title: Protection Against Rectal Chimeric Simian/Human Immunodeficiency Virus Transmission in Macaques by Rectal-Specific Gel Formulations of Maraviroc and Tenofovir.
abstract: BACKGROUND
  Rectal human immunodeficiency virus (HIV) transmission is an important driver of the HIV epidemic. Optimally formulated gels of antiretroviral drugs are under development for preventing rectally acquired HIV. We investigated in a macaque model the pharmacokinetics and efficacy of 3 rectal gel formulations
  
  
  METHODS
  Single-dose pharmacokinetics of low-osmolar 1% maraviroc (MVC), 1% tenofovir (TFV), or 1% MVC/1% TFV combination gel were evaluated in blood, rectal fluids, colorectal biopsy specimens, and rectal lymphocytes. Efficacy was evaluated over 10 twice-weekly rectal SHIV162p3 challenges in rhesus macaques that received either placebo (n = 7), MVC (n = 6), TFV (n = 6), or MVC/TFV (n = 6) gel 30 minutes before each challenge.
  
  
  RESULTS
  MVC and TFV were detected in plasma 30 minutes after gel application and remained above 95% inhibitory concentrations in rectal fluids at 24 hours. MVC, TFV, and TFV diphosphate (TFV-DP) concentrations in colorectal tissues collected up to 30 cm from the anal margin were all high at 2 hours, demonstrating rapid and extended tissue dosing. TFV-DP concentrations in tissue homogenates and rectal lymphocytes were highly correlated (r(2) = 0.82). All 3 gel formulations were highly protective (82% efficacy; P ≤ .02 by the log-rank test).
  
  
  CONCLUSIONS
  Desirable pharmacokinetic profiles and high efficacy in this macaque model support the clinical development of these gel formulations for preventing rectal HIV infection.
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Dobard
authors.affiliation: Total Solutions, Madison, Alabama.
authors.forename: Andrew
authors.initials: A
authors.lastname: Taylor
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia.
authors.forename: Sunita
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado School of Pharmacy, Aurora.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Anderson
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado School of Pharmacy, Aurora.
authors.forename: Lane R
authors.initials: LR
authors.lastname: Bushman
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia.
authors.forename: Dinh
authors.initials: D
authors.lastname: Chuong
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia.
authors.forename: Chou-Pong
authors.initials: CP
authors.lastname: Pau
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia.
authors.forename: Debra
authors.initials: D
authors.lastname: Hanson
authors.affiliation: Magee Women's Research Institute, University of Pittsburgh, Pennsylvania.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia.
authors.forename: J Gerardo
authors.initials: JG
authors.lastname: Garcia-Lerma
authors.affiliation: Magee Women's Research Institute, University of Pittsburgh, Pennsylvania.
authors.forename: Ian
authors.initials: I
authors.lastname: McGowan
authors.affiliation: Magee Women's Research Institute, University of Pittsburgh, Pennsylvania.
authors.forename: Lisa
authors.initials: L
authors.lastname: Rohan
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia.
authors.forename: Walid
authors.initials: W
authors.lastname: Heneine
mesh_terms: D000287:Administration, Topical; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D003510:Cyclohexanes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D018562:Disease Transmission, Infectious / Q000517:prevention & control*; D005782:Gels / Q000008:administration & dosage*; D008251:Macaca; D000077592:Maraviroc; D010919:Placebos / Q000008:administration & dosage; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control*; D000068698:Tenofovir / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D019380:Anti-HIV Agents; D003510:Cyclohexanes; D005782:Gels; D010919:Placebos; D014230:Triazoles; D000068698:Tenofovir; D000077592:Maraviroc
keywords: HIV prevention; macaque model; maraviroc; rectal microbicides; repeat-challenge; tenofovir