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Background: Multipurpose prevention technologies that provide protection against HIV acquisition and unintended pregnancy, are safe and acceptable, and support flexible use, are critically needed. We report results from a Phase I study evaluating the safety, pharmacokinetics (PK), pharmacodynamics (PD), and acceptability of CONRAD's tenofovir/levonorgestrel (TFV/LNG) intravaginal ring (IVR) following 3 months of continuous or interrupted use in women. Methods: CONRAD A15-138 was an outpatient, randomized, partially blinded, placebo-controlled, parallel study conducted in Norfolk, VA and the Dominican Republic. Participants were healthy, 18 to 50 years old, had a body mass index Results: We screened 68 women; 47 were randomized onto study and 40 completed all visits. IVRs were safe with no significant changes in cervicovaginal epithelium, immune cell populations or soluble immune and inflammatory markers from baseline. Most TFV/LNG IVR users reported no change in their menstrual cycle or fewer/lighter bleeding days. Median vaginal fluid TFV concentrations were 546 to 3077 ng/mg throughout 90 days of use. Median TFV-DP tissue concentrations exceeded 1000 fmol/mg within 72 hours of IVR insertion. At 1 and 3 months of use, vaginal fluid of women using TFV/LNG IVRs had significantly greater inhibitory activity against HIV growth in vitro compared to baseline and to placebo (p < 0.01). TFV/LNG IVR users had mean serum LNG concentrations exceeding 200 pg/mL within 2 hours of IVR insertion. All placebo users ovulated each month, while only 39% to 71% of TFV/LNG users ovulated during months 1, 2 or 3, consistent with previously tested, effective contraceptive LNG IVRs. TFV/LNG IVR users had significantly lower cervical mucus (CM) Insler scores and a higher proportion of poor or abnormal in vitro CM sperm penetration (p < 0.05). Conclusions: The TFV/LNG IVR was safe, acceptable and delivered high TFV concentrations locally correlating with local PD. The micro-dose of LNG caused changes in CM, sperm penetration and ovulation compatible with contraceptive efficacy, while inducing acceptable changes in menstrual bleeding patterns., OA06.03 A. Thurman (1); V Brache (2); A.L. Ouattara (1); N. Chandra (1); T. Jacot (1); S. Jackson (1); M. Clark (1); M.M. Peet (1); H. Hanif (1); T. McCormick [...]

Background: CAB LA dosed at 2-month intervals demonstrated viro-logic efficacy in maintaining HIV-1 suppression as part of a dual regimen with rilpivirine LA and is undergoing Phase 3 evaluation as a single agent for HIV-1 pre-exposure prophylaxis (PrEP). CAB pharma-cokinetics (PK) in plasma and mucosal tissues associated with sexual HIV-1 transmission were evaluated following single CAB LA IM injection. Methods: Participants received 4 weeks of daily oral CAB 30 mg, followed by 14 to 42 day washout and a single ultrasound-guided gluteal IM injection of CAB LA 600 mg (3 mL). PK samples were collected after oral dosing and through 12 weeks post-injection in plasma, rectal tissue (RT), cervical tissue (CT), vaginal tissue (VT), cervicovaginal fluid (CF), and rectal fluid (RF). CAB concentrations were determined by HPLC-MS/MS. PK parameters were estimated using noncompartmental analysis. Pearson correlations of time-matched tissue and plasma concentration pairs were determined. Results: Nineteen participants (10F, 9M) enrolled with mean age 33 years, weight 79.4 kg, and BMI 27.2 kg/[m.sup.2]. Two participants withdrew before injections, one did not undergo tissue sampling, and one was hospitalized for unrelated serotonin syndrome. Median CAB concentration-time profiles are presented by matrix (Figure 1). Median CAB tissue:plasma ratio was 9% to 10% in RT (r = 0.96), 14% to 18% in CT (r = 0.94), 14% to 16% in VT (r = 0.92), 8% to 13% in CF (r = 0.65), 32% to 45% in RF (r = 0.19). Geometric mean (CVb%) plasma half-life was 19.1 (81.4%) days. Conclusions: Plasma CAB PK was consistent with prior studies, and CAB concentrations in tissue and fluid were proportional to plasma over time. Correlations with plasma concentrations were stronger for tissue (RT, CT, VT) than for luminal fluid (CF and RF). Tissue concentrations were 1/6th (CT, VT) to 1/10th (RT) of plasma concentrations. With sufficient distribution into mucosal tissues associated with sexual HIV-1 transmission, CAB tissue:plasma ratios may serve as important measurements in evaluating CAB LA as an effective PrEP agent., OA04.03 E. Weld (1); J. Sadik Shaik (2); S. Edick (3); E. Fuchs (4); S. Riddler (3); M. Marzinke (1); R. D'Amico (5); K. Bakshi (2); Y. Lou (6); C.W. [...]

