Objective: Islatravir is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) under development for HIV-1 treatment. We aimed to evaluate the pharmacokinetics (PK) of islatravir and its active form, islatravir-triphosphate, in blood and mucosal tissues. Design: This was an exploratory substudy of a randomized, double-blind, placebo-controlled, multicenter, Phase 2a study of once-monthly islatravir in adults at low likelihood of HIV-1 exposure (NCT04003103). Methods: Participants were randomly assigned 2 : 2 : 1 to receive 6 once-monthly oral doses of islatravir 60 mg, islatravir 120 mg, or placebo. Plasma, peripheral blood mononuclear cell (PBMC), and cervical, vaginal, and rectal tissue samples were collected at Weeks 1, 4, 24, and 32. Samples were assayed by liquid chromatography with tandem mass spectrometry. Intercompartmental ratios and regression analyses were assessed. Results: The analyses included 44 participants who received islatravir 60 mg or 120 mg (73% assigned female at birth; median age 30 years). Following 6 once-monthly doses, islatravir-triphosphate trough concentrations were comparable across homogenized mucosal tissue samples and isolated rectal cells. Median venous whole blood islatravir (total of islatravir and key anabolites) to mucosal tissue islatravir-triphosphate concentration ratios ranged from 0.565 to 1.490 four weeks after the sixth islatravir dose. Adjusted R 2 coefficients between islatravir concentrations in venous whole blood and islatravir-triphosphate concentrations in rectal, cervical, and vaginal tissues across sampling times were 0.67, 0.76, and 0.75, respectively. Conclusions: The favorable tissue distribution of islatravir and islatravir-triphosphate following oral administration supports the evaluation of NRTTIs for HIV-1 preexposure prophylaxis.

BACKGROUND:The HIV Prevention Trials Network (HPTN) 083 Trial demonstrated the superiority of long-acting, injectable cabotegravir (CAB) over daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for HIV pre-exposure prophylaxis among cisgender men (MSM) and transgender women (TGW) who have sex with men. Plasma CAB concentrations associated with HIV protection in humans are unknown. METHODS:We conducted a nested case-control study to investigate the association between plasma CAB concentrations and HIV risk. Plasma CAB concentrations were estimated for participants with confirmed HIV and for HIV-negative controls, who were matched on region, gender, and race. The window of HIV acquisition for cases was defined as the time between the last HIV-negative visit and the first HIV-positive visit; this window was used to evaluate CAB exposure for cases and their matched controls. Participants were categorized by the minimum estimated CAB concentration (CABmin) during this window relative to the protein-adjusted 90% CAB inhibitory concentration (1× PA-IC90) and 4× PA-IC90. HIV risk was modeled using conditional logistic regression. RESULTS:Plasma CABmin was ≥4× PA-IC90 in 26% of HIV-positive cases, compared with 76% of matched controls. Plasma CABmin ≥4× PA-IC90 was associated with a 93% reduction in risk of HIV acquisition compared with CABmin <1× PA-IC90 (95% CI: 76%, 98%, P < .001). CABmin between 1× and 4× PA-IC90 had an estimated risk reduction of 79% compared with CABmin <1× PA-IC90 (95% CI: -19%, 96%, P = .07). CONCLUSIONS:Consistent plasma CAB concentrations ≥4× PA-IC90 were estimated to provide 93% protection against HIV in MSM and TGW.

Oral tenofovir is a key antiretroviral used for treatment and pre-exposure prophylaxis (PrEP) of human immunodeficiency virus (HIV). A gel form has been tested for vaginal and rectal PrEP. We have shown that 7 days of tenofovir 1% gel had broad-ranging effects on gene expression in the rectum, especially suppression of anti-inflammatory mediators and induction of cell proliferation. Similarly, oral PrEP induced type I/III interferon-stimulated genes in the gut. It is unknown how long these effects last and whether they occur in other relevant body compartments. We measured the transcriptomes and proteomes of tissue samples obtained before and after daily topical tenofovir 1% gel application for 14 days (Microbicide Trials Network [MTN]-014 trial, rectal and vaginal) or 56 days (MTN-017 trial, rectal). While many changes seen after 7 days diminish after 14 and 56 days, some remain, notably increases in cell proliferation- and type I/III interferon-related genes. Vaginal gel uniquely induces changes related to epithelial-mesenchymal transition and angiogenesis. Induction of type I/III interferon-related genes is the most consistent and persistent mucosal response to tenofovir, occurring after both oral and topical use and at all tested time points. Hypothetically, interferon induction could improve antiviral efficacy, but also contribute to an increased chronic disease burden in people with HIV.IMPORTANCEAnalyzing gene expression data from three separate clinical trials, we find that the antiretroviral drug tenofovir, which belongs to the class of nucleotide analogue reverse transcriptase inhibitors, induces the type I/III interferon system of innate immunity in the mucosa. This effect occurs in the absence of HIV infection and manifests itself over various treatment durations and after both oral and topical drug delivery. Tenofovir and other related medications are important components of long-term antiretroviral treatment taken by people living with HIV. Therefore, this unexpected immunological effect might need to be considered as a potential contributor to comorbidities in people living with HIV, as well as an immunopharmacological co-factor when testing novel HIV cure interventions.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT01768962, NCT01687218, and NCT01232803.

