, Marybeth; Hendrix, Craig W; Landovitz, Raphael J; HPTN 077 Study Team | Abstract: ObjectivesTo evaluate whether hormonal contraceptive use among cisgender women is associated with differences in pharmacokinetic (PK) parameters of a long-acting injectable formulation of the integrase strand transfer inhibitor, cabotegravir (CAB-LA).SettingThis is a secondary analysis of 85 cisgender women enrolled in HPTN 077, a phase 2a multicenter study that enrolled HIV-uninfected, low-risk individuals in Malawi, Brazil, South Africa, and the United States.MethodsParticipants received 4-week daily oral cabotegravir lead-in, followed by CAB-LA 800 mg injection every 12 weeks (cohort 1) or 600 mg every 8 weeks (after 4-week initial interval between injections, cohort 2), over 41 weeks. Participants were followed 52-76 weeks subsequent to final injection. Generalized estimating equations and linear regression were used to evaluate differences in CAB-LA PK parameters (peak concentration, trough concentration, area under the curve, apparent terminal half-life, and time to lower limit of quantification) and self-reported hormonal contraceptive stratified by type (oral, injectable, implants, and other), controlling for body mass index and cohort.ResultsCompared to women reporting no hormonal contraception (n = 6), oral contraceptive use (n = 18) was associated with lower CAB-LA peak concentration but was not associated with differences in other PK parameters. No other hormonal contraceptive type (injectable, implants, and other) was associated with significant differences in CAB-LA PK parameters.ConclusionAlthough oral contraceptive use was associated with differences in CAB-LA peak concentration, no differences were observed in other PK parameters, suggesting that this association is not likely to be clinically significant. However, these data highlight the need for further research exploring potential drug-drug interactions between CAB-LA and hormonal contraceptives.

Introduction A vaginal ring containing 25 mg of the antiretroviral dapivirine has demonstrated efficacy in reducing women’s risk of sexually acquiring HIV‐1; however, imperfect ring use likely diluted efficacy estimates in clinical trials. The amount of dapivirine remaining in returned rings may reflect the extent of product use, permitting estimation of HIV protection in the context of consistent use. Methods We measured the amount of dapivirine in returned rings from a placebo‐controlled trial of the dapivirine vaginal ring conducted between August 2012 and June 2015 among 2629 African women. Phase I/II studies established that greater than 4 mg of dapivirine on average is released from the ring when used consistently over 28 days and ≤0.9 mg released suggested non‐use. We assessed the relative risk reduction associated with levels of ring use using residual dapivirine in returned rings as a time‐dependent covariate for HIV‐1 infection in multivariable Cox models, including multiple exploratory analyses designed to estimate upper limits of efficacy given uncertainty in timing of HIV‐1 acquisition. All models were adjusted for baseline covariates associated with HIV risk and adherence. Results Residual dapivirine levels indicating at least some use (>0.9 mg released over a month) were associated with a 48% relative reduction in HIV‐1 acquisition risk (95% confidence interval (CI): 21% to 66%; p = 0.002) compared to the placebo. Exploratory analyses accounting for potential misclassification in timing of HIV‐1 acquisition estimated 75% to 91% HIV‐1 risk reduction with> 4 mg released when compared to placebo. Results limited to the subgroup of women

BACKGROUND: Young women aged 15–24 years are disproportionately affected by the HIV epidemic. Two phase III trials of a vaginal ring containing 25-mg dapivirine demonstrated HIV-1 risk reduction in adult women older than 21 years but not in those aged 18–21 years. Lack of protection was correlated with low adherence. METHODS: In this phase-IIa, randomized, double-blind, placebo-controlled, US, multicenter trial of the dapivirine ring in sexually active females, aged 15–17 years, participants were randomized 3:1 to a dapivirine or placebo ring to be inserted monthly for 6 months (NCT02028338). Primary safety end points included grade 2 product related adverse events and any grade 3 and higher adverse events. Adherence to ring use was assessed by plasma dapivirine concentrations, residual levels in used rings, and self-report. A plasma dapivirine concentration of >95 pg/mL was used to define short-term adherence; a residual ring level of

