A Phase One Pharmacokinetic Study of Ledipasvir/Sofosbuvir in Pregnant Women with Hepatitis C Virus

Abstract

Background: Hepatitis C virus (HCV) infection is increasing among pregnant women due to the opioid epidemic, yet there are no interventions to reduce perinatal HCV transmission or to treat HCV during pregnancy. Physiologic changes in pregnancy alter the pharmacokinetics of some medications; thus, our objective was to compare the pharmacokinetic parameters of ledipasvir 90mg-sofosbuvir 400mg during pregnancy to nonpregnant women.

Methods: This was an open-label, phase 1 study, of pregnant women with genotype 1 HCV infection and their infants. Participants were enrolled between 23-24 weeks’ gestation and began a 12-week course of ledipasvir/sofosbuvir. Three 12-hour intensive pharmacokinetic visits were performed at 25-26, 29-30, and 33-34 weeks’ gestation and individual pharmacokinetics were summarized by geometric mean across the three visits. The primary outcome was the ledipasvir/sofosbuvir area under the concentration time curve (AUC_tau) during pregnancy compared to female participants from ledipasvir/sofosbuvir phase 2/3 studies by geometric mean ratio with 90% confidence intervals.Secondarily, maternal and infant adverse events, pregnancy outcomes, the sustained virologic response (SVR) 12 weeks after therapy and infant HCV RNA were summarized.

Findings: Of 29 pregnant women who were screened, 9 (31·0%) were enrolled. Ledipasvir/sofosbuvir exposures were similar in the pregnant vs. non-pregnant controls [AUCtau ledipasvir 89·3 (68·7, 116)% sofosbuvir 91·1 (78·0, 106)%]. All participants achieved SVR and infants are HCV-negative. All drug-related adverse events were Grade 1 or 2. 

Interpretation: Ledipasvir/sofosbuvir was safe and effective without clinically meaningful differences in drug exposure among pregnant vs. non-pregnant women. 

Trial Registration: ClinicalTrials.gov Identifier: NCT02683005

Funding: NIH/NICHD (R21HD089457), NIH/OWHR (K12HD043441), Gilead Sciences (CO-US-337-2117)

Declaration of Interests: Catherine Chappell, Debra Bogen, Ingrid Macio and Elizabeth Krans are receiving research funding from Gilead Sciences and Catherine Chappell has served as a consultant for Gilead Sciences. Elizabeth Krans and Catherine Chappell are receiving research funding from Merck and Sharon Hillier has served as a consultant for Merck. Brian Kirby, Vithika Suri, Anuj Gaggar are employed by Gilead Sciences. The other authors have no other disclosures.

Ethics Approval Statement: Recruitment materials and the study protocol were approved by the University of Pittsburgh Institutional Review Board. This study was conducted under a Food and Drug Administration Investigational New Drug Application (#129502) from the investigator at the University of Pittsburgh. All participants gave written informed consent before the screening procedures.