Cisgender women face an increased risk of HIV acquisition during pregnancy and postpartum. Oral pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir disoproxil fumarate (F/TDF) is recommended in pregnancy despite limited published pharmacokinetic (PK) and efficacy data during pregnancy. Altered PK during pregnancy may reduce prophylactic efficacy and necessitate higher adherence. Tenofovir alafenamide (TAF) is a newer tenofovir prodrug with higher tenofovir diphosphate (TFV-DP) exposure in peripheral blood mononuclear cells (PBMCs), but the prophylactic efficacy of F/TAF across different reproductive stages in women is understudied. We adapted a multiscale modeling framework to predict the prophylactic efficacy of F/TDF and F/TAF across varying adherence levels and during the second trimester, third trimester, and 6-12 weeks postpartum. Clinical trial simulations were conducted utilizing PBMC TFV-DP and emtricitabine triphosphate concentrations as surrogate markers for F/TAF and F/TDF efficacy. For both F/TDF and F/TAF, prophylactic efficacy was lowest during the second trimester, increased in the third trimester (but remained below nonpregnant levels), and was highest postpartum. At high adherence levels of five or more pills per week, predicted effectiveness remained high across pregnancy and postpartum and effectiveness exceeded 97% for both regimens, with maximum decreases in the second trimester of only 0.9 percent point for F/TDF and 0.3 percent point for F/TAF. These findings suggest that adherence is the primary determinant of PrEP effectiveness during pregnancy and postpartum, while pregnancy-related PK changes have a limited impact on efficacy.

The human immunodeficiency virus (HIV) infected approximately 1.1 million individuals in 2024. There is no effective vaccine or cure, and funding cuts in resource-limited settings threaten treatment access. Cost-effective and widely available prevention strategies, such as oral emtricitabine/tenofovir disoproxil fumarate pre-exposure prophylaxis (FTC/TDF-PrEP), are therefore essential. Current PrEP guidelines differ between cisgender women and men who have sex with men (MSM), based on mechanistic differences in tissue-level pharmacokinetics (PK) at vaginal vs. colorectal exposure sites. To test these mechanistic hypothesis, we use data from major FTC/TDF-PrEP trials to establish PrEP efficacy when used in MSM. We independently predict efficacy utilizing different PK-matrices in a mechanistic model, simulate each clinical trial informed by adherence data and compare the predictions with clinical efficacy estimates. With this combined approach, two of the five trials (HPTN 083, DISCOVER) yield sufficient statistical power to conclude that rectal tissue pharmacokinetics do not predict PrEP efficacy in MSM. In contrast, PBMC-based predictions agree with clinical PrEP efficacy and support the suitability of on-demand use of oral PrEP in MSM. When combining our findings with recent results on suitable pharmacokinetic markers in women, our work suggests that adherence requirements for cisgender women and MSM may not differ.

