HCV Antiviral Drugs Have the Potential to Adversely Perturb the Fetal-Maternal Communication Axis through Inhibition of CYP3A7 DHEA-S Oxidation

Abstract

The hepatitis C virus (HCV) poses a great risk to pregnant people and their developing fetus, yet no HCV antiviral treatment guidelines have been established. While there has been a substantial increase in the development of HCV antivirals, the effect they have on the developing fetus remains poorly defined. Many of these drugs are metabolized through the cytochrome P450 CYP3A pathway, which is mediated by CYP3A7 in the fetus and developing infant. In this study, we sought to investigate the effect HCV antivirals have on CYP3A7 metabolism, as this CYP enzyme plays a vital role in proper fetal and neonatal development. Of the thirteen HCV antivirals we investigated, eight (~62%) inhibited CYP3A7 metabolic activity by 50% or more at a concentration of 20 µM. Furthermore, paritaprevir, asunaprevir, simeprevir, danoprevir, and glecaprevir all had observed half-maximal inhibitory concentrations between the range of 10-20 µM, which is physiologically relevant in comparison to the K m of DHEA-S oxidation (reported to be between 5 to 20 µM). We also discovered that paritaprevir is a timedependent inhibitor of CYP3A7, which shifts the IC 50 ~2-fold from 11 µM to 5 µM. Upon further characterization, paritaprevir inactivates DHEA-S metabolism by CYP3A7, with K I and K inact values of 4.66 µM and 0.00954 min -1 , respectively. Depending on treatment plan and off-label drug use, HCV treatment could adversely affect the fetal-maternal communication axis by blocking fetal CYP3A7 metabolism of important endogenous hormones.

Special Section on Cytochrome P450 Enzymes in Toxicology and as Drug Targets—Editorial

“…Dr. Lampe has a shared interest in studying CYP3A enzymology in understudied populations. In this special section, Dr. Jed N. Lampe and coauthors publish a research article on "HCV antiviral drugs have the potential to adversely perturb the maternal-fetal communication axis through inhibition of CYP3A7 DHEA-S oxidation" (Work et al, 2024). The prevalence of hepatitis C virus (HCV) in pregnant people is estimated to be between 1% and 8% of the global population, and many of these mothers may receive antiviral drugs.…”