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Background: On-demand topical products could be an important tool for human immunodeficiency virus (HIV) prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG, 20 mg/16 mg) insert administered rectally., Methods: MTN-039 was a phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid, and rectal tissue were collected over 72 hours following rectal administration of 1 and 2 TAF/EVG inserts for each participant., Results: TAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4 ng/mL and TFV 4.4 ng/mL. Rectal tissue EVG peaked at 2 hours (median, 2 inserts = 9 ng/mg) but declined to below limit of quantification in the majority of samples at 24 hours, whereas tenofovir diphosphate (TFV-DP) remained high >2000 fmol/million cells for 72 hours with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each time point for both 1 and 2 inserts (P < .065 and P < .039, respectively)., Discussion: Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours. Clinical Trials Registration . NCT04047420., Competing Interests: Potential conflicts of interest. S. A. R. received research grants from Gilead Sciences and Merck. P. L. A. received research contracts from Gilead Sciences paid to his institution. S. L. H. received research grants and consulting fees from Merck. G. F. D. received research grants from Gilead Sciences. C. W. H. has received clinical research funding from Gilead Sciences and Merck; he is a coinventor of 2 issued US patents related to microbicides; and is founder of Prionde BioPharma, LLC, a microbicide company. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Tenofovir-based oral pre-exposure prophylaxis is currently approved for HIV prevention; however, adherence in women has been low. A vaginal gel containing tenofovir (TFV) demonstrated partial protection to HIV but protection was not confirmed in additional studies. Vaginal rings offer user-controlled long-acting HIV prevention that could overcome adherence and protection challenges. TFV may also help prevent herpes simplex virus type 2 acquisition when delivered intravaginally. We evaluated the pharmacokinetics, safety, adherence and acceptability of a 90-day TFV ring., Methods: Between January and June 2019, Microbicide Trials Network (MTN)-038 enrolled 49 HIV-negative participants into a phase 1, randomized (2:1) trial comparing a 90-day ring containing 1.4 grams (g) TFV to a placebo ring. TFV concentrations were quantified in plasma, cervicovaginal fluid (CVF), rectal fluid and cervical tissue, and TFV-diphosphate (TFV-DP) in cervical tissue. Used rings were analysed for residual TFV. Safety was assessed by adverse events (AEs); acceptability and adherence by self-report., Results: Mean age was 29.5; 46 identified as cisgender-female and three gender non-conforming. There were no differences in the proportion of participants with grade ≥2 genitourinary AEs in the TFV versus placebo arms (p = 0.41); no grade ≥3 AEs were reported. Geometric mean TFV concentrations increased through day 34 in CVF/rectal fluid and day 59 in plasma, but declined across compartments by day 91. Geometric mean TFV-DP tissue concentrations exceeded the 1000 fmol/mg target through day 56, but fell to 456 fmol/mg at day 91. Among 32 rings returned at the end of the study, 13 had no or low (<0.1 g) residual TFV. Residual TFV did not differ by socio-demographics, sexual activity, Nugent Score or vaginal microbiota. Most participants reported being fully adherent to ring use: 85% and 81% in the TFV and placebo arms, respectively (p = 1.00). A majority of participants reported liking the ring (median 8 on a 10-point Likert scale) and reported a high likelihood of using the ring in the future, if effective (median 9)., Conclusions: The 90-day TFV ring was well-tolerated, acceptable and exceeded target cervical tissue concentrations through day 56, but declined thereafter. Additional studies are needed to characterize the higher release from TFV rings in some participants and the optimal duration of use., (© 2024 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Given challenges with adherence to existing HIV prevention products, the development of an extended duration vaginal ring could improve adherence while reducing patient and provider burden. Additionally, women have other interlinked sexual health concerns such as unintended pregnancy. We evaluated acceptability of a 90-day ring to prevent HIV and hypothetical preferences for a dual (HIV and contraceptive) indication. This was a secondary analysis of a Phase 1, two-arm, multi-site, placebo-controlled randomized trial evaluating safety and pharmacokinetics of a 90-day vaginal ring containing tenofovir for HIV prevention (N = 49). We used a mixed methods approach to assess quantitative data on acceptability (n = 49) and used qualitative data from a random subset to explain the quantitative findings (N = 25). The 3-month extended duration tenofovir ring was highly acceptable. Participants perceived the ring to be easy to use, comfortable and reported liking it more over time. About half felt the ring during sex but most of those participants said it bothered them only a little. Concerns about hygiene increased over the study period but were often outweighed by the benefits of an extended duration ring. Interest in a multi-purpose ring was high (77%) and even higher among those who were sexually active and had male partners. The 3-month extended duration tenofovir ring for HIV prevention was highly acceptable among women and interest in an MPT was high., Competing Interests: Dr. Chen receives research grants from Medicines360 and Sebela, which are all managed by Magee-Womens Research Institute. All other authors declare no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: As daily oral preexposure prophylaxis (PrEP) becomes standard for HIV prevention, routine use of PrEP is likely to increase within clinical trials of novel preventive agents. We describe the prevalence and characteristics of participants reporting nonstudy oral PrEP use within Microbicide Trials Network-017 (MTN-017), a phase 2 trial of a rectal microbicide., Setting and Methods: One hundred ninety-five HIV-uninfected men who have sex with men and transgender women were enrolled and followed in MTN-017 across 8 sites in the United States, Thailand, South Africa, and Peru from 2013 to 2015. Nonstudy oral PrEP use was recorded on case report forms and progress notes. Characteristics of PrEP users and non-PrEP users were compared using tests of statistical significance., Results: Overall, 11% of participants reported nonstudy oral PrEP use, all from the San Francisco (SF) site, accounting for 58% (22/38) of participants enrolled in SF. There was a higher median number of sex partners reported in the past 8 weeks before enrollment among oral PrEP users vs. nonusers (7 vs. 2, P = 0.02). Most PrEP users (18/22, 82%) began PrEP treatment during screening/after enrollment, and most (19/22, 86%) decided to continue oral PrEP after study completion., Conclusion: Nonstudy oral PrEP use in the first phase 2 study of tenofovir reduced-glycerin 1% gel was high at a single site in SF where community PrEP availability and use was expanding. Investigators should consider the evolving context of nonstudy oral PrEP use across trial sites when designing and interpreting trials of novel biomedical prevention modalities.

