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Simultaneous Evaluation of Safety, Acceptability, Pericoital Kinetics, and Ex Vivo Pharmacodynamics Comparing Four Rectal Microbicide Vehicle Candidates.

ABSTRACT: Preexposure prophylaxis (PrEP) of HIV infection with tenofovir-containing regimens is effective, but plagued by poor adherence in some studies. Options for safe, effective, and acceptable PrEP products, especially for men and women at risk of HIV via receptive anal intercourse (RAI), are needed. We performed a randomized, partially blinded, first-in-human evaluation of four candidate rectal microbicide vehicles-aqueous gel, aqueous fluid, lipid gel, and lipid fluid-to select a prototype for further clinical development. Eight seronegative participants received three doses of each product with each dose separated by at least 2 weeks: one dose was given alone without simulated RAI in clinic, another dose was followed by simulated RAI in clinic, and another dose was self-administered at home in the context of RAI with a partner. Assessments included safety, acceptability, colon histology, ex vivo HIV infectivity of colon tissue explants, and colonic luminal distribution of vehicle and HIV surrogates. Adverse events were all mild and mainly sigmoidoscopy associated. There were minor differences in colon distribution of products and little effect of RAI. Vehicle distribution covered 95% (±7% standard deviation) of the distribution of an HIV surrogate in the colonic lumen. The lipid fluid vehicle increased HIV colon tissue infectability 5-fold [log10 p24 0.68 (95% confidence interval 0.08, 1.28)] and aqueous gel provided 6-fold protection [log10 p24 0.80 (95% confidence interval 0.20, 1.41)] compared to no product baseline. Colon permeability of lipid vehicles was more than 10-fold greater than aqueous vehicles. All products received similar acceptability ratings, though trends favored the gel products. Intensive simultaneous assessment of safety and toxicity, luminal and tissue distribution, ex vivo HIV infectivity, and product acceptability in relevant sexual contexts provided clear differentiation among candidate gels very early in product development. We selected the aqueous gel for further development as a rectal microbicide vehicle.

SUBMITTER: Leyva F

PROVIDER: S-EPMC4651043 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Project description:Successful control of the HIV/AIDS pandemic requires reduction of HIV-1 transmission at sexually-exposed mucosae. No prevention studies of the higher-risk rectal compartment exist. We report the first-in-field Phase 1 trial of a rectally-applied, vaginally-formulated microbicide gel with the RT-inhibitor UC781 measuring clinical and mucosal safety, acceptability and plasma drug levels. A first-in-Phase 1 assessment of preliminary pharmacodynamics was included by measuring changes in ex vivo HIV-1 suppression in rectal biopsy tissue after exposure to product in vivo.HIV-1 seronegative, sexually-abstinent men and women (N?=?36) were randomized in a double-blind, placebo-controlled trial comparing UC781 gel at two concentrations (0.1%, 0.25%) with placebo gel (1?1?1). Baseline, single-dose exposure and a separate, 7-day at-home dosing were assessed. Safety and acceptability were primary endpoints. Changes in colorectal mucosal markers and UC781 plasma drug levels were secondary endpoints; ex vivo biopsy infectibility was an ancillary endpoint.All 36 subjects enrolled completed the 7-14 week trial (100% retention) including 3 flexible sigmoidoscopies, each with 28 biopsies (14 at 10 cm; 14 at 30 cm). There were 81 Grade 1 adverse events (AEs) and 8 Grade 2; no Grade 3, 4 or procedure-related AEs were reported. Acceptability was high, including likelihood of future use. No changes in mucosal immunoinflammatory markers were identified. Plasma levels of UC781 were not detected. Ex vivo infection of biopsies using two titers of HIV-1(BaL) showed marked suppression of p24 in tissues exposed in vivo to 0.25% UC781; strong trends of suppression were seen with the lower 0.1% UC781 concentration.Single and 7-day topical rectal exposure to both concentrations of UC781 were safe with no significant AEs, high acceptability, no detected plasma drug levels and no significant mucosal changes. Ex vivo biopsy infections demonstrated marked suppression of HIV infectibility, identifying a potential early biomarker of efficacy. (Registered at ClinicalTrials.gov; #NCT00408538).

Project description:Efforts to develop a range of HIV prevention products that can serve as behaviorally congruent viable alternatives to consistent condom use and oral pre-exposure prophylaxis (PrEP) remain crucial. MTN-035 was a randomized crossover trial seeking to evaluate the safety, acceptability, and adherence to three placebo modalities (insert, suppository, enema) prior to receptive anal intercourse (RAI). If participants had no RAI in a week, they were asked to use their assigned product without sex. We hypothesized that the modalities would be acceptable and safe for use prior to RAI, and that participants would report high adherence given their behavioral congruence with cleansing practices (e.g., douches and/or enemas) and their existing use to deliver medications (e.g., suppositories; fast-dissolving inserts) via the rectum. Participants (N = 217) were sexual and gender minorities enrolled in five different countries (Malawi, Peru, South Africa, Thailand, and the United States of America). Mean age was 24.9 years (range 18-35 years). 204 adverse events were reported by 98 participants (45.2%); 37 (18.1%) were deemed related to the study products. The proportion of participants reporting "high acceptability" was 72% (95%CI: 65% - 78%) for inserts, 66% (95%CI: 59% - 73%) for suppositories, and 73% (95%CI: 66% - 79%) for enemas. The proportion of participants reporting fully adherent per protocol (i.e., at least one use per week) was 75% (95%CI: 69% - 81%) for inserts, 74% (95%CI: 68% - 80%) for suppositories, and 83% (95%CI: 77% - 88%) for enemas. Participants fully adherent per RAI-act was similar among the three products: insert (n = 99; 58.9%), suppository (n = 101; 58.0%) and enema (n = 107; 58.8%). The efficacy and effectiveness of emerging HIV prevention drug depends on safe and acceptable delivery modalities that are easy to use consistently. Our findings demonstrate the safety and acceptability of, and adherence to, enemas, inserts, and suppositories as potential modalities through which to deliver a rectal microbicide.

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Simultaneous Evaluation of Safety, Acceptability, Pericoital Kinetics, and Ex Vivo Pharmacodynamics Comparing Four Rectal Microbicide Vehicle Candidates.

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