Approaches to understanding antiretroviral pharmacology in difficult-to-access tissues for HIV treatment and prevention.

Abstract

The persistence of Human Immunodeficiency Virus (HIV) in tissue reservoirs, such as the central nervous system (CNS) and genital tissues, presents a challenge for HIV treatment and prevention. Antiretroviral drugs can achieve viral suppression in the circulatory system, but their suboptimal distribution and exposure in tissues may contribute to viral persistence. This dissertation investigated the distribution of antiretroviral drugs in difficult-to-access tissues, such as the brain and female genital tissues, and predicts exposure of tenofovir in both circulatory system and female genital tissue with a physiologically based pharmacokinetic (PBPK) modeling approach.The study analyzed postmortem tissues collected from decedents with HIV who were on antiretroviral therapy. In chapter 2, the concentration and tissue-to-plasma penetration ratios of four antiretroviral drugs in 13 brain regions were analyzed, revealing statistically significant regional differences. In chapter 3, the concentration and tissue-to-plasma penetration ratios of four drugs in upper and lower female genital tissues were assessed, with higher penetration observed in the vagina tissue compared to the commonly used representative for the entire female genital tract, the cervix. These findings provide insights into viral compartmentalization mechanisms. The potential confounding effects of postmortem redistribution on antiretroviral drug analysis were investigated in chapter 4, revealing different trends of redistribution depending on the drug, tissue, and postmortem time. Rapid autopsy is emphasized as a valuable tool for future pharmacological study based on postmortem analysis. PBPK modeling was used in chapter 5 to predict drug exposure in tissues, with the development of tenofovir models integrated with a female genital compartment and validated with clinical data. Nonadherence behavior patterns were evaluated, with an interesting finding that taking “drug vacation” intermittently instead of consecutively could increase the protection of oral tenofovir, a component of preexposure prophylaxis for HIV. Overall, this dissertation highlights the importance of understanding drug distribution in tissues for HIV treatment and prevention efforts. The findings provide valuable insights into the pharmacology of antiretroviral drugs in the brain and female genital tissues and pave the way for future studies to identify viral compartmentalization mechanisms and optimize drug exposure in tissues.