Background:Pregnant women are vulnerable to HIV acquisition. Oral HIV pre-exposure prophylaxis (PrEP) is safe and effective for use during pregnancy. We describe PrEP adherence among pregnant women using multiple measures.Methods:We conducted a secondary data analysis among women enrolled in a study evaluating an adherence intervention for PrEP among those planning for and with pregnancy in South Africa. Our analysis included women who used PrEP and became pregnant. Longitudinal PrEP use was assessed using concentrations of tenofovir (TFV) in plasma, tenofovir diphosphate (TFV-DP) in dried blood spots, and electronic pillcap data from quarterly visits. Plasma TFV <= 10 ng/mL and TFV-DP <= 16.6 fmol/punch were below quantifiable limits. Data were analyzed during prepregnancy (quarter before pregnancy) and pregnancy trimesters.Results:Among 35 women, 69% were 18-24 years old, 40% were nulliparous, and 94% did not know their partner's HIV serostatus. Median pillcap adherence was 55%-80% and was highest during prepregnancy (72%, interquartile range: 54%-86%) and third trimester (80%, interquartile range: 30%-94%). The proportion of women with quantifiable TFV was 47% (n = 8/17) prepregnancy and 33% (n = 9/27), 19% (n = 4/21), and 14% (n = 2/14) for trimesters 1-3, respectively. TFV-DP was detected in 75% of samples (n = 12/16) prepregnancy, and 50% (n = 13/26), 29% (n = 6/21), and 27% (n = 4/15) for trimesters 1-3, respectively. No women acquired HIV during pregnancy.Conclusions:PrEP use declined during pregnancy by all measures. Discrepancies between pillcap measurements and drug concentrations could be due to physiologic changes during pregnancy or under- or overuse of the pillcaps. Determining what drug metabolite concentrations are needed to confer protection during pregnancy is important for optimizing counseling and prevention support.

Background and ObjectiveTenofovir (TFV)-based regimens are backbones of both HIV treatment and pre-exposure prophylaxis during pregnancy. Multiple studies have shown up to one-third decreases in dried blood spot tenofovir-diphosphate concentrations during pregnancy among participants taking tenofovir disoproxil fumarate (TDF). Currently, there are no mechanism-based models describing the pharmacokinetics of tenofovir diphosphate (the active anabolite) in peripheral blood mononuclear cells (PBMCs) of pregnant individuals receiving TDF or tenofovir alafenamide (TAF), and the mechanisms behind observed differences between dried blood spots and PBMCs remain unclear.MethodsTo address this gap, we developed a semi-mechanistic model to simultaneously describe the pharmacokinetics of all clinically relevant TDF and TAF-derived moieties and conducted clinical trial simulations to compare TDF and TAF pharmacokinetics during pregnancy and postpartum.ResultsThe pharmacokinetics of plasma TAF and TFV were best described by one-compartment and two-compartment models, respectively, with first-order absorption. A transit compartment was included to reflect the slower elimination rate of plasma TFV after receiving TAF. Cellular matrix PBMC and dried blood spots were included using a biophase model. For TDF, plasma TFV apparent clearance increased by 24.9% and 13.1% during the second and third trimesters of pregnancy, respectively, compared with non-pregnant populations. In the postpartum period, plasma TFV apparent clearance in pregnant women was 9.3% lower than in non-pregnant women. The bioavailability for TAF decreased by 17.3% and 5.1% during the second and third trimesters, respectively, and increased by 18% during the postpartum period relative to non-pregnant women. In pregnant women, simulations showed that TAF maintains approximately five times higher tenofovir diphosphate concentrations in PBMCs compared with TDF during the second and third trimesters, despite a decrease in PBMC tenofovir diphosphate concentrations for both drugs. This finding is consistent with the higher PBMC loading effect of TAF observed in non-pregnant populations.ConclusionsOur semi-mechanistic model provides a framework for understanding pregnancy-associated pharmacokinetic changes and supports future research to refine dosing strategies for HIV treatment and prevention in pregnancy.

BACKGROUND:Unprotected receptive anal intercourse carries the highest sexual HIV transmission risk. The need for diverse pre-exposure prophylaxis (PrEP) options has encouraged the development of on-demand, topical PrEP products for those preferring nonsystemic or occasional PrEP. We assessed end users' proficiency in preparing tenofovir douches from sachets containing 2 different powder types, lyophilized and spray dried, and evaluated their experience. METHODS:Cisgender adult men with a history of RAI-related douching were consented, screened, and randomized 1:1 to the order of the powder type prepared. All participants prepared at least 3 enema bottles of each powder type. Aliquots from each prepared douche bottle were analyzed for tenofovir (TFV) concentration, osmolality, and pH. User experience and likelihood of future product use were assessed by questionnaire. RESULTS:Twenty-one eligible participants were enrolled. Most participants reported both products as easy or very easy to prepare and likely or very likely to be used. Participants preferred the lyophilized product. The lyophilized and spray-dried douche bottles prepared met the osmolality specifications 89% and 61% of the time and TFV content specifications 81% and 29% of the time, respectively. Questionnaires indicated the most common challenges were tearing open the sachets and transferring the spray-dried product. CONCLUSIONS:Most participants reported the douches were easy to prepare and indicated likely future use. Although the lyophilized sachets were prepared sufficiently to establish preparation feasibility, the spray-dried sachets often fell outside specifications. Failure analysis provided insights to guide product modifications to improve the proficiency of douche preparation and future product use.

