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First Phase 1 Double-Blind, Placebo-Controlled, randomized rectal microbicide trial using UC781 gel with a novel index of ex vivo efficacy

Anton, PA and Saunders, T and Elliott, J and Khanukhova, E and Dennis, R and Adler, A and Cortina, G and Tanner, K and Boscardin, J and Cumberland, WG and Zhou, Y and Ventuneac, A and Carballo-Diéguez, A and Rabe, L and McCormick, T and Gabelnick, H and Mauck, C and McGowan, I (2011) First Phase 1 Double-Blind, Placebo-Controlled, randomized rectal microbicide trial using UC781 gel with a novel index of ex vivo efficacy. PLoS ONE, 6 (9).

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Objectives: 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. Methods: 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. Results: 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. Conclusions: 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; #NCT00408538). © 2011 Anton et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Anton, PA
Saunders, T
Elliott, J
Khanukhova, E
Dennis, R
Adler, A
Cortina, G
Tanner, K
Boscardin, J
Cumberland, WG
Zhou, Y
Ventuneac, A
Carballo-Diéguez, A
Rabe, L
McCormick, T
Gabelnick, H
Mauck, C
McGowan, Iimcgowan@pitt.eduIMCGOWAN
ContributionContributors NameEmailPitt UsernameORCID
Date: 28 September 2011
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 6
Number: 9
DOI or Unique Handle: 10.1371/journal.pone.0023243
Refereed: Yes
MeSH Headings: Administration, Rectal; Adult; Anilides--therapeutic use; Anti-Infective Agents--therapeutic use; Biopsy; Endoscopy--methods; Female; Furans--therapeutic use; Gels; HIV Infections--prevention & control; HIV Infections--virology; HIV Seronegativity; Humans; Male; Middle Aged; Placebos; Rectum--microbiology; Rectum--pathology; Time Factors
Other ID: NLM PMC3182160
PubMed Central ID: PMC3182160
PubMed ID: 21969851
Date Deposited: 05 Sep 2012 20:04
Last Modified: 22 Jun 2021 13:56


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