Introduction Oral HIV Pre‐Exposure Prophylaxis (PrEP) with tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC) is highly effective. Transgender women (TGW) have increased HIV risk, but have been underrepresented in trials. For TGW on oestrogens for gender‐affirming hormone treatment (GAHT), TDF/FTC‐oestrogen interactions may negatively affect HIV prevention or gender‐affirming goals. Our aim was to evaluate any pharmacokinetic drug‐drug interaction between GAHT and TDF/FTC. Methods We performed a pharmacokinetic study, in an urban outpatient setting in 2016 to 2018, of the effects of GAHT on TFV, FTC and the active forms TFV diphosphate (TFV‐DP) and FTC triphosphate (FTC‐TP) in eight TGW and eight cisgender men (CGM). At screening, participants were HIV negative. TGW were to maintain their GAHT regimens and have plasma oestradiol concentrations >100 pg/mL. Under direct observation, participants took oral TDF/FTC daily for seven days. At the last dose, blood was collected pre‐dose, one, two, four, six, eight and twenty‐four hours, and colon biopsies were collected at 24 hours to measure drug concentration. TGW versus CGM concentration comparisons used non‐parametric tests. Blood and colon tissue were also obtained to assess kinase expression. Results Plasma TFV and FTC C24 (trough) concentrations in TGW were lower by 32% (p = 0.010) and 32% (p = 0.038) respectively, when compared to CGM. Plasma TFV and FTC 24‐hr area under the concentration‐time curve in TGW trended toward and was significantly lower by 27% (p = 0.065) and 24% (p = 0.028) respectively. Peak plasma TFV and FTC concentrations, as well as all other pharmacokinetic measures, were not statistically significant when comparing TGW to CGM. Oestradiol concentrations were not different comparing before and after TDF/FTC dosing. Plasma oestrogen concentration, renal function (estimated creatinine clearance and glomerular filtration rate), and TFV and FTC plasma concentrations (trough and area under the concentration‐time curve) were all correlated. Conclusions GAHT modestly reduces both TFV and FTC plasma concentrations. In TGW taking GAHT, it is unknown if this reduction will impact the HIV protective efficacy of a daily PrEP regimen. However, the combination of an on demand (2 + 1 + 1) PrEP regimen and GAHT may result in concentrations too low for reliable prevention of HIV infection.

Efforts to prevent human immunodeficiency virus (HIV) infection via pre-exposure prophylaxis (PrEP) include the development of anti-HIV drugs as microbicides for topical application to the mucosal sites of infection; however, although understanding the distribution profiles of these drugs in target mucosal tissues is of critical importance to guiding their optimization, data in this regard are largely lacking. With this in mind, we developed a matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) approach to visualize tenofovir (TFV), an HIV nucleotide analog reverse-transcriptase inhibitor under investigation for use as a topical microbicide, and its active metabolite TFV-diphosphate (TFV-DP) in colorectal biopsies obtained from healthy volunteers who received TFV-containing enemas. Application of MALDI MSI resulted in sufficient spatial resolution to visualize both TFV and TFV-DP and revealed heterogeneity in the distribution profiles of both analytes, including the presence of regions in which TFV and TFV-DP were undetectable, in colorectal tissue at two different time points and concentrations. Cell-specific staining for CD4 T and CD11c dendritic cells, which are important to the establishment of HIV infection, demonstrated that the TFV and TFV-DP distributions were independent of these cell types. MALDI MSI of endogenous lipids demonstrated that the heterogeneity observed for TFV and TFV-DP was not a function of tissue composition or processing. These data provide unique insight into the spatial distribution of TFV and TFV-DP in human colorectal tissue. In addition, this work establishes an approach that can be leveraged to directly detect and visualize these clinically important analytes more broadly in tissue.

To inform the development of HIV-prevention rectal douches, we reviewed the scientific literature and online instructional videos on rectal douching associated with receptive anal intercourse (RAI). Up to 88% of men who practice RAI ever have douched, while 43–64% have douched recently. Of them, 87–97% douche before RAI and 13–48% afterwards. Water, occasionally mixed with soap or salt, is used most often, although up to 31% of men use commercial products. Douching is more common among individuals reporting substance use, sexually transmitted infections, or being HIV-infected. Scant literature is available on women’s rectal douching practices, but it is apparently less frequent than among men (32% vs. 70%). Videos advise using 2–3 doses of liquid and retaining it for 10–30 seconds before expelling. These findings can inform the development of a safe and acceptable rectal douche for HIV prevention.