ObjectivesDREAM-01 was an open label, dose-escalation and variable osmolarity study to identify a tenofovir HIV-prevention douche/enema that could achieve protective colon tissue cell concentrations and high acceptability. To assess impact on sexual enjoyment, iso-osmolar and hypo-osmolar placebo douches were provided for at-home use before receptive anal sex (RAS).MethodsEighteen HIV-uninfected men who have RAS were administered three tenofovir douches at the research clinic: Product A, an iso-osmolar dose; Product B, an iso-osmolar escalation dose; and Product C, a hypo-osmolar escalation dose. Following Products A and C, participants were given a saline douche of matching osmolarity to use at home before RAS. Participants reported acceptability via a computer-assisted self-interview and in-depth interview in this mixed-methods study.ResultsAll three products were rated acceptable by 17 (95%) of the participants. A majority (94%) would be likely or very likely to use any of the three products before RAS. Of those who used the saline douches before RAS and then rated their sexual enjoyment, most reported that their sexual enjoyment was not affected. Interview data revealed that participants found the product easy to incorporate into their regular routine, but would prefer to use more liquid for cleansing.ConclusionsThese findings indicate that the hypo-osmolar Product C, which also provides the most rapid delivery of tenofovir for HIV prevention, is acceptable for future safety trials and that our sample reports high likelihood of using a rectal microbicide douche for HIV prevention. Our findings support continued pursuit of a tenofovir rectal microbicide douche.Trial registration numberNCT02750540.

BACKGROUND:Men who have sex with men are at high risk of human immunodeficiency virus (HIV) acquisition through unprotected receptive anal intercourse (RAI). Behaviorally congruent HIV preexposure prophylaxis (PrEP) has long been advocated by individuals who find adherence challenging or prefer minimizing systemic drug concentrations. We developed an event-driven, behaviorally congruent rectal tenofovir douche as a PrEP option for RAI and demonstrated product safety/acceptability in a previous clinical study. Here, our goal was to compare colorectal distribution of an HIV surrogate and tenofovir douche when the tenofovir douche preceded or followed simulated RAI (sRAI). METHODS:Five participants completed 2 paired study visits. At visit one, participants received an 111indium-diethylenetriaminepentaacetic acid-labelled tenofovir douche prior to sRAI using 99mTc-sulfur colloid in autologous semen as HIV surrogate. At visit two, the radiolabeled tenofovir douche was administered following radiolabeled sRAI. Colorectal distribution of both douche and HIV surrogate radioisotopes were assessed using single-photon emission computed tomography/transmission computed tomography. Systemic permeability was assessed by plasma TFV concentrations. RESULTS:Colorectal distribution of the douche was not different between sequences. Conversely, the majority of HIV surrogate was within the rectosigmoid when the douche was administered prior to sRAI, but the distribution extended into descending colon when the douche was administered following sRAI. Regardless of sequence, an early plasma TFV peak 20 minutes after dosing was observed. CONCLUSIONS:Douching following RAI may increase HIV distribution in the colon with uncertain impact on HIV acquisition risk. The early plasma TFV suggests even more rapid time to protection than reported in prior studies. CLINICAL TRIALS REGISTRATION:NCT04195776.