Background: HIV prevention needs persist, in part, because of daily oral PrEP challenges, hence, interest in on demand topical options. The dapivirine vaginal ring demonstrated 30% risk reduction in HIV-1 infections, but has not been evaluated for rectal use. We evaluated rectal safety, pharmacokinetics (PK) and pharmacodynamics (PD) of a dapivirine gel formulation. Methods: We enrolled HIV-uninfected men and women, 18 to 45 years of age, at Thailand and United States sites. We randomized eligible participants 2:1 to receive blinded dapivirine (0.05%) or placebo gel via rectal applicator. A single dose phase was followed by observed daily dosing for seven days. Plasma, and fluid and tissue from both rectum and cervix were collected at baseline and 5 times over 72 hours after each dose for PK, ex vivo HIV-1 biopsy challenge (PD), tissue histology, and flow cytometry. Results: We randomized 28 participants; two terminated early. Nine participants were female and 19 male (sex at birth); 12 were white, 11 Asian, 4 black, 1 other race/ethnicity. Mean years of age were 28.5 and 34.2 in the dapivirine and placebo arms, respectively. Thirty adverse events occurred (Grade 1 or 2, except one unrelated Grade 3) without study arm differences or any drug related discontinuation. Dapivirine rectal tissue concentrations (median [interquartile range]) 0.5 to 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 to 72 hours; multiple dose concentrations were similar. Peak dapivirine plasma concentrations were 0.33 ng/mL (0.15, 0.48) after one dose and 0.40 (0.33, 0.49) after seven doses. Cervical tissue and fluid concentrations were all BLQ. Flow cytometry indicated no changes or study arm differences. Ex vivo biopsy challenge showed ~10-fold reduction in viral replication, but only through 2 hours after dosing. Conclusions: Dapivirine gel was well-tolerated with dapivirine plasma concentrations similar to those of the dapivirine vaginal ring observed in clinical trials. However, the rectal ex vivo antiviral effect and tissue concentrations were only transient and well below vaginal tissue results with the dapivirine vaginal ring. A long-acting reformulation or higher dose is likely needed to provide protection from anal sex., OA16.05 C. Hoesley (1); K. Ho (2); E. Dunne (3); C. Dominguez Islas (4); M. Marzinke (5); R.P. Kunjara Na Ayudhya (6); J. Piper (7); J. Bauermeister (8); S. Johnson [...]

