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.

Keywords: Antiretrovirals; Clinical Pharmacology; Female Genital Tract; Gynecology; HIV/AIDS; Infectious Diseases; PrEP; Virology; Women's Health.

Figure 1:. Potential modifiers of antiretroviral efficacy in the female genital tract

Drug efficacy in the female genital tract is likely dependent on the concentration-response relationship within the mucosal tissue. Depending on the route of drug delivery, concentrations of antiretrovirals in the FGT are highly variable and may be influenced directly or indirectly by hormone and/or inflammation status. In addition, the concentration of HIV target cells can affect risk of HIV acquisition; this may affect the potency of antiretrovirals to prevent HIV infection. HIV target cell expression can also be affected by hormonal and inflammatory regulation. The net effect of these complex and intertwined interactions is difficult to predict.

Figure 2:. Vulnerabilities to HIV along the female genital tract

The upper female genital tract, fallopian tubes, uterus, and endocervix are comprised of a single layer of columnar epithelium. HIV target cells are present throughout these tissues and, following sexual intercourse, semen can be transported to the uterus and the oocytes. Coupled with the large surface, these factors indicate that HIV prevention efforts should consider the upper genital tract as a site vulnerable to HIV infection. Less is known about the pharmacologic factors related to the upper female genital tract such as drug exposure, transporter expression, and local mechanisms of metabolism.

The lower female genital tract, ectocervix and vagina is comprised of multiple layers of squamous epithelium. Differences in pharmacologic factors between the cervix and lower FGT have not been well defined so these are displayed together Epithelial breaches from trauma, particularly during sexual intercourse are not uncommon. Cervical ectopy, common in pregnant women or women on hormonal contraception, may increase HIV risk since it increases surface area of endocervical columnar epithelium. HIV target cells are present throughout the lower female genital tract. As the site for many STIs, tissues are susceptible to inflammatory conditions which may alter HIV risk and expression of target cells. Changes in microflora in the vaginal tract can affect HIV susceptibility as well as interactions with local drug concentrations. High expression of efflux transporters in vaginal epithelium may also contribute to low drug exposure in vaginal tissue.. In addition, high concentrations of endogenous nucleotides in cervical and vaginal tissue have been documented and may necessitate higher exposures to nucleotide-based PrEP interventions.