End-user feedback early in product development is important for optimizing multipurpose prevention technologies for HIV and pregnancy prevention. We evaluated the acceptability of the 90-day dapivirine levonorgestrel ring (DPV-LNG ring) used for 14 days compared to a dapivirine-only ring (DVR-200mg) in MTN-030/IPM 041 (n = 23), and when used for 90 days cyclically or continuously in MTN-044/IPM 053/CCN019 (n = 25). We enrolled healthy, non-pregnant, HIV-negative women aged 18-45 in Pittsburgh, PA and Birmingham, AL (MTN-030 only). Self-reports of vaginal bleeding and adherence (ring removals, expulsions) were collected via daily short message service. Acceptability data were recorded in face-to-face interviews at study exit. We assessed differences in acceptability by product characteristics and adherence; and associations between baseline characteristics/demographics, number of bleeding days, adherence, and overall acceptability. Most (21/23) women in the 14-day MTN-030 study and about half (13/25) in the 90-day MTN-044 study liked their assigned rings. In MTN-030 there were no significant associations between any variables and overall acceptability of either ring. In MTN-044, women who disliked the DPV-LNG ring had a significantly higher incidence of unanticipated vaginal bleeding, and reporting that vaginal bleeding changes were unacceptable than those who liked it. Although we found no overall association between adherence and acceptability, significantly more women who disliked (versus liked) the DPV-LNG ring reported expulsions during toileting. The DPV-LNG ring could meet the needs of women seeking simultaneous protection from HIV and unintended pregnancy. Addressing issues related to vaginal bleeding and expulsions early in product development will likely enhance acceptability of the DPV-LNG ring. Trial registration: Clinical Trial Registration: MTN-030/IPM 041: ClinicalTrials.gov NCT02855346; MTN-044/IPM 053/CCN019: ClinicalTrials.gov NCT03467347.

BACKGROUND:Islatravir, a nucleoside reverse transcriptase translocation inhibitor, exhibits high potency against human immunodeficiency virus type 1 (HIV-1), with a long intracellular half-life. The safety, tolerability, and pharmacokinetics of once-monthly oral islatravir were evaluated in adults at low risk of acquiring HIV-1. METHODS:In this double-blind, placebo-controlled trial, participants were randomized 2:2:1 to receive 6 once-monthly doses of islatravir 60 mg, islatravir 120 mg, or placebo. Objectives included assessing safety, tolerability, and pharmacokinetic profiles of islatravir in plasma and its active metabolite, islatravir triphosphate (ISL-TP), in peripheral blood mononuclear cells (PBMCs). RESULTS:Of 242 participants (islatravir 60 mg, n = 97; islatravir 120 mg, n = 97; placebo, n = 48), most were aged ≤45 years (90.1%), female (67.4%), and White (52.9%). Proportions of participants experiencing ≥1 adverse event (AE) were similar in the islatravir (60 mg: 68.0%; 120 mg: 64.9%) and placebo (75.0%) arms. AEs were generally mild to moderate, with infection-related AEs comparable across arms. Lymphocyte count decreased in the islatravir arms, with mean percentage changes of -21.3% ± 20.1% (60 mg) and -35.6% ± 22.8% (120 mg) versus +4.4% ± 25.9% (placebo) at week 24. Median intracellular PBMC ISL-TP concentrations remained above the prespecified pharmacokinetic threshold for HIV-1 prophylaxis (0.050 pmol/106 cells) through 4 weeks after the first dose and ≥8 weeks after the last dose. CONCLUSIONS:Oral islatravir 60 mg and 120 mg once monthly demonstrated similar tolerability and AE profiles to placebo, except for dose-dependent decreases in total lymphocyte counts. A partial recovery in total lymphocyte counts was observed. In most participants, both islatravir doses achieved PBMC ISL-TP exposure levels projected to be effective for once-monthly oral HIV-1 preexposure prophylaxis. CLINICAL TRIALS REGISTRATION:NCT04003103.

