All ETDs from UAB

Advisory Committee Chair

Jennifer R King

Advisory Committee Members

Stephen Barnes

Martin Johnson

Ighovwerha Ofotokun

Mark Prichard

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Human Immunodeficiency Virus (HIV) is one of the leading infectious diseases in the world. In spite of substantial progress in the advancement of antiretroviral therapy for HIV treatment, new infections outpace the number of infected persons initiating ART. Therefore, the prevention of HIV remains a crucial health issue. Pre-Exposure Prophylaxis, (PrEP), which involves using one or more antiretroviral agents to reduce the risk of HIV infection prior to potential exposure, has shown effectiveness at reducing HIV transmission in study volunteers with different sexual orientation around the world. The clinical pharmacology of antiretroviral drugs, specifically tenofovir (TFV) and emtricitabine (FTC), in relation to their ability to prevent HIV transmission is still being evaluated. The objective of this dissertation was to develop pharmacokinetic models of TFV and FTC in the plasma and eventually peripheral blood mononuclear cells (PBMCs) and the female genital tract (FGT), which can be used to simulate the appropriate dosing interval needed to achieve optimal drug concentrations for PrEP in each compartment. The development of liquid chromatography/ mass spectrometry (LC/MS/MS) methods resulted in successful quantification of TFV and FTC in plasma, PBMCs, cervical fluid, and endothelial cells of the FGT from 30 HIV-seropositive (HIV+) women. Also, utilizing the LC/MS/MS methods developed, in vitro TFV and FTC uptake in non-monocyctic genital tract cells was determined and compared in the presence and absence of hormonal contraceptives. The major results demonstrated 1) CD4+ and squamous epithelia cells exhibited significantly increased uptake relative to control for both antiretrovirals; 2) individually, synthetic estrogen and progesterone significantly altered uptake across all cell lines except squamous epithelium cells for TFV and CD4+ cells for FTC; and 3) CD8+ and dendritic cells demonstrated decreased uptake of TFV and FTC when dosed one hour prior to being dosed with combined hormonal contraceptives. Development of predictive pharmacokinetic models of TFV and FTC concentration-time profiles in the plasma was achieved using population pharmacokinetic analysis software. Collectively, the results expand upon current knowledge of antiretroviral penetration into the FGT for the use of evaluating PrEP agents and help guide PrEP research on ideal dosing for prevention and transmission of HIV.

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