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J Acquir Immune Defic Syndr. 2015 Apr 1;68(4):369-76. doi: 10.1097/QAI.0000000000000472.

Models for predicting effective HIV chemoprevention in women.

Author information

1
*Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC; †Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC; and ‡Departments of Medicine and §Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC (Melanie R. Nicol is now with the Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN).

Abstract

OBJECTIVE:

Model systems that rapidly identify tissue drug concentrations protective of HIV infection could streamline the development of chemoprevention strategies. Tissue models are promising, but limited concentration targets exist, and no systematic comparison to cell models or clinical studies has been performed.

DESIGN:

We explored the efficacy of maraviroc (MVC) and tenofovir (TFV) for HIV prevention by comparing Emax models from TZM-bl cells to vaginal tissue explants and evaluated their predictive capabilities with a dose-challenge clinical study.

METHODS:

HIV-1JR-CSF was used for viral challenge. Drug efficacy was assessed using a luciferase reporter assay in TZM-bl cells and real-time PCR to quantify spliced RNA in a tissue explant model. Cell and tissue concentrations of MVC, TFV, and the active metabolite tenofovir diphosphate were measured by liquid chromatography with tandem mass spectrometry and used to create Emax models of efficacy. Efficacy after a single oral dose of 600 mg MVC and 600 mg tenofovir disoproxil fumarate was predicted from cell and tissue models and confirmed in a clinical study with viral biopsy challenge postdose.

RESULTS:

TFV was >10-fold and MVC >1000-fold, more potent in TZM-bl cells compared with vaginal explant tissue. In the dose-challenge study, tissues from 3 of 6 women were protected from HIV infection, which was 49% lower than predicted by TZM-bl data and 36% higher than predicted by tissue explant data.

CONCLUSIONS:

Comparative effective concentration data were generated for TFV and MVC in 3 HIV chemoprophylaxis models. These results provide a framework for future early investigations of antiretroviral efficacy in HIV prevention to optimize dosing strategies in clinical investigations.

PMID:
25501616
PMCID:
PMC4334725
DOI:
10.1097/QAI.0000000000000472
[Indexed for MEDLINE]
Free PMC Article

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