Background: Rectal microbicides are promising strategies for local, non-systemic delivery of HIV pre-exposure prophylaxis, especially in men who have sex with men. Tenofovir gel administered intrarectally with an applicator had lower acceptability as compared to a daily oral PrEP regimen and traditional lubricant use in prior phase II studies. Data to enhance the behaviorally congruent delivery of rectal microbicides as lubricants are scant. Methods: MTN-033, a single site, open label, sequence randomized, crossover study, enrolled HIV negative men to receive 0.05% dapivirine (DPV) gel by intrarectal dosing using an applicator (2.5 g) and self-administered on an artificial phallus as lubricant (up to 10 g). Plasma, rectal fluid, and rectal biopsies were collected over 24 hr post dose. Participants completed behavioral acceptability surveys after each dosing regimen. We compared delivery methods using Wilcoxon tests for PK parameters. Results: 16 participants used DPV gel by applicator and 15/16 participants used gel as lubricant (mean 1.8 g, SD 0.8). No related adverse events were reported. Participants all felt the gel was easy to use. Peak DPV concentration in plasma (pg/mL) was higher using an applicator, median 319 (interquartile range [IQR] 247, 603), than use as lubricant, 85 (IQR 54, 218; p < 0.01). Plasma DPV 24 hour area under the curve (ng-hr/mL) after applicator (median 3.5; IQR 3.1, 6.2) was higher than after use as lubricant (median 1.3, IQR 0.7 to 2.4; p < 0.01) Mean DPV concentrations in rectal fluid 1 hr post dose were similar with applicator and as lubricant, 20.9 (SD 33.6) and 25.6 (SD 23.8) pg/mg respectively. DPV was detected in only 1/31 rectal biopsies collected at 1 and 4 hr post dose. Conclusions: Evidence of local delivery and systemic absorption of DPV when dosed as an anal lubricant indicates potentially feasible development of lubricant delivered rectal microbicides. However, roughly 3-fold lower DPV exposure in plasma and lack of detectable DPV in tissue biopsies indicate formulation changes are necessary to achieve protective tissue concentrations informed by vaginal microbicide experience. Our data suggests that DPV gel was safe and easy to use. Further development of a lubricant microbicide strategy is warranted., OA16.03 K. Ho (1); C. Dominguez-Islas (2); D. Szydlo (3); N. Macagna (4); R. Brand (1); J. Piper (5); J. Bauermeister (6); M. Marzinke (7); S. Riddler (1); S. Edick [...]

Abstract Background While initiation of highly active antiretroviral therapy (HAART) during primary HIV-1 infection occasionally results in transient control of viral replication after treatment interruption, the vast majority of patients eventually experience a rebound in plasma viremia. Results Here we report a case of a patient who was started on HAART during symptomatic primary infection and who has subsequently maintained viral loads of < 50 copies/mL for more than nine years after the cessation of treatment. This patient had a high baseline viral load and has maintained a relatively high frequency of latently infected CD4+ T cells. In addition, he does not have any known protective HLA alleles. Thus it is unlikely that he was destined to become a natural elite controller or suppressor. The mechanism of control of viral replication is unclear; he is infected with a CCR5/CXCR4 dual-tropic virus that is fully replication-competent in vitro. In addition, his spouse, who transmitted the virus to him, developed AIDS. The patient's CD4+ T cells are fully susceptible to HIV-1 infection, and he has low titers of neutralizing antibodies to heterologous and autologous HIV-1 isolates. Furthermore, his CD8+ T cells do not have potent HIV suppressive activity. Conclusion This report suggests that some patients may be capable of controlling pathogenic HIV-1 isolates for extended periods of time after the cessation of HAART through a mechanism that is distinct from the potent cytotoxic T lymphocyte (CTL) mediated suppression that has been reported in many elite suppressors.

The Division of AIDS (DAIDS) Good Clinical Laboratory Practice (GCLP) Guidelines establish a framework to guide the oversight of laboratories supporting DAIDS-sponsored clinical research or trials. Compliance with these guidelines promotes data reliability, validity, and safety of the clinical research or trial participants and laboratory staff and ensures adherence to regulatory requirements. Acknowledgment and adoption of the DAIDS GCLP Guidelines are critical in building laboratory capacity and preparedness for conducting clinical trials. In collaboration with DAIDS, laboratory experts support the implementation of the DAIDS Integrated Laboratory Oversight Framework (Framework) activities. This article describes the implementation of the GCLP Guidelines, the Framework activities, and the coordinated efforts to strengthen laboratory performance. The Framework activities include four components: Quality Assurance Oversight, GCLP Audits, GCLP Training, and Laboratory Quality Improvement. Comparison of GCLP Guidelines with other regulations or standards, including U.S. Clinical Laboratory Improvement Amendments regulation 42 CFR 493, College of American Pathologists, World Health Organization GCLP, and International Organization for Standardization, ISO 15189:2012 standards, highlighted the differences and similarities to guide integration and harmonization efforts. Processes related to the Framework activities are outlined in detail, including key data derived from the managed activities of over 175 laboratories worldwide. Via the evolution of the DAIDS GCLP Guidelines and laboratory oversight workflows, the laboratories participating in DAIDS-sponsored clinical research and trials have successfully participated in internal and external regulatory audits. The collaborative and integrated oversight approach promotes knowledge-sharing and accountability to support the implementation of the DAIDS GCLP Guidelines and compliance monitoring. Lessons learned have helped with the implementation of the DAIDS integrated laboratory oversight approach and quality oversight programs at multiple laboratories worldwide.

