Protection Against Rectal Chimeric Simian/Human Immunodeficiency Virus Transmission in Macaques by Rectal-Specific Gel Formulations of Maraviroc and Tenofovir

J Infect Dis. 2015 Dec 15;212(12):1988-95. doi: 10.1093/infdis/jiv334. Epub 2015 Jun 12.

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.

Keywords: HIV prevention; macaque model; maraviroc; rectal microbicides; repeat-challenge; tenofovir.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Administration, Topical
  • Animals
  • Anti-HIV Agents / administration & dosage*
  • Anti-HIV Agents / pharmacokinetics
  • Cross-Over Studies
  • Cyclohexanes / administration & dosage*
  • Cyclohexanes / pharmacokinetics
  • Disease Models, Animal
  • Disease Transmission, Infectious / prevention & control*
  • Gels / administration & dosage*
  • Macaca
  • Maraviroc
  • Placebos / administration & dosage
  • Simian Acquired Immunodeficiency Syndrome / prevention & control*
  • Tenofovir / administration & dosage*
  • Tenofovir / pharmacokinetics
  • Treatment Outcome
  • Triazoles / administration & dosage*
  • Triazoles / pharmacokinetics

Substances

  • Anti-HIV Agents
  • Cyclohexanes
  • Gels
  • Placebos
  • Triazoles
  • Tenofovir
  • Maraviroc