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., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Evidence is lacking regarding whether vaginal pre-exposure prophylaxis with topical tenofovir (TFV) reduces the risk of rectal HIV acquisition., Setting: Bronx, NY., Methods: MTN-014 was a phase 1, cross-over, randomized sequence trial comparing the cross-compartment pharmacokinetics and pharmacodynamics of daily TFV reduced-glycerin 1% gel after 14 days each of rectal and vaginal application, with directly observed dosing and a 6-week washout period between phases., Results: Fourteen HIV-uninfected women enrolled; 91% of doses were observed and 13 women completed all study procedures. TFV and TFV diphosphate (TFV-DP) were detected in most samples collected from the dosing compartment. After vaginal dosing, TFV was detected in 10/14 samples of rectal fluid (RF) (median 4.4 ng/sponge) and 1/13 rectal tissue samples (0.2 ng/mg); TFV-DP was detected in 2/13 rectal tissue samples at 59.8 and 76.5 fmol/mg. After rectal dosing, TFV was detected in 9/14 samples of vaginal fluid (median 1.1 ng/swab) and in 6/14 vaginal tissue samples (median below limit of quantification); TFV-DP was detected in 3/14 vaginal tissue samples at 17.3, 87.6, and 77.1 fmol/mg. Neither cervicovaginal lavage fluid nor RF collected 24 hours after rectal or vaginal dosing resulted in a statistically significant suppression of viral replication., Conclusions: In this study of 14 days each of vaginal and rectal application of TFV reduced-glycerin 1% gel, we found only a small degree of cross-compartment distribution of TFV in RF and vaginal fluids and no pharmacodynamic activity in ex vivo testing. Although high TFV concentrations in the dosing compartment may be protective, low cross-compartment tissue concentrations are not likely to be protective.