INTRODUCTION:HPTN 084 found that long-acting cabotegravir (CAB-LA) was well-tolerated and significantly reduced the risk of HIV acquisition in women compared to tenofovir disoproxil fumarate/emtricitabine (F/TDF). During the blinded phase of the trial, participants were required to use an effective method of contraception, including an injectable or implantable hormonal contraceptive (HC) agent. A contraceptive sub-study assessed the pharmacokinetic interactions between pre-exposure prophylaxis agents (CAB-LA or F/TDF) and etonogestrel (ENG), medroxyprogesterone acetate (MPA) or norethindrone enanthate (NET-EN). METHODS:Participants were enrolled in a nested sub-study between 24 February 2020 and 26 October 2020. Via a convenience sampling strategy, plasma concentrations of ENG, MPA and NET-EN were evaluated at enrolment and weeks 25, 49 and 73; plasma tenofovir (TFV) and CAB concentrations were determined at contemporaneous visits. Participants were allowed to switch contraceptives, and HC assessments were adjusted accordingly. Geometric mean concentrations were calculated and compared using t-tests or Fisher's exact tests. RESULTS:One hundred and seventy participants were included in this analysis. Hormone concentrations at all study visits were comparable between the CAB-LA and F/TDF study arms. Among participants randomized to the CAB-LA arm, geometric mean concentrations declined from enrolment to the follow-up period for ENG (335 to 202 pg/ml), MPA (1520 to 1138 pg/ml) and NET-EN (3715 to 1888 pg/ml); similar findings were observed among participants randomized to the F/TDF arm. Observed HC declines are likely attributed to the timing of contraceptive administration relative to sampling; the percentage of participants with hormone concentrations above thresholds associated with ovulation suppression was high (73-100%) and did not differ between arms. CAB concentrations were comparable across contraceptive types, with 97.8-98.1% of participants yielding trough CAB concentrations above the protocol-specified target threshold. TFV concentrations were unquantifiable for most participants, irrespective of contraceptive agent, rendering comparisons largely uninformative. CONCLUSIONS:Given the comparable hormone concentrations between arms and the likely influence of the timing of sample collection on observed measurements, clinically significant interactions between CAB-LA and HC are not expected. Associations between F/TDF and hormone concentrations could not be effectively evaluated due to low adherence to F/TDF. CLINICAL TRIAL REGISTRATION:NCT0316456.

BACKGROUND:Young men who have sex with men (YMSM) are disproportionately affected by human immunodeficiency virus (HIV); however, use of oral preexposure prophylaxis (PrEP) remains suboptimal. This study evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and acceptability of a novel tenofovir (TFV) rectal microbicide douche for HIV prevention. METHODS:Eight HIV-negative YMSM (aged 18-24 years) participated in a single-dose, open-label trial. Each received 660 mg of TFV in a 125-mL rectal douche. Safety was assessed via clinical monitoring and adverse event (AE) reporting. PK analysis measured TFV and TFV-diphosphate (TFV-DP) concentrations in blood and rectal tissue. PD was evaluated using ex vivo HIV-1 challenge assays in rectal biopsies. RESULTS:No serious AEs occurred. Five mild to moderate AEs (eg, nausea, hyperglycemia) were reported, none related to the product. Median peak plasma TFV concentration (14.5 ng/mL) remained below levels seen with oral TDF. Median peak (24-hour) rectal tissue cell TFV-DP concentrations were 8319 fmol/106 cells with a corresponding 0.9 log10 HIV-1 p24 antigen reduction observed in ex vivo challenge assays. Rectal tissue TFV-DP concentrations exceeded those associated with on-demand oral 2-1-1 dosing from 1 to 72 hours and suppressed HIV-1 p24 antigen production in colonic explants. Acceptability was high: 87.5% reported satisfaction, and 75% would consider future use. CONCLUSIONS:The TFV rectal douche was safe, well tolerated, and acceptable to YMSM. Its favorable PK and PD profiles support further investigation as a behaviorally congruent, on-demand PrEP strategy. Additional studies are needed to assess long-term safety and efficacy in larger, more diverse populations. CLINICAL TRIALS REGISTRATION:NCT04686279.