Introduction: HIV pre-exposure prophylaxis (PrEP) significantly reduces the risk of HIV acquisition. However, studies have demonstrated discordance between self-reported measures and biomedical benchmarks of PrEP adherence. We estimated the correlation between self-reported PrEP adherence and PrEP biomarkers and explored factors associated with adherence among men who have sex with men (MSM) in Nigeria., Methods: TRUST-PrEP, an open-label, prospective study; conducted in Abuja between April 2018 and May 2019. MSM ≥ 18 years with substantial HIV risk were enrolled. Participants reported PrEP adherence in the last month using a 4-point scale from "poor" to "perfect" and serum samples for PrEP biomarkers were collected at months 3 and 9. Serum tenofovir concentration was measured by liquid chromatography-tandem mass spectrometry and considered protective for adherence if ≥ 4.2 ng/ml. Spearman's rank correlation was used to estimate correlation between self-reported adherence and measured tenofovir levels. Generalized estimating equations with a logit link was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for associations between self-reported adherence and laboratory-measured adherence., Results: A total of 219 MSM with median age 23 (interquartile range 20-27) years had at least one PrEP biomarker assay. Only 66/219 (30%) had at least one record of protective tenofovir concentration. Correlation between tenofovir and self-reported adherence at 3 and 9 months were 0.1 and 0.02 respectively. Furthermore, 17/219 (8%,) and 49/219 (22%) had serum tenofovir of 4.2-35.4 ng/mL and ≥ 35.5 ng/mL, corresponding to at least 4 and 7 days' PrEP use in a week, respectively. PrEP adherence was higher among participants introduced to PrEP in the clinics compared with communities (aOR: 8.35, 95%CI: [3.24, 21.5]) and those with same-sex practices family disclosure (aOR: 3.60 95% CI: [1.73, 7.51])., Conclusion: Self-reported PrEP adherence poorly correlated with biomarkers. Facilitating clinic-based PrEP introduction and disclosure of same-sex practices to family among MSM may improve PrEP adherence., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Adeyemi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Safe 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., Methods: We 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., Results: The 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., Conclusions: CAB-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.)., (Copyright © 2021 Massachusetts Medical Society.)