The MTN-008 trial was the first multi-dose study conducted to evaluate the safety of a microbicide gel (2:1 randomized to tenofovir 1% or hydroxycellulose (HEC) placebo gel) during pregnancy. The study aim was to evaluate safety, tolerability and pharmacokinetics of the study products. Procedures included daily gel administration, with Day 0 and Day 6 in clinic, and Days 1-5 at home. Because pregnancy may pose unique challenges to consistent gel use and acceptability, evaluation of adherence and acceptability was a secondary objective of the trial. The study enrolled healthy, HIV-negative, pregnant women aged 18-40 in Pittsburgh, PA and Birmingham, AL, USA in 2 consecutive groups: cohort 1 was 37-39 weeks gestation, cohort 2 was 34-36 weeks. Ninety-one women completed the study (45 and 46 in each cohort, respectively) and were evaluable per protocol. Adherence was evaluated using self-reports: participants completed a web-based computer-assisted self-interview (CASI) at Days 0 and 6 about gel attitudes and behaviors. At Day 6 trained research staff conducted a short interviewer-administered questionnaire with both structured and open-ended questions. Frequencies of quantitative data were tabulated in SAS and descriptive statistics are presented; open-ended textual data were summarized by a behavioral scientist experienced in qualitative analysis. Participants reported generally neutral perceptions of gel characteristics. A small number of women (7-8%) reported pain (6/90), other physical discomfort (7/90), or mental discomfort (7/90) associated with the process of applicator insertion. About 5% reported the same for the gel itself. Two-thirds (61/90) thought the gel was runny, many complained of bothersome gel leakage and several cited this reason for not inserting a full dose. The majority were not worried the gel would cause problems for their pregnancy or babies. Ninety-seven percent (83/86) said they would use the gel in the future if they were pregnant, and 90% (81/90) when nonpregnant. Self-reported adherence was high with 88% (79/90) reporting daily gel use on both the computerized and interviewer-administered questionnaires. The majority (67/90) reported no difficulty with daily use. However, drug was undetectable (<0.31 ng/mL) among 45% (27/60; 95% CI 32-58%) of the women on active product prior to observed dosing at Day 6. The most common reason for reported nonuse (N = 6) was forgetting. Study gel was generally acceptable, but many complained of a runny consistency (61/90) and leakage (83/90). No frequent or strong concerns about the effects of the study gel on the pregnancy/fetus were reported. Self-reported adherence to study gel self-administered at home for 5 days was high, however plasma drug levels suggest actual use may have been considerably lower. Findings from this study can provide insights relevant to use of other antiretroviral-based, vaginally-inserted HIV prevention methods during pregnancy.

Oral pre-exposure prophylaxis (PrEP) can prevent HIV transmission. Yet, some may prefer not to take systemic daily medication. MTN-017 was a 3-period, phase 2 safety and acceptability study of microbicide gel applied rectally either daily or before and after receptive anal intercourse (RAI), compared to daily oral tablet. At baseline, cisgender men and transgender women who reported RAI (N = 187) rated the daily oral regimen higher in overall liking, ease of use, and likelihood of future use than the gel regimens. After trying all three, 28% liked daily oral the least. Gel did not affect sexual enjoyment (88%) or improved it (7-8%). Most partners had no reaction to gel use. Ease of gel use improved significantly between the first and the last few times of daily use. A rectal gel used before and after RAI may constitute an attractive alternative to daily tablet. Experience with product use may increase acceptability.

