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

  • ️Thu Jan 01 2015

. 2015 Dec 15;212(12):1988-95.

doi: 10.1093/infdis/jiv334. Epub 2015 Jun 12.

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

Charles W Dobard et al. J Infect Dis. 2015.

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.

Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

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Figures

Figure 1.
Figure 1.

Pharmacokinetic parameters of rectum-specific gels containing maraviroc (MVC) and tenofovir (TFV). MVC and TFV concentrations over 24 hours following rectal gel dosing. A, The time of maximum concentration (Tmax) and subsequent decay of MVC and TFV concentrations in plasma after rectal dosing with single-drug and combined-drug gel are shown. B, MVC and TFV concentrations in rectal fluids after gel dosing.

Figure 2.
Figure 2.

Pharmacokinetic correlation of tenofovir diphosphate (TFV-DP) concentration in rectal tissues and lymphocytes. The relationship between TFV-DP concentrations in tissue homogenates (log fmol/mg tissue) and isolated lymphocytes (log fmol/106 cells) is shown for paired samples (n = 14) collected at necropsy from proximal, medial, and distal tissues 2 and 24 hours after administration of a 1% maraviroc/1% TFV gel dose.

Figure 3.
Figure 3.

Rectal gels containing maraviroc (MVC) and tenofovir (TFV) provide high protection against rectal chimeric simian/human immunodeficiency virus 162P3 (SHIV162P3) infection. Survival curves of the cumulative percentage of uninfected macaques as a function of the number of weeks to SHIV positivity. Small black arrows indicate times of SHIV exposure (2 per week). Animals received gel twice weekly 1 week before, during, and 1 week after the challenge period (shaded area). After 5 weeks (10 SHIV162p3 exposures), challenges were stopped, and animals were monitored for 10 additional weeks in the absence of virus challenge. Animals that became infected continued to receive gel up twice-weekly to 10 weeks after infection.

Figure 4.
Figure 4.

Drug absorption was similar in protected and breakthrough infections. Assessment of plasma drug levels in macaques at 30 minutes after gel dosing for each chimeric simian/human immunodeficiency virus exposure during the 5-week challenge period. Protected and infected macaques were treated with 1% maraviroc (MVC; A), 1% tenofovir (TFV) gel (B), and 1% MVC/1% TFV (C) gel. Solid black line indicates mean drug levels.

Figure 5.
Figure 5.

Viral replication in breakthrough infections is similar to that in controls and shows no evidence of K65R emergence. Individual virus load kinetics of chimeric simian/human immunodeficiency virus (SHIV)–infected controls (black dotted) and mean viral load kinetics of the 2 breakthrough infections under continued gel dosing twice weekly with 1% maraviroc (MVC; red), 1% tenofovir (TFV; blue), and 1% MVC/1% TFV (green) are shown (standard error bars shown in same color). Time 0 indicates SHIV RNA levels at first detection. Wild-type SHIV detected at time 0, at week 2, and among all samples tested during follow-up (up to 10 weeks after infection).

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