New tools are needed to support pre-exposure prophylaxis (PrEP) adherence for human immunodeficiency virus (HIV) prevention, including those that enable real-time feedback. In a large, completed PrEP trial, adequate urine tenofovir levels measured using a novel immunoassay predicted HIV protection and showed good sensitivity and specificity for detectable plasma tenofovir., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Daily oral TDF/FTC is protective against HIV infection when used for pre-exposure prophylaxis (PrEP). However, daily adherence to oral PrEP is difficult for many; therefore, finding alternative PrEP strategies remains a priority. HPTN 076 evaluated the long-acting injectable form of rilpivirine (RPV), known as RPV LA for safety, pharmacokinetics and acceptability., Methods: HPTN 076 (NTC 02165202) was a phase 2, double-blind, 2:1 randomized trial comparing the safety of 1200mg RPV LA (LA) to placebo (P). The study included a 28-day oral run-in phase of daily, self- administered oral RPV (25 mg), with directly observed oral dosing about six times. Of 136 enrolled sexually active, HIV-uninfected, low HIV-risk African (100) and US (36) adult women, injectable product was administered in two gluteal, intramuscular (IM) injections once every eight weeks to 122 participants following the oral run-in phase. A maximum of six injection time points occurred over a 48-week period. Acceptability, safety, tolerability and pharmacokinetic (PK) data were collected throughout the study. This paper includes primary endpoint data collected up to the week 52 post enrollment., Findings: The median age of the enrolled population was 31 years (IQR: 25,38), median weight 75 kg (IQR: 64, 89), median body mass index (BMI) 30 (IQR: 27, 35), 46% married, 94% Black and 60% unemployed. A total of 122 (80 LA, 42 P) women received at least one injection and 98 (64 LA, 34 P) received all six injections. During the injection phase, three women withdrew from the study (2 LA, 1 P) and 16 women discontinued study product (10 LA, 6 P). Fourteen women (11 LA and 3 P) discontinued oral study product and did not enter the injection phase. Study product discontinuations were not significantly different between the two arms throughout. Of the product discontinuations in the injection phase, 8% in LA and 5% in P arm were due to adverse events (AEs), including one randomized to the P arm with prolonged QTc interval on EKG. The proportion of women who experienced Grade 2 or higher AEs during the injection phase as the primary outcome was not significantly different between the two arms [73.8%, 95% CI: (63.2%, 82.1%) for LA and 73.8%, 95% CI: (58.9%, 84.7%), p>0.99]. Transient Grade ≥2 liver abnormalities occurred in 14% of women in the LA arm compared with 12% in P arm. Three LA women (4%) developed Grade 3 injection site reactions compared with none in P arm. In participants who received at least 1 injection, the geometric mean of overall RPV trough concentrations (C trough ) was 62.2 ng/mL. In participants who received all six injections, the geometric mean of C Trough through the injection phase and after the last injection were 72.8 ng/mL and 100.9 ng/mL, respectively. At week 52 (eight weeks after last injection), the geometric mean of RPV C trough was 75.0 ng/mL. At the last injection visit (Week 44), 80 % of women who answered acceptability questions strongly agreed that they would think about using- and 68% that they would definitely use a PrEP injectable in the future., Interpretation: RPV LA IM injections every eight weeks in African and US women were safe and acceptable. Overall, despite more injection site reactions and pain in the participants receiving RPV LA the injections were well tolerated. Data from this study support the further development of injectable PrEP agents., Competing Interests: Linda-Gail Bekker serves on advisory boards and has received honoraria from Merck, GSK and Gilead. She has also been recipient of donated antivirals for clinical trials from Gilead. Craig W. Hendrix reports grants from NIH during the conduct of the study. He also reports grants from Gilead, ViiV/GSK, the Gates Foundation, and Merck, as well as personal fees and non-financial support from Merck, non-financial support from Gilead outside the submitted work. In addition, he has a patent US 10, 092, 509 B2 issued to Johns Hopkins University. Mark Marzinke reports grants from NIH during the conduct of the study and grants from NIH and ViiV/GSK outside the submitted work. Peter Williams reports other support from Johnson & Johnson, outside the submitted work., (© 2020 Published by Elsevier Ltd.)

We describe the in vitro and in vivo evaluation of a subcutaneous reservoir implant delivering tenofovir alafenamide hemifumarate (TAF) for the prevention of HIV infection. These long-acting reservoir implants were able to deliver antiretroviral drug for over 90 days in vitro and in vivo We evaluated the implants for implantation site histopathology and pharmacokinetics in plasma and tissues for up to 12 weeks in New Zealand White rabbit and rhesus macaque models. A dose-ranging study in rabbits demonstrated dose-dependent pharmacokinetics and local inflammation up to severe necrosis around the active implants. The matched placebos showed normal wound healing and fibrous tissue encapsulation of the implant. We designed a second implant with a lower release rate and flux of TAF and achieved a median cellular level of tenofovir diphosphate of 42 fmol per 10 6 rhesus macaque peripheral blood mononuclear cells at a TAF dose of 10 μg/kg/day. This dose and flux of TAF also resulted in adverse local inflammation and necrosis near the implant in rhesus macaques. The level of inflammation in the primates was markedly lower in the placebo group than in the active-implant group. The histological inflammatory response to the TAF implant at 4 and 12 weeks in primates was graded as a severe reaction. Thus, while we were able to achieve a sustained target dose, we observed an unacceptable inflammatory response locally at the implant tissue interface., (Copyright © 2020 Su et al.)