Placebo-controlled HIV-1 prevention trials of pre-exposure prophylaxis (PrEP) have not generally used concurrent measurement of adherence because of the potential risk of unblinding. However, several pre-exposure prophylaxis trials for HIV-1 prevention among women failed to show effectiveness because of low product adherence. Evaluation of product adherence objectively during a study provides the opportunity for strengthening adherence activities at sites having low adherence.During MTN-020/ASPIRE, a phase III, placebo-controlled trial of the dapivirine intravaginal ring, we implemented an adherence monitoring system. Monitoring began in quarter 1 (Q1) 2013 and continued through the conclusion of the trial. Blood plasma was collected quarterly and tested for dapivirine concentrations while maintaining blinding among study team members involved in participant management. Dapivirine concentrations95 pg/mL, reflecting8 hours of continuous use, were assessed as signaling product use. Study leadership monitored results on a monthly basis and provided feedback to site investigators. Experiences were shared across sites to motivate staff and counsel participants to strive toward higher adherence levels.An upward trend in adherence was observed (P0.0001); the proportion of samples from subjects in the active arm with dapivirine95 pg/mL increased from 63% in Q1 2013 to 84% by Q1 2015.Ongoing drug level testing as a marker of adherence in MTN-020/ASPIRE demonstrates the feasibility of real-time adherence monitoring while maintaining study blinding at the level of participants, sites, and study leadership. This approach is novel for large-scale effectiveness studies for HIV-1 prevention.

MTN-017 compared the safety and acceptability of daily oral emtricitabine/tenofovir disoproxil fumarate, daily reduced-glycerin 1% tenofovir gel applied rectally, and the same gel applied before and after receptive anal intercourse. The Data Convergence Interview (DCI) and the Pharmacokinetic Data Convergence Interview (PK-DCI) were brief, collaborative interactions conducted with participants during adherence counseling sessions to improve accurate measurement of adherence to study product use. DCIs converged data from product return counts and participants’ responses to daily text messages. PK-DCIs, conducted 4 weeks later, converged results of the DCI with PK from the corresponding period. CIs were easily incorporated into adherence counseling sessions, increased the accuracy of adherence data, and provided valuable context to data on product use. Participants were readily engaged in the interviews but, if they felt confronted, provided more guarded responses. As such, how these CIs are conducted is critical to engage participants, even those with poor adherence, to openly discuss challenges with product use.

HPTN 067/ADAPT evaluated tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) pre-exposure prophylaxis (PrEP) in women (South Africa) and men who have sex with men (Thailand, US). Participants received once-weekly directly observed TDF/FTC (DOT), and were then randomized to daily, time-driven, or event-driven PrEP. This report describes characterization of 12 HIV seroconversion events in this trial. HIV rapid testing was performed at study sites. Retrospective testing included: 4th generation assays; HIV RNA testing; Western blot; an HIV-1/2 discriminatory assay; resistance testing; and antiretroviral (ARV) drug testing. Six of the 12 seroconverters received TDF/FTC in the DOT phase, but were not randomized (3 were acutely infected at enrollment; 2 were infected during the DOT phase; one was not randomized due to pregnancy). One of the six randomized participants had acute infection at randomization but was not diagnosed for 3-4 months because HIV rapid tests were non-reactive; continued daily PrEP use was associated with false-negative antibody tests and low HIV RNA levels. The five participants infected after randomization included four with low adherence to the PrEP regimen, and one who reported a 7-day period without dosing prior to infection. Three participants had TDF/FTC resistance (M184I, K65R), including two who received only four once-weekly TDF/FTC doses; most TDF/FTC mutations were detected by next generation sequencing only. In HPTN 067/ADAPT, participants who acquired HIV infection had infrequent PrEP dosing or low/suboptimal adherence. Sensitive assays improved detection of HIV infection and drug resistance. Drug resistance was observed with limited PrEP exposure. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

Sharing of pre-exposure prophylaxis (PrEP) medications is a concern for PrEP implementation. For HIV-1 serodiscordant couples, sharing may undermine the HIV-1 prevention benefit and also cause antiretroviral resistance if taken by HIV-1 infected partners. Within a PrEP efficacy trial among HIV-1 serodiscordant couples, we assessed the occurrence of PrEP sharing by self-report and plasma tenofovir concentrations in HIV-1 infected partners. PrEP sharing was self-reported at