Trials to assess microbicide safety require strict adherence to prescribed regimens. If adherence is suboptimal, safety cannot be adequately assessed. MTN-017 was a phase 2, randomized sequence, open-label, expanded safety and acceptability crossover study comparing 1) daily oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), 2) daily use of reduced-glycerin 1% tenofovir (RG-TFV) gel applied rectally, and 3) RG-TFV gel applied before and after receptive anal intercourse (RAI)-if participants had no RAI in a week, they were asked to use two doses of gel within 24 hours. Product use was assessed by mixed methods including unused product return count, text messaging reports, and qualitative plasma TFV pharmacokinetic (PK) results. Convergence interviews engaged participants in determining the most accurate number of doses used based on product count and text messaging reports. Client-centered adherence counseling was also used. Participants (N = 187) were men who have sex with men and transgender women enrolled in the United States (42%), Thailand (29%), Peru (19%) and South Africa (10%). Mean age was 31.4 years (range 18-64 years). Based on convergence interviews, over an 8-week period, 94% of participants had ≥80% adherence to daily tablet, 41% having perfect adherence; 83% had ≥80% adherence to daily gel, 29% having perfect adherence; and 93% had ≥80% adherence to twice-weekly use during the RAI-associated gel regimen, 75% having perfect adherence and 77% having ≥80% adherence to gel use before and after RAI. Only 4.4% of all daily product PK results were undetectable and unexpected (TFV concentrations <0.31 ng/mL) given self-reported product use near sampling date. The mixed methods adherence measurement indicated high adherence to product use in all three regimens. Adherence to RAI-associated rectal gel use was as high as adherence to daily oral PrEP. A rectal microbicide gel, if efficacious, could be an alternative for individuals uninterested in daily oral PrEP.

Background: Human immunodeficiency virus (HIV) disproportionately affects men who have sex with men (MSM) and transgender women (TGW). Safe and acceptable topical HIV prevention methods that target the rectum are needed., Methods: MTN-017 was a phase 2, 3-period, randomized sequence, open-label, expanded safety and acceptability crossover study comparing rectally applied reduced-glycerin (RG) 1% tenofovir (TFV) and oral emtricitabine/TFV disoproxil fumarate (FTC/TDF). In each 8-week study period 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., Results: MSM and TGW (n = 195) were enrolled from 8 sites in the United States, Thailand, Peru, and South Africa with mean age of 31.1 years (range 18-64). There were no differences in ≥grade 2 adverse event rates between daily gel (incidence rate ratio [IRR], 1.09; P = .59) or RAI gel (IRR, 0.90; P = .51) compared to FTC/TDF. High adherence (≥80% of prescribed doses assessed by unused product return and Short Message System reports) was less likely in the daily gel regimen (odds ratio [OR], 0.35; P < .001), and participants reported less likelihood of future daily gel use for HIV protection compared to FTC/TDF (OR, 0.38; P < .001)., Conclusions: Rectal application of RG TFV gel was safe in MSM and TGW. Adherence and product use likelihood were similar for the intermittent gel and daily oral FTC/TDF regimens, but lower for the daily gel regimen., Clinical Trials Registration: NCT01687218., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

VOICE-a phase 2B, placebo-controlled, randomized trial testing daily use of an antiretroviral tablet (tenofovir or Truvada) or daily use of tenofovir gel in 5029 women from South Africa, Uganda, and Zimbabwe-found none of the drug regimens effective in reducing HIV-1 acquisition in the intent-to-treat analysis. More than half of women assigned to active products in a case cohort sample had no drug detected in any plasma specimens tested during the trial. Yet, in response to questions asked of participants during the trial, ≥90 % of doses were reportedly taken. To explore factors associated with low adherence, a behavioral termination visit questionnaire was developed after early closure of the oral tenofovir and vaginal gel arms. We hypothesized that participants would be more forthcoming about nonuse after they exited the trial than during monthly/quarterly follow-up visits. Comparison of adherence reporting at routine follow-up visits with reporting at trial termination, however, indicates that disclosure of product nonadherence did not increase at the termination visit as anticipated. In resource-limited settings where women value the ancillary benefits provided by trial participation and are concerned that disclosure of nonuse may jeopardize trial participation, objective measures of adherence may yield more meaningful data regarding the inability or reluctance to use than measures of product use derived from self-report.