Objective: 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., Methods: 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., Results: 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]., Conclusions: 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.

HIV pre-exposure prophylaxis (PrEP) strategies have the potential to prevent millions of incident HIV infections each year. However, the efficacy of PrEP strategies has been plagued by issues of non-adherence, likely because of the difficulty in motivating otherwise healthy people to adhere to treatment regimens that require significant behavioral changes and daily discipline. An alternative approach to PrEP is to focus on strategies that fit in to normal, and even desirable, sexual behaviors, such as the use of cleansing enemas by men who have sex with men (MSM) prior to receptive anal intercourse (RAI). Here, we describe preclinical efforts toward optimizing a tenofovir (TFV)-based enema formulation for rectal PrEP. Using a murine model, we compared the plasma and tissue pharmacokinetics of TFV and various TFV prodrugs, including tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and hexadecyloxypropyl tenofovir (CMX157), after dosing as enema formulations with varying osmolality and ion content. We observed that the enema vehicle composition played a more important role than the TFV prodrug properties in achieving rapid and therapeutically relevant tenofovir diphosphate (TFV-DP) concentrations in mouse colorectal tissue. Our results support the next steps, which are further preclinical (non-human primate) and clinical development of a hypo-osmolar TFV enema product for rectal PrEP., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Young women in southern Africa have substantial risk of HIV acquisition. Female-controlled biomedical interventions are needed to mitigate this risk. We aimed to assess the safety and efficacy of a pericoitally applied tenofovir 1% gel., Methods: We did a phase 3, double-blind, randomised, placebo-controlled trial at nine community-based clinical trial sites in South Africa to evaluate the safety and efficacy of tenofovir 1% gel. Sexually active women who were HIV negative and aged 18-30 years were enrolled. Participants were randomly assigned (1:1) using sequential participant numbers to either tenofovir 1% gel or a placebo gel (one dose within 12 h before sex and one dose within 12 h after sex [BAT-24 regimen]), using dynamic permuted block sizes of 8 and 16 within each site. Women received monthly HIV-1 testing, risk reduction support, physical examinations, and product dispensing for up to 27 months. The primary efficacy outcome was incident HIV infection and the primary safety outcome was occurrence of grade 2-4 adverse events, both analysed in the modified intention-to-treat population. To assess the efficacy of tenofovir gel, the cumulative probability of HIV infection was calculated for each treatment using the Kaplan-Meier method. This trial is registered with ClinicalTrials.gov, number NCT01386294., Findings: From Oct 11, 2011, to Aug 29, 2014, 3844 women were screened, 2059 enrolled, and 2029 included in the primary analysis (1032 in the tenofovir group and 1027 in the placebo group); 39 (4%) in the tenofovir group and 36 (4%) in the placebo group were lost to follow-up. 123 HIV-1 infections occurred over 3036 woman-years of observation; 61 in the tenofovir group (HIV incidence 4·0 per 100 woman-years, 95% CI 3·1-5·2) and 62 in the placebo group (4·0 per 100 woman-years, 3·1-5·2; incidence rate ratio [IRR] 0·98, 95% CI 0·7-1·4). A higher incidence of grade 2 adverse events was observed in the tenofovir group than in the placebo group (IRR 1·09, 95% CI 1·0-1·2; p=0·02). The most common grade 2 or higher product-related adverse events were hypophosphataemia (n=22 for tenofovir vs n=22 for placebo), genital symptoms (n=6 for tenofovir vs n=2 for placebo), or elevated transaminases (n=2 for tenofovir vs n=2 for placebo). No product-related serious adverse events were reported, and no differences in product-related adverse events (p=0·78), grade 3 events (p=0·64), or grade 4 events (p=0·74) were observed between treatment groups., Interpretation: Overall, pericoital tenofovir gel did not prevent HIV-1 acquisition in this population of young women at risk of HIV infection in South Africa. Alternate safe and effective products that are less user dependent than this product or do not require high adherence are needed., Funding: The US Agency for International Development (USAID), the Bill & Melinda Gates Foundation, and the South African Department of Science and Technology and Department of Health., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: 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., Methods: 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 concentrations >95 pg/mL, reflecting >8 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., Results: An upward trend in adherence was observed (P < 0.0001); the proportion of samples from subjects in the active arm with dapivirine >95 pg/mL increased from 63% in Q1 2013 to 84% by Q1 2015., Conclusions: 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.