Antiretroviral pre-exposure prophylaxis (PrEP) has been demonstrated to decrease HIV acquisition in multiple efficacy trials, but medication adherence is critical, and was suboptimal in several studies. Fifty HIV-uninfected at risk men who have sex with men (MSM) were randomized to a cognitive behavioral intervention condition or a time and session-matched comparison counseling intervention. The experimental intervention entailed four nurse-delivered initial and two booster sessions based on Life-Steps, an ART treatment adherence intervention. The comparison condition provided information and supportive counseling. The primary analyses compared adherence (Wisepill and tenofovir plasma levels) at 3 and 6 months. Fifty-eight MSM were screened to enroll 50 participants. Median age was 38.2 years old, 86% were white; 64% had completed college. Wisepill adherence was high in both groups, and not statistically different. Plasma tenofovir levels were significantly higher in the intervention group at 6 months using mean substitution analysis (i.e., computing missing variables) (p = 0.037), however, in the completer analyses (i.e., using only those completing all study visits), there were no statistically significant differences between randomization conditions. Medication adherence was high across a cognitive-behavioral (Life-Steps) and time-matched counseling intervention for PrEP adherence, with some evidence suggesting superiority of Life-Steps in this pilot RCT. Further evaluation in a fully powered efficacy trial is warranted to assess the robustness of this intervention.

Topical microbicides are products with anti-HIV activity, generally incorporating a direct-acting antiretroviral agent, that when applied to the vagina or rectum have the potential to prevent the sexual acquisition of HIV in women and men. Microbicides can provide personal control over HIV prevention and offer the possibility of discreet use, qualities that may be particularly important for receptive partners in sexual relationships such as women and transgender women and men, who together account for the clear majority of new HIV infections worldwide. The promise of a topically-applied product under the control of a receptive partner was proposed nearly three decades ago; proof-of-concept that a topical microbicide can prevent HIV has been demonstrated only within the last decade. A robust pipeline of micobicidal gels, films, inserts and rings has been evaluated in multiple studies among at-risk women and men, and refinement of products that meet population needs of ease of use, reversibility, and high safety is the priority for the field. Topical microbicides join other antiretroviral-containing products that act as pre-exposure prophylaxis (PrEP), occupying a unique niche offering strong personal control, the ability to initiate and discontinue easily, and resulting in minimal systemic exposure to the active anti-HIV agent which may consequently minimize side effects and the need for safety monitoring. Topical microbicides may respond to the prevention desires of individuals and groups at risk for HIV worldwide for whom oral daily PrEP has not been acceptable. Continued microbicide development offers the possibility that all populations may achieve HIV prevention success.

The Partners Demonstration Project was a prospective, open-label, implementation science-driven study of preexposure prophylaxis (PrEP) among heterosexual HIV serodiscordant couples in Kenya and Uganda. Adherence data were collected using the Medication Event Monitoring System (MEMS), and time of sexual activity was collected using the mobile phone short message service (SMS). Two plasma samples were collected at a single study visit. We integrated adherence, pharmacokinetics, and SMS data using a population pharmacokinetic (PopPK) model to simulate tenofovir plasma concentrations from PrEP at the time of sexual activity. In the first stage of this analysis, we used data from the current study to update a prior PopPK model of tenofovir (TFV) developed with data from the Partners PrEP Study (a phase III clinical trial). The second stage involved simulating plasma concentrations at the time of sexual activity using empirical Bayes estimates (EBEs) derived from the final model. In addition, EBEs from a previously published parent metabolite model of TFV (MTN-001, an open-label 3-way crossover study in healthy women) was used to simulate tenofovir diphosphate (TFV-DP) concentrations. We estimated percent PrEP “coverage” as the number of reported sexual events during which simulated concentrations were above an a priori threshold concentrations associated with a high degree of protection from HIV infection: plasma TFV of >40 ng/ml and peripheral blood mononuclear cell (PBMC) TFV-DP concentration of >36 fmol/million cells. The levels of coverage were 72% for TFV and 81% for TFV-DP. These levels are consistent with a high degree of protection against HIV acquisition in this study of a pragmatic delivery model for antiretroviral-based HIV prevention.