Lactation studies are necessary evaluations of medications for reproductive-age women. We evaluated pharmacokinetics (PK), pharmacodynamics, safety, and adherence profiles associated with 7 days of 1% tenofovir (TFV) vaginal gel use during lactation. Tenofovir levels (maternal/infant serum, milk) and anti-HIV activity (milk), adverse events (AEs), and adherence were measured for 17 HIV-1-seronegative breast-feeding mother-infant pairs. Tenofovir use was well-tolerated and detected at low levels in maternal serum, milk, and infant serum but demonstrated no anti-HIV activity in milk., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Background: Limited data exist on effect of tenofovir disoproxil fumarate (TDF) when used for preexposure prophylaxis (PrEP) on bone mineral density (BMD) in HIV-negative women. We evaluated the effect of daily oral TDF and emtricitabine/TDF compared with placebo on BMD among women enrolled in an HIV-1 PrEP trial., Methods: HIV-uninfected women in Uganda and Zimbabwe had BMD measurements of lumbar spine (LS) and total hip (TH) by dual-energy x-ray absorptiometry at baseline and every 24 weeks for 48 weeks of active treatment and for 48 weeks after discontinuation of study medication. Plasma tenofovir levels were assessed every 12 weeks for the first 48 weeks., Results: Of 518 women enrolled, 432 had dual-energy x-ray absorptiometry results at baseline and week 48. In the primary analysis, no significant differences in percent BMD change in hip or spine between arms observed, likely because of low product adherence. Among the subset with tenofovir detection in 75%-100% of plasma samples, the mean percent BMD change from baseline to week 48 in the LS was 1.4% lower for TDF or emtricitabine/TDF recipients than for placebo (P = 0.002) and TH BMD was 0.9% lower (P = 0.018). BMD changes from end of active treatment to 48 weeks were significantly greater in the active arm participants compared with placebo participants with a net difference of approximately +0.9% at the LS (P = 0.007) and +0.7% (P = 0.003) at the TH., Conclusions: TDF-containing oral PrEP resulted in small but significant reversible decreases in hip and spine BMD among young African women.

Introduction: In the Microbicide Trial Network MTN-003 (VOICE) study, a Phase IIB pre-exposure prophylaxis trial of daily oral or vaginal tenofovir (TFV), product adherence was poor based on pharmacokinetic (PK) drug detection in a random subsample. Here, we sought to compare behavioural and PK measures of adherence and examined correlates of adherence misreporting., Methods: We included participants with PK and behavioural data from VOICE random subsample. Behavioural assessments included face-to-face interviews (FTFI), audio computer-assisted self-interviewing (ACASI) and pharmacy-returned product counts (PC). TFV concentrations < 0.31 ng/mL in plasma (oral group) and < 8.5 ng/swab in vaginal group were defined as "PK non-adherent." Logistic regression models were fit to calculate the combined predictive ability of the behavioural measures as summarized by area under the curve (AUC). Baseline characteristics associated with over-reporting daily product use relative to PK measures was assessed using a Generalized Linear Mixed Model., Results: In this random adherence cohort of VOICE participants assigned to active products, (N = 472), PK non-adherence was 69% in the oral group (N = 314) and 65% in the vaginal group (N = 158). Behaviourally, ≤ 10% of the cohort reported low/none use with any behavioural measure and accuracy was low (≤ 43%). None of the regression models had an AUC > 0.65 for any single or combined behavioural measures. Significant (p < 0.05) correlates of over-reporting included being very worried about getting HIV and being unmarried for the oral group; whereas for the vaginal group, being somewhat worried about HIV was associated with lower risk of over-reporting., Conclusions: PK measures indicated similarly low adherence for the oral and vaginal groups. No behavioural measure accurately predicted PK non-adherence. Accurate real-time measures to monitor product adherence are urgently needed., Trial Registration: ClinicalTrials.gov identifier: NCT00705679.

