Pharmacology of Antiretrovirals in the Female Genital Tract for HIV Prevention

Abstract

Preexposure prophylaxis (PrEP) is a powerful tool that, as part of a comprehensive prevention package, has potential to significantly impact the HIV epidemic. PrEP effectiveness is believed to be dependent on the exposure and efficacy of antiretrovirals at the site of HIV transmission. Clinical trial results as well as modeling and simulation indicate the threshold of adherence required for PrEP efficacy of emtricitabine/tenofovir disoproxil fumarate may differ between sites of HIV transmission with less forgiveness for missed doses in women exposed through genital tissue compared to people exposed through colorectal tissue. This suggests a role for local and host factors to influence mucosal pharmacology. Here we review the mucosal pharmacology of antiretrovirals in the female genital tract and explore potential determinants of PrEP efficacy. Host factors such as inflammation, coinfections, hormonal status, and the vaginal microbiome will be explored as well as the role of drug-metabolizing enzymes and transporters in regulating local drug exposure. The use of preclinical and early clinical models to predict clinical effectiveness is also discussed.

Early Colorectal Responses to HIV-1 and Modulation by Antiretroviral Drugs

“…Vaccine candidates have so far been designed to induce virus-specific antibody of T cell responses; however, animal studies and clinical trials have shown limited protection highlighting the need to better understand the links between innate and adaptive response(s) capable of mediating protection. Drug based prevention approaches have shown greater success with antiretroviral drugs (ARVs) such as Truvada, a combination of two nucleot(s)ide reverse transcriptase inhibitors (Tenofovir/Emtricitabine) [ 1 , 2 , 3 ], although lack of user adherence and mucosal factors such as inflammation and microbiota have been shown to hinder the efficacy of ARVs [ 4 ]. Hence, new approaches to HIV prophylaxis are urgently needed and understanding the innate responses induced in the first hours of exposure to HIV is essential to design such strategies.…”

Smart Freeze-Dried Bigels for the Prevention of the Sexual Transmission of HIV by Accelerating the Vaginal Release of Tenofovir during Intercourse

“…Around 66% of these were in sub-Saharan Africa, where women continue to be disproportionately represented in these data, with 59% of new infections by HIV among adults in that year [1]. Sex with men remains the most significant threat to women in terms of their infection by this virus [2]. “One in three women worldwide has experienced physical or sexual violence” according to UNAIDS, and this latter factor has a direct bearing on their vulnerability to HIV infection [1].…”

Efficacy, Adherence and Side Effects of PrEP for HIV-1 Prevention

“…In another study, reduced concentrations of TDF metabolites were found in vaginal tissues compared to that in rectal tissues (Koss et al, 2018). The intricate milieu of the female genital tract may be susceptible to factors such as hormonal changes, microbiome, and inflammation (Nicol, Corbino, & Cottrell, 2018;Farcasanu & Kwon, 2018;Karim et al, 2018), which may also affect the efficacy. Besides these potential gender-related differences, adherence has been considered to play a critical role in PrEP efficacy.…”