AbstractIntroductionLong‐acting injectable cabotegravir (CAB‐LA) for pre‐exposure prophylaxis significantly reduced HIV acquisition in HPTN 084. We report on the safety and CAB‐LA pharmacokinetics in pregnant women during the blinded period of HPTN 084.MethodsParticipants were randomized 1:1 to either active cabotegravir (CAB) plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) placebo or active TDF/FTC plus CAB placebo. Pregnancy testing was performed at each visit; participants with a positive test had study product withheld and were offered open‐label TDF/FTC. Pregnancies were confirmed on two tests at least 4 weeks apart. All participants with a positive pregnancy test prior to November 5, 2020 are included in this analysis. Pregnancy incidence, maternal adverse event (AE) incidence, pregnancy outcomes (including composite outcome of spontaneous abortion <20 weeks, intrauterine foetal death or stillbirth ≥20 weeks, premature birth <37 weeks, or small for gestational age) were assessed. The apparent terminal phase half‐life (t1/2app) of CAB‐LA in pregnant women in HPTN 084 was compared to non‐pregnant women from the phase 2a HPTN 077 trial. Multivariable models assessed associations with t1/2app.ResultsFifty‐seven pregnancies (30 CAB‐LA, 27 TDF/FTC) were confirmed over 3845 person‐years [py] (incidence 1.5/100 py, 95% CI 1.1−1.9). CAB‐LA group participants had a median 342 days (IQR 192, 497) of CAB‐LA exposure prior to pregnancy detection. Grade 2 or higher maternal AE incidence did not differ by study arm (CAB 157, 95% CI 91−271 per 100 py vs. TDF/FTC 217, 95% CI 124–380 per 100 py; p = 0.256). Most pregnancies (81%) resulted in live births (25 CAB‐LA, 22 TDF/FTC). Composite poor pregnancy outcomes did not differ significantly by group (CAB 6/30 vs. TDF/FTC 4/27; p = 0.476). No congenital anomalies were observed. The CAB t1/2app geometric mean was 52.8 days (95% CI 40.7−68.4) in pregnant women compared to 60.3 days (95% CI 47.7−76.3; p = 0.66) in non‐pregnant women; neither pregnancy nor body mass index were significantly associated with t1/2app.ConclusionsCAB‐LA concentrations post‐cessation of injections were generally well tolerated in pregnant women. The t1/2app was comparable between pregnant and non‐pregnant women. Ongoing studies will examine the safety and pharmacology of CAB‐LA in women who choose to continue CAB‐LA through pregnancy and lactation.

Introduction Peritoneal dialysis (PD) is an effective renal replacement modality in people with HIV (PWH) with end-stage kidney disease (ESKD), particularly those with residual kidney function. Data on pharmacokinetics (PK) of antiretrovirals in patients on peritoneal dialysis are limited.Methods A single-participant study was performed on a 49-year-old gentleman with ESKD on PD and controlled HIV on once daily dolutegravir (DTG) 50 mg + tenofovir alafenamide (TAF) 25 mg / emtricitabine (FTC) 200 mg. He underwent serial blood plasma, peripheral blood mononuclear cell, and urine PK measurements over 24 h after an observed DTG + FTC/TAF dose.Results Plasma trough (Cmin) concentrations of TAF, tenofovir (TFV), FTC, and DTG were 0.05, 164, 1,006, and 718 ng/mL, respectively. Intracellular trough concentrations of TFV-DP and FTC-TP were 1142 and 11,201 fmol/million cells, respectively. Compared to published mean trough concentrations in PWH with normal kidney function, observed TFV and FTC trough concentrations were 15.5- and 20-fold higher, while intracellular trough concentrations of TFV-DP and FTC-TP were 2.2-fold and 5.4-fold higher, respectively. TFV and FTC urine levels were 20 times lower than in people with normal GFR.Conclusions In a single ESKD PWH on PD, daily TAF was associated with plasma TFV and intracellular TFV-DP trough concentrations 15-fold and 2-fold higher than those of people with uncompromised kidney function, potentially contributing to nephrotoxicity. This suggests that TFV accumulates on PD; thus, daily TAF in PD patients may require dose adjustment or regimen change to optimize treatment, minimize toxicity, and preserve residual kidney function.

Background Confounding introduced by individuals' sexual risk behavior is potentially a significant source of bias in HIV-1 prevention intervention studies. To more completely account for sexual behaviors when assessing the efficacy of the monthly dapivirine ring, a new longer-acting HIV-1 prevention option for women, we estimated per-sex-act risk reduction associated with product use.Methods We conducted a secondary analysis of data from MTN-020/ASPIRE, a phase 3, randomized, placebo-controlled efficacy trial of the dapivirine ring that recruited HIV-uninfected, African women aged 18-45 years. With cumulative sex acts as the time scale, we used multivariable Cox regression with inverse probability of censoring weights to estimate HIV-1 risk reduction associated with a rate of dapivirine release indicative of consistent product use.Results Women in the dapivirine ring group (n = 1187) had an estimated incidence rate of 2.3 (95% confidence interval [CI], 1.8-3.1) HIV-1 acquisition events per 10 000 sex acts versus 3.6 (95% CI, 2.9-4.4) per 10 000 acts in the placebo group (n = 1187). Dapivirine release indicative of consistent ring use was associated with a 63% (95% CI, 33%-80%) per-sex-act HIV-1 risk reduction.Conclusions These results support the efficacy of the dapivirine vaginal ring for HIV-1 prevention and help to inform decision-making for women, providers, and policymakers regarding product use.Clinical Trials Registration NCT01617096. Among cisgender African women using the dapivirine vaginal ring for HIV-1 prevention, drug release rates consistent with continuous product use were associated with a 63% (95% CI, 33%-80%) per-sex-act HIV-1 risk reduction, further supporting the product's efficacy.

