Ledipasvir plus sofosbuvir in pregnant women with hepatitis C virus infection: a phase 1 pharmacokinetic study

Abstract

Summary Background Hepatitis C virus (HCV) infection is increasing among pregnant women because of the opioid epidemic, yet there are no interventions to reduce perinatal HCV transmission or to treat HCV during pregnancy. Physiological changes in pregnancy alter the pharmacokinetics of some medications; thus, our aim was to compare the pharmacokinetic parameters of ledipasvir 90 mg plus sofosbuvir 400 mg during pregnancy with non-pregnant women. Methods This was an open-label, phase 1 study of pregnant women with genotype 1 HCV infection and their infants. A reference group of women who had participated in pharmacokinetic studies of ledipasvir–sofosbuvir during phase 2 and 3 trials was used. Participants were enrolled at Magee-Womens Hospital (Pittsburgh, PA, USA) between 23 and 24 weeks’ gestation and had a 12-week course of oral ledipasvir–sofosbuvir (daily 90 mg ledipasvir plus 400 mg sofosbuvir). Three 12-h intensive pharmacokinetic visits were done at 25–26, 29–30, and 33–34 weeks’ gestation and individual pharmacokinetics were summarised by geometric mean across the three visits. The primary outcome, analysed in all participants without suspected dosing errors, was the ledipasvir–sofosbuvir area under the concentration–time curve of the dosing interval (AUC tau ) during pregnancy compared with the reference group by geometric mean ratio. This study is registered with ClinicalTrials.gov , NCT02683005 . Findings From Oct 1, 2016, to Sept 30, 2018, 29 pregnant women were screened and nine (31%) were enrolled. Eight (89%) women were included in the primary analysis. Ledipasvir and sofosbuvir exposures were similar in the pregnant women versus the non-pregnant reference group (geometric mean ratio of AUC tau ledipasvir 89·3% [90% CI 68·7–116·1]; sofosbuvir 91·1% [78·0–106·3]). Interpretation Ledipasvir–sofosbuvir was safe and effective without clinically meaningful differences in drug exposure among pregnant versus non-pregnant women. Funding National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health/Office of Research on Women’s Health, and Gilead Sciences.

Enhancing Linkage to Hepatitis C Virus Treatment Following Pregnancy in Women Identified During Perinatal Care

“…Clinical trials are ongoing to test DAA safety and efficacy, and treatment during pregnancy may be a possibility in the future. ( 14 , 15 ) Currently, women can be linked to HCV care for treatment after pregnancy and cessation of breastfeeding.…”

Pregnancy outcome of anti‐HCV direct‐acting antivirals: Real‐life data from an Egyptian cohort

“…To date, two studies with a small number of patients showed no safety concerns for using sofosbuvir during pregnancy and high sustained virological response when using ledipasvir/sofosbuvir 6,10 . Although ribavirin is contraindicated during pregnancy based on animal data showing teratogenic and/or embryocidal effects, none of these effects were reported among the studied cohort of five patients who received ribavirin in combination with SOF/DCV or paritaprevir/ritonavir/ombitasvir.…”

Society for Maternal-Fetal Medicine Consult Series #56: Hepatitis C in pregnancy—updated guidelines

“…A phase 1 trial assessing ledipasvir plus sofosbuvir for the treatment of chronic HCV infection during pregnancy showed 100% cure rates, large declines in viral loads within 10 to 21 days of starting treatment, and no clinically meaningful adverse effects on the mother/infant dyad. 56 In the meantime, until more data exist, if a patient becomes pregnant while taking one of the DAA therapies, they should be counseled that animal data do not suggest teratogenic risk, but human data are lacking. 1 In these scenarios, shared decision-making regarding risks and benefits of cessation vs continuation should occur.…”