Objective: To evaluate the potential for a clinically relevant drug-drug interaction with concomitant use of a dapivirine vaginal ring, a novel antiretroviral-based HIV-1 prevention strategy, and hormonal contraception by examining contraceptive efficacies with and without dapivirine ring use., Design: A secondary analysis of women participating in MTN-020/ASPIRE, a randomized, double-blind, placebo-controlled trial of the dapivirine vaginal ring for HIV-1 prevention., Methods: Use of a highly effective method of contraception was an eligibility criterion for study participation. Urine pregnancy tests were performed monthly. Pregnancy incidence by arm was calculated separately for each hormonal contraceptive method and compared using an Andersen-Gill proportional hazards model stratified by site and censored at HIV-1 infection., Results: Of 2629 women enrolled, 2310 women returned for follow-up and reported using a hormonal contraceptive method at any point during study participation (1139 in the dapivirine arm and 1171 in the placebo arm). Pregnancy incidence in the dapivirine arm versus placebo among women using injectable depot medroxyprogesterone acetate was 0.43% vs. 0.54%, among women using injectable norethisterone enanthate was 1.15% vs. 0%, among women using hormonal implants was 0.22% vs. 0.69%, and among women using oral contraceptive pills was 32.26% vs. 28.01%. Pregnancy incidence did not differ by study arm for any of the hormonal contraceptive methods., Conclusions: Use of the dapivirine ring does not reduce the effectiveness of hormonal contraceptives for pregnancy prevention. Oral contraceptive pill use was associated with high pregnancy incidence, potentially because of poor pill adherence. Injectable and implantable methods were highly effective in preventing pregnancy.

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.

Objectives: American Congress of Obstetricians and Gynecologists recommends a single dose of antibiotic prophylaxis before all cesarean sections (C/S). This recommendation is based on pharmacokinetic studies that include only non-obese patients. We sought to evaluate 1) cefazolin plasma concentrations among obese and non-obese patients after administration of a 2-g cefazolin dose for prevention of surgical wound infections, and 2) whether cefazolin concentration in fetal circulation may be protective against pathogens that cause early onset neonatal sepsis., Methods: Maternal and fetal cefazolin plasma concentrations were compared between obese (body mass index [BMI] ≥ 30 kg/m 2 ) and non-obese (BMI < 25 kg/m 2 ) healthy, term pregnant women undergoing scheduled C/S. Liquid chromatographic-tandem mass spectrometric (LC-MS/MS) methods were used for quantification of total and free cefazolin concentrations in maternal blood (MB) and umbilical cord blood (UCB)., Results: Eight women were screened and consented. There was no difference between groups in MB total and free cefazolin concentrations. All MB samples had total and free cefazolin concentrations greater than the minimum inhibitory concentration 90 (MIC90) for Group B Streptococcus (GBS), Staphylococcus aureus, and Escherichia coli. All UCB samples had total and free cefazolin concentrations greater than MIC90 for GBS and S aureus, even when administered as briefly as 18 minutes before delivery. A lower concentration of total cefazolin was detected in UCB of neonates of obese women compared to non-obese women (p > 0.05)., Conclusions: Administration of 2 g of cefazolin to women undergoing scheduled C/S might be an adequate prophylactic dose for surgical wound infection in both non-obese and obese patients; and cefazolin concentration in fetal circulation may be protective against GBS and S aureus., Competing Interests: Disclosure The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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