Background: Tenofovir (TFV) gel partially protected against human immunodeficiency virus (HIV) in one but not subsequent trials. The disappointing results were attributed largely to poor adherence. However, timing of gel application relative to sex may impact pharmacokinetics and contribute to outcomes. Thus, we conducted a single-dose pharmacokinetic study of TFV gel applied 1 or 24 hours before or 1 hour before and 1 hour after (BAT) sex and compared results with dosing without sex., Methods: Twenty-four couples were enrolled; cervicovaginal lavage (CVL) and tissue were collected 2 hours after sex with matching timed collections at no sex visits and assayed for drug concentrations and CVL anti-HIV activity., Results: Compared with dosing without sex, median TFV concentrations after sex decreased 72% and 78% (P < .001) in CVL, 75% and 71% (P < .001) in vaginal tissue, and 75% (P = .06) and 55% (P < .001) in cervical tissue with -1 hour and -24 hour dosing, respectively. Median concentration of TFV-diphosphate also decreased significantly in cervical tissue with -1 hour, dosing. BAT dosing resulted in drug levels at least as great as those in the absence of sex. Percent inhibition of HIV infection by post-coital CVL increased significantly from median (interquartile range) of 55% (54%) in the absence of gel to 99% (7%), 77% (57%), and 100% (0.4%) with -1 hour, -24 hour, or BAT dosing, respectively, and correlated significantly with drug concentration., Conclusions: Timing of TFV gel application relative to sex significantly impacts drug levels. BAT dosing or sustained delivery may be optimal for preexposure prophylaxis., (© 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.)

Objectives: In VOICE, a phase IIB trial of daily oral and vaginal tenofovir for HIV prevention, at least 50% of women receiving active products had undetectable tenofovir in all plasma samples tested. MTN-003D, an ancillary study using in-depth interviews (IDIs) and focus group discussions (FGDs), together with retrospective disclosure of plasma tenofovir pharmacokinetic results, explored adherence challenges during VOICE., Methods: We systematically recruited participants with pharmacokinetic data (median six plasma samples), categorized as low (0%, N = 79), inconsistent (1-74%, N = 28) or high (≥75%; N = 20) on the basis of frequency of tenofovir detection. Following disclosure of pharmacokinetic results, reactions were captured and adherence challenges systematically elicited; IDIs and FGDs were audio-recorded, transcribed, coded and thematically analysed., Results: We interviewed 127 participants from South Africa, Uganda and Zimbabwe. The most common reactions to pharmacokinetic results included surprise (41%; low pharmacokinetic), acceptance (39%; inconsistent pharmacokinetic) and happiness (65%; high pharmacokinetic). On the basis of participants' explanations, we developed a typology of adherence patterns: noninitiation, discontinuation, misimplementation (resulting from visit-driven use, variable taking, modified dosing or regimen) and adherence. Fear of product side effects/harm was a frequent concern, fuelled by stories shared among participants. Although women with high pharmacokinetic levels reported similar concerns, several described strategies to overcome challenges. Women at all pharmacokinetic levels suggested real-time drug monitoring and feedback to improve adherence and reporting., Conclusion: Retrospective provision of pharmacokinetic results seemingly promoted candid discussions around nonadherence and study participation. The effect of real-time drug monitoring and feedback on adherence and accuracy of reporting should be evaluated in trials.

Tenofovir gel is being evaluated for vaginal and rectal pre-exposure prophylaxis against HIV transmission. Because this is a new prevention strategy, we broadly assessed its effects on the mucosa. In MTN-007, a phase-1, randomized, double-blinded rectal microbicide trial, we used systems genomics/proteomics to determine the effect of tenofovir 1% gel, nonoxynol-9 2% gel, placebo gel or no treatment on rectal biopsies (15 subjects/arm). We also treated primary vaginal epithelial cells from four healthy women with tenofovir in vitro. After seven days of administration, tenofovir 1% gel had broad-ranging effects on the rectal mucosa, which were more pronounced than, but different from, those of the detergent nonoxynol-9. Tenofovir suppressed anti-inflammatory mediators, increased T cell densities, caused mitochondrial dysfunction, altered regulatory pathways of cell differentiation and survival, and stimulated epithelial cell proliferation. The breadth of mucosal changes induced by tenofovir indicates that its safety over longer-term topical use should be carefully monitored.