Background Despite highly effective HIV preexposure prophylaxis (PrEP) options, no options provide on-demand, nonsystemic, behaviorally congruent PrEP that many desire. A tenofovir-medicated rectal douche before receptive anal intercourse may provide this option.Methods Three tenofovir rectal douches-220 mg iso-osmolar product A, 660 mg iso-osmolar product B, and 660 mg hypo-osmolar product C-were studied in 21 HIV-negative men who have sex with men. We sampled blood and colorectal tissue to assess safety, acceptability, pharmacokinetics, and pharmacodynamics.Results The douches had high acceptability without toxicity. Median plasma tenofovir peak concentrations for all products were several-fold below trough concentrations associated with oral tenofovir disoproxil fumarate (TDF). Median colon tissue mucosal mononuclear cell (MMC) tenofovir-diphosphate concentrations exceeded target concentrations from 1 hour through 3 to 7 days after dosing. For 6-7 days after a single product C dose, MMC tenofovir-diphosphate exceeded concentrations expected with steady-state oral TDF 300 mg on-demand 2-1-1 dosing. Compared to predrug baseline, HIV replication after ex vivo colon tissue HIV challenge demonstrated a concentration-response relationship with 1.9 log10 maximal effect.Conclusions All 3 tenofovir douches achieved tissue tenofovir-diphosphate concentrations and colorectal antiviral effect exceeding oral TDF and with lower systemic tenofovir. Tenofovir douches may provide a single-dose, on-demand, behaviorally congruent PrEP option, and warrant continued development. Clinical Trials Registration . NCT02750540.Conclusions All 3 tenofovir douches achieved tissue tenofovir-diphosphate concentrations and colorectal antiviral effect exceeding oral TDF and with lower systemic tenofovir. Tenofovir douches may provide a single-dose, on-demand, behaviorally congruent PrEP option, and warrant continued development. Clinical Trials Registration . NCT02750540. Tenofovir formulated as a rectal douche offers the potential for a single-dose, on-demand, acceptable, and behaviorally congruent option for HIV preexposure prophylaxis supported by colorectal tissue tenofovir diphosphate and antiviral effect exceeding similar measures associated with oral tenofovir disoproxil fumarate.

Background: Anal sex remains the greatest HIV transmission risk for men who have sex with men and carries substantial population attributable risk among women. Despite a growing array of HIV preexposure prophylaxis (PrEP) options, rectal microbicides remain desirable as on-demand, nonsystemic PrEP. Rectal microbicide product development for PrEP requires understanding the spatiotemporal distribution of HIV infectious elements in the rectosigmoid to optimize formulation development. Setting: Outpatient setting with healthy research participants. Methods: Six healthy men underwent simulated receptive anal sex with an artificial phallus fitted with a triple-lumen catheter in the urethral position. To simulate ejaculation of HIV-infected semen, autologous seminal plasma laden with autologous blood lymphocytes from apheresis labeled with 111 Indium-oxine (cell-associated) and 99m Technetium-sulfur colloid (cell-free) as HIV surrogates was injected into the rectal lumen through the phallic urethra. Spatiotemporal distribution of each radioisotope was assessed using single-photon emission computed tomography/CT over 8 hours. Analysis of radiolabel distribution used a flexible principal curve algorithm to quantitatively estimate rectal lumen distribution. Results: Cell-free and cell-associated HIV surrogates distributed to a maximal distance of 15 and 16 cm, respectively, from the anorectal junction (∼19 and ∼20 cm from the anal verge), with a maximal signal intensity located at 6 and 7 cm, respectively. There were no significant differences in any distribution parameters between cell-free and cell-associated HIV surrogates. Conclusions: Cell-free and cell-associated HIV surrogate distribution in the rectosigmoid can be quantified with spatiotemporal pharmacokinetic methods. These results describe the ideal luminal target distribution to guide rectal microbicide development.