Background: None of the 3 regimens tested in the VOICE study showed protection against human immunodeficiency virus (HIV) infection in intent-to-treat analyses. Plasma tenofovir concentrations demonstrated poor adherence to the study product among study subjects. Statistical analyses to explore the causal treatment effect on the prevention of HIV infection among adherent individuals are needed., Methods: We developed an analytical strategy to evaluate whether conventional covariate adjustment removes confounding and thereby reveals a prevention effect among adherent individuals. We applied this strategy to the VOICE study, using 2 dichotomized proxy measures of product use: detection of tenofovir in plasma at least once during follow-up and detection of tenofovir in plasma at the 3-month follow-up visit., Results: After adjustment for a set of baseline predictors of the risk of HIV transmission, the confounding associated with comparison of adherent individuals in the tenofovir gel arm to placebo recipients was nearly eliminated. The relative risk for a prevention effect among those ever having tenofovir detected was 0.53 (P = .038); the relative risk among those having tenofovir detected at 3 months was 0.40 (P = .045)., Conclusions: A novel regression approach was proposed for causal as-treated analyses in the VOICE study. While intent-to-treat analyses yield null results, this exploratory approach presented evidence suggesting a prevention effect among gel users., Clinical Trials Registration: NCT00705679., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: Antiretroviral preexposure prophylaxis (PrEP), using daily oral combination tenofovir disoproxil fumarate plus emtricitabine, is an effective human immunodeficiency virus (HIV) prevention strategy for populations at high risk of HIV acquisition. Although the primary mode of action for the protective effect of PrEP is probably direct antiviral activity, nonhuman primate studies suggest that PrEP may also allow for development of HIV-specific immune responses, hypothesized to result from aborted HIV infections providing a source of immunologic priming. We sought to evaluate whether PrEP affects the development of HIV-specific immune response in humans., Methods and Results: Within a PrEP clinical trial among high-risk heterosexual African men and women, we detected HIV-specific CD4(+) and CD8(+) peripheral blood T-cell responses in 10%-20% of 247 subjects evaluated. The response rate and magnitude of T-cell responses did not vary significantly between those assigned PrEP versus placebo, and no significant difference between those assigned PrEP and placebo was observed in measures of innate immune function., Conclusions: We found no evidence to support the hypothesis that PrEP alters either the frequency or magnitude of HIV-specific immune responses in HIV-1-exposed seronegative individuals. These results suggest that PrEP is unlikely to serve as an immunologic prime to aid protection by a putative HIV vaccine., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: National Institute of Mental Health Project Accept (HIV Prevention Trials Network [HPTN] 043) is a large, Phase III, community-randomized, HIV prevention trial conducted in 48 matched communities in Africa and Thailand. The study intervention included enhanced community-based voluntary counseling and testing. The primary endpoint was HIV incidence, assessed in a single, cross-sectional, post-intervention survey of >50,000 participants., Methods: HIV rapid tests were performed in-country. HIV status was confirmed at a central laboratory in the United States. HIV incidence was estimated using a multi-assay algorithm (MAA) that included the BED capture immunoassay, an avidity assay, CD4 cell count, and HIV viral load., Results: Data from Thailand was not used in the endpoint analysis because HIV prevalence was low. Overall, 7,361 HIV infections were identified (4 acute, 3 early, and 7,354 established infections). Samples from established infections were analyzed using the MAA; 467 MAA positive samples were identified; 29 of those samples were excluded because they contained antiretroviral drugs. HIV prevalence was 16.5% (range at study sites: 5.93% to 30.8%). HIV incidence was 1.60% (range at study sites: 0.78% to 3.90%)., Conclusions: In this community-randomized trial, a MAA was used to estimate HIV incidence in a single, cross-sectional post-intervention survey. Results from this analysis were subsequently used to compare HIV incidence in the control and intervention communities., Trial Registration: ClinicalTrials.gov NCT00203749.