BackgroundLimited data exist on effect of tenofovir disoproxil fumarate (TDF) when used for preexposure prophylaxis (PrEP) on bone mineral density (BMD) in HIV-negative women. We evaluated the effect of daily oral TDF and emtricitabine/TDF compared with placebo on BMD among women enrolled in an HIV-1 PrEP trial.MethodsHIV-uninfected women in Uganda and Zimbabwe had BMD measurements of lumbar spine (LS) and total hip (TH) by dual-energy x-ray absorptiometry at baseline and every 24 weeks for 48 weeks of active treatment and for 48 weeks after discontinuation of study medication. Plasma tenofovir levels were assessed every 12 weeks for the first 48 weeks.ResultsOf 518 women enrolled, 432 had dual-energy x-ray absorptiometry results at baseline and week 48. In the primary analysis, no significant differences in percent BMD change in hip or spine between arms observed, likely because of low product adherence. Among the subset with tenofovir detection in 75%-100% of plasma samples, the mean percent BMD change from baseline to week 48 in the LS was 1.4% lower for TDF or emtricitabine/TDF recipients than for placebo (P = 0.002) and TH BMD was 0.9% lower (P = 0.018). BMD changes from end of active treatment to 48 weeks were significantly greater in the active arm participants compared with placebo participants with a net difference of approximately +0.9% at the LS (P = 0.007) and +0.7% (P = 0.003) at the TH.ConclusionsTDF-containing oral PrEP resulted in small but significant reversible decreases in hip and spine BMD among young African women.

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 < .001). All three routes of pre-exposure prophylaxis (PrEP) administration resulted in the inhibition of explant infection (p < .05), and there was a significant inverse correlation between explant HIV-1 p24 and tissue concentrations of TFV and FTC (p < .0001). Despite significant differences in systemic and mucosal drug concentrations, all three PrEP regimens were able to protect rectal explants from ex vivo HIV infection. These data suggest that there is a rationale for co-development of oral and topical antiretroviral PrEP for HIV prevention. Clinical Trial Registration number: NCT01687218. [ABSTRACT FROM AUTHOR]

Introduction: Vaginal tenofovir (TFV) 1% gel may reduce incident HIV-1 and herpes simplex virus 2 infection. Pregnancy may increase risk of HIV acquisition, and incident HIV in pregnancy potentiates perinatal HIV transmission. Our objective was to investigate the safety and pharmacokinetics of seven days of TFV 1% vaginal gel in term and near-term pregnancy.Methods: Ninety-eight healthy pregnant women, stratified to a term cohort followed by a near-term cohort, were enrolled into a 2:1 randomized, double-blinded, placebo-controlled trial. Women received TFV or placebo gel for seven consecutive days with pharmacokinetic sampling on days 0 and 6. Maternal and cord blood were collected at delivery. Primary end points included laboratory and genital adverse events, adverse pregnancy and neonatal outcomes, and maternal TFV levels.Results: Most adverse events were grade 1 and none of the grade 3 or 4 adverse events were related to study product. There was no significant difference in safety end points between the two pregnancy cohorts (p=0.18); therefore, their data were combined. Primary safety end point rates were similar for mothers randomized to the TFV gel vs placebo arm (72.7 and 68.8%, p=0.81). The same was true for newborns in the TFV gel vs placebo arms (4.5% vs 6.3%, p=0.66). All women randomized to TFV had quantifiable serum levels within eight hours of dosing, with low overall median (interquartile range) day 0 and day 6 peak values (3.8 (2.0 to 7.0) and 5.8 (2.6 to 9.4) ng/mL, respectively).Conclusions: Daily TFV 1% vaginal gel use in term and near-term pregnancy appears to be safe and produces low serum drug levels. [ABSTRACT FROM AUTHOR]

