PMID- 21969851
OWN - NLM
STAT- MEDLINE
DCOM- 20120413
LR  - 20240317
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 6
IP  - 9
DP  - 2011
TI  - First phase 1 double-blind, placebo-controlled, randomized rectal microbicide 
      trial using UC781 gel with a novel index of ex vivo efficacy.
PG  - e23243
LID - 10.1371/journal.pone.0023243 [doi]
LID - e23243
AB  - 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 (1ratio1ratio1). 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 ClinicalTrials.gov; 
      #NCT00408538).
FAU - Anton, Peter A
AU  - Anton PA
AD  - Center for HIV Prevention Research, UCLA AIDS Institute, Department of Medicine, 
      David Geffen School of Medicine at the University of California Los Angeles, Los 
      Angeles, California, United States of America. panton@mednet.ucla.edu
FAU - Saunders, Terry
AU  - Saunders T
FAU - Elliott, Julie
AU  - Elliott J
FAU - Khanukhova, Elena
AU  - Khanukhova E
FAU - Dennis, Robert
AU  - Dennis R
FAU - Adler, Amy
AU  - Adler A
FAU - Cortina, Galen
AU  - Cortina G
FAU - Tanner, Karen
AU  - Tanner K
FAU - Boscardin, John
AU  - Boscardin J
FAU - Cumberland, William G
AU  - Cumberland WG
FAU - Zhou, Ying
AU  - Zhou Y
FAU - Ventuneac, Ana
AU  - Ventuneac A
FAU - Carballo-Dieguez, Alex
AU  - Carballo-Dieguez A
FAU - Rabe, Lorna
AU  - Rabe L
FAU - McCormick, Timothy
AU  - McCormick T
FAU - Gabelnick, Henry
AU  - Gabelnick H
FAU - Mauck, Christine
AU  - Mauck C
FAU - McGowan, Ian
AU  - McGowan I
LA  - eng
SI  - ClinicalTrials.gov/NCT00408538
GR  - P30 AI028697/AI/NIAID NIH HHS/United States
GR  - P30 MH043520/MH/NIMH NIH HHS/United States
GR  - U19 AI060614/AI/NIAID NIH HHS/United States
GR  - AI28697/AI/NIAID NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110928
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Anilides)
RN  - 0 (Anti-Infective Agents)
RN  - 0 (Furans)
RN  - 0 (Gels)
RN  - 0 (Placebos)
RN  - 0 (Thioamides)
RN  - L7K247H29H (UC-781)
SB  - IM
MH  - Administration, Rectal
MH  - Adult
MH  - Anilides/*therapeutic use
MH  - Anti-Infective Agents/*therapeutic use
MH  - Biopsy
MH  - Endoscopy/methods
MH  - Female
MH  - Furans/*therapeutic use
MH  - Gels
MH  - HIV Infections/*prevention & control/virology
MH  - HIV Seronegativity
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Placebos
MH  - Rectum/microbiology/pathology
MH  - Thioamides
MH  - Time Factors
PMC - PMC3182160
COIS- Competing Interests: The following authors have the following competing 
      interests: 1) Financial: Paid employment by CONRAD: Tim McCormick, Christine 
      Mauck, Henry Gabelnick. 2) Own stock or shares in CONRAD: None. This affiliation 
      does not affect the authors' adherence to all PLoS ONE policies on sharing data 
      and materials.
EDAT- 2011/10/05 06:00
MHDA- 2012/04/14 06:00
PMCR- 2011/09/28
CRDT- 2011/10/05 06:00
PHST- 2011/03/28 00:00 [received]
PHST- 2011/07/11 00:00 [accepted]
PHST- 2011/10/05 06:00 [entrez]
PHST- 2011/10/05 06:00 [pubmed]
PHST- 2012/04/14 06:00 [medline]
PHST- 2011/09/28 00:00 [pmc-release]
AID - PONE-D-11-05485 [pii]
AID - 10.1371/journal.pone.0023243 [doi]
PST - ppublish
SO  - PLoS One. 2011;6(9):e23243. doi: 10.1371/journal.pone.0023243. Epub 2011 Sep 28.