Pre-Exposure Prophylaxis for HIV: Linking Antiretroviral Pharmacokinetics and Pharmacodynamics to Identify Optimal Dosing Strategies

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  • March 19, 2019
Creator
  • Nicol, Melanie
    • Affiliation: Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics
Abstract
  • Despite utilization of potent combination antiretroviral therapy, the incidence of HIV in the U.S. has not declined over recent years. Several clinical trials recently demonstrated that antiretrovirals can protect vulnerable mucosal surfaces against infection. However, the protection conferred ranged from 0% to 73%, underscoring the importance of identifying drug concentrations needed at mucosal surfaces. Additionally, antiretrovirals have complex pharmacology in mucosal tissues with unpredictable drug penetration within and between drug classes. The ultimate goal of this work was to identify factors influencing variability in drug penetration and to develop an explant tissue culture model that could be used to evaluate the efficacy of tenofovir and maraviroc, two antiretroviral candidates for oral pre-exposure prophylaxis strategies. Using real-time PCR and immunochemistry, mRNA and protein expression of three efflux (ABCB1/MDR1, ABCC2/MRP2, ABCC4/MRP4) and three uptake (SLC22A6/OAT1, SLC22A8/OAT3, SLCO1B1/OATP1B1) transporters was described in female genital (FGT) and colorectal tissues (CRT) from 99 donors. Epithelial expression of efflux transporters was found to be two- to four-fold greater in FGT than CRT. These data support clinical findings of higher maraviroc and tenofovir concentrations in CRT compared to FGT after oral dosing. Quantifying mucosal transporter expression and localization was a useful technique to understand drug tissue distribution and facilitate antiretroviral selection to target these tissues. Explant models may be one way to identify target concentrations for prevention but current methods are high variable and require long incubation times in culture. Here, an explant tissue model was developed using the R5, T-tropic strain HIV-1 <sub>JR-CSF</sub> as the inoculum, and was coupled with a novel real-time PCR assay to quantify spliced RNA that detected replication within 24-72 hours after HIV exposure. In this model, concentrations required to protect vaginal explants were 10-1000 fold higher than in a TZM-bl cell monolayer. A single oral dose of tenofovir and maraviroc at 200% treatment doses protected cervical and vaginal biopsies in 3/6 healthy volunteer women. TZM-bl cells over predicted efficacy by 49%, and tissue explants under predicted by 36%. This translational approach, comparing concentration-response relationships in cells, explant tissue, and healthy volunteers, presents a model framework for future investigations of antiretrovirals for prevention.
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  • In Copyright
Advisor
  • Nelson, Julie
  • Kroetz, Deanna
  • Corbett, Amanda
  • Hall, James E.
  • Kashuba, Angela
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2014
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Place of publication
  • Chapel Hill, NC
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  • This item is restricted from public view for 1 year after publication.
Date uploaded
  • April 22, 2015

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