Introduction: In the Microbicide Trial Network MTN-003 (VOICE) study, a Phase IIB pre-exposure prophylaxis trial of daily oral or vaginal tenofovir (TFV), product adherence was poor based on pharmacokinetic (PK) drug detection in a random subsample. Here, we sought to compare behavioural and PK measures of adherence and examined correlates of adherence misreporting. Methods: We included participants with PK and behavioural data from VOICE random subsample. Behavioural assessments included face-to-face interviews (FTFI), audio computer-assisted self-interviewing (ACASI) and pharmacy-returned product counts (PC). TFV concentrations <0.31 ng/mL in plasma (oral group) and <8.5 ng/swab in vaginal group were defined as ''PK non-adherent.'' Logistic regression models were fit to calculate the combined predictive ability of the behavioural measures as summarized by area under the curve (AUC). Baseline characteristics associated with over-reporting daily product use relative to PK measures was assessed using a Generalized Linear Mixed Model. Results: In this random adherence cohort of VOICE participants assigned to active products, (N=472), PK non-adherence was 69% in the oral group (N=314) and 65% in the vaginal group (N=158). Behaviourally, ≤10% of the cohort reported low/none use with any behavioural measure and accuracy was low (≤43%). None of the regression models had an AUC >0.65 for any single or combined behavioural measures. Significant (p<0.05) correlates of over-reporting included being very worried about getting HIV and being unmarried for the oral group; whereas for the vaginal group, being somewhat worried about HIV was associated with lower risk of over-reporting. Conclusions: PK measures indicated similarly low adherence for the oral and vaginal groups. No behavioural measure accurately predicted PK non-adherence. Accurate real-time measures to monitor product adherence are urgently needed. Trial registration: ClinicalTrials.gov identifier: NCT00705679 [ABSTRACT FROM AUTHOR]

Objective: Rectal microbicides are needed to reduce the risk of HIV acquisition associated with unprotected receptive anal intercourse. The MTN-007 study was designed to assess the safety (general and mucosal), adherence, and acceptability of a new reduced glycerin formulation of tenofovir 1% gel. Methods: Participants were randomized 1∶1:1∶1 to receive the reduced glycerin formulation of tenofovir 1% gel, a hydroxyethyl cellulose placebo gel, a 2% nonoxynol-9 gel, or no treatment. Each gel was administered as a single dose followed by 7 daily doses. Mucosal safety evaluation included histology, fecal calprotectin, epithelial sloughing, cytokine expression (mRNA and protein), microarrays, flow cytometry of mucosal T cell phenotype, and rectal microflora. Acceptability and adherence were determined by computer-administered questionnaires and interactive telephone response, respectively. Results: Sixty-five participants (45 men and 20 women) were recruited into the study. There were no significant differences between the numbers of ≥ Grade 2 adverse events across the arms of the study. Likelihood of future product use (acceptability) was 87% (reduced glycerin formulation of tenofovir 1% gel), 93% (hydroxyethyl cellulose placebo gel), and 63% (nonoxynol-9 gel). Fecal calprotectin, rectal microflora, and epithelial sloughing did not differ by treatment arms during the study. Suggestive evidence of differences was seen in histology, mucosal gene expression, protein expression, and T cell phenotype. These changes were mostly confined to comparisons between the nonoxynol-9 gel and other study arms. Conclusions: The reduced glycerin formulation of tenofovir 1% gel was safe and well tolerated rectally and should be advanced to Phase 2 development. Trial Registration: ClinicalTrials.gov NCT01232803. [ABSTRACT FROM AUTHOR]

Tenofovir (TFV) 1% vaginal gel has been found to decrease sexual transmission of human immunodeficiency virus. To initiate investigations during pregnancy, 16 healthy pregnant women scheduled for cesarean delivery received a single application of TFV gel preoperatively. Maternal serum drug concentrations were determined and fetal cord blood, amniotic fluid, placental tissue, and endometrial tissue specimens were collected. The median maternal peak concentration and cord blood TFV concentrations were 4.3 and 1.9 ng/mL, respectively (∼100- and 40-fold lower than after TFV oral dosing, respectively). No adverse events were related to the use of TFV gel. These findings support ongoing and future investigations of TFV gel in pregnancy. [ABSTRACT FROM AUTHOR]

The article discusses research which examined preexposure prophylaxis against HIV-1 infection in women in Africa. Topics covered include the use of oral tenofovir disoproxil fumarate, oral tenofovir-emtricitabine or tenofovir vaginal gel in patients, the incidence of HIV-1 infection among study participants and the elevations of serum creatinine levels among participants.