title: 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.
authors.affiliation: 1 Department of Medicine (Clinical Pharmacology), The Johns Hopkins University School of Medicine , Baltimore, Maryland.
authors.forename: Francisco
authors.initials: F
authors.lastname: Leyva
authors.affiliation: 1 Department of Medicine (Clinical Pharmacology), The Johns Hopkins University School of Medicine , Baltimore, Maryland.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Fuchs
authors.affiliation: 1 Department of Medicine (Clinical Pharmacology), The Johns Hopkins University School of Medicine , Baltimore, Maryland.
authors.forename: Rahul
authors.initials: R
authors.lastname: Bakshi
authors.affiliation: 2 Department of Medicine (Gastroenterology), The Johns Hopkins University School of Medicine , Baltimore, Maryland.
authors.forename: Alex
authors.initials: A
authors.lastname: Carballo-Dieguez
authors.affiliation: 2 Department of Medicine (Gastroenterology), The Johns Hopkins University School of Medicine , Baltimore, Maryland.
authors.forename: Ana
authors.initials: A
authors.lastname: Ventuneac
authors.affiliation: 3 Department of Biostatistics, The Johns Hopkins University Bloomberg School of Public Health , Baltimore, Maryland.
authors.forename: Chen
authors.initials: C
authors.lastname: Yue
authors.affiliation: 3 Department of Biostatistics, The Johns Hopkins University Bloomberg School of Public Health , Baltimore, Maryland.
authors.forename: Brian
authors.initials: B
authors.lastname: Caffo
authors.affiliation: 4 Department of Radiology, The Johns Hopkins University School of Medicine , Baltimore, Maryland.
authors.forename: Yong
authors.initials: Y
authors.lastname: Du
authors.affiliation: 5 Department of Pathology, Mayo Clinic , Rochester, Minnesota.
authors.forename: Michael
authors.initials: M
authors.lastname: Torbenson
authors.affiliation: 1 Department of Medicine (Clinical Pharmacology), The Johns Hopkins University School of Medicine , Baltimore, Maryland.
authors.forename: Liye
authors.initials: L
authors.lastname: Li
authors.affiliation: 6 HIV Center for Clinical and Behavioral Studies, Columbia University , New York, New York.
authors.forename: Gerald
authors.initials: G
authors.lastname: Mullin
authors.affiliation: 6 HIV Center for Clinical and Behavioral Studies, Columbia University , New York, New York.
authors.forename: Linda
authors.initials: L
authors.lastname: Lee
authors.affiliation: 7 Magee Womens Research Institute, University of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Lisa
authors.initials: L
authors.lastname: Rohan
authors.affiliation: 8 UCLA Center for HIV Prevention Research, UCLA AIDS Institute , Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Anton
authors.affiliation: 1 Department of Medicine (Clinical Pharmacology), The Johns Hopkins University School of Medicine , Baltimore, Maryland.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Hendrix
mesh_terms: D000285:Administration, Rectal; D000328:Adult; D000890:Anti-Infective Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D003106:Colon / Q000473:pathology; D018592:Cross-Over Studies; D018562:Disease Transmission, Infectious / Q000517:prevention & control*; D005260:Female; D015658:HIV Infections / Q000517:prevention & control*; D006651:Histocytochemistry; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010342:Patient Acceptance of Health Care; D065129:Pre-Exposure Prophylaxis / Q000379:methods*
chemical_list: D000890:Anti-Infective Agents