Abstract Body

Background:

Treatment of hepatitis C virus (HCV) with direct acting antivirals during pregnancy could cure maternal HCV during antenatal care engagement and prevent perinatal HCV transmission. A study of ledipasvir/sofosbuvir in pregnancy (NCT02683005) showed good efficacy and favorable pharmacokinetics (PK), but a pan-genotypic regimen was needed. Our objectives were to compare the PK parameters of sofosbuvir/velpatasvir (SOF/VEL) in pregnant versus nonpregnant women, and to assess delivery outcomes and viral response.

Methods:

In this open-label, phase 1 study, HIV-negative pregnant women with chronic HCV infection were enrolled between 23-25 weeks’ gestation. At entry, participants began SOF-400mg/VEL-100mg daily for 12 weeks. Twenty-four-hour intensive PK visits were performed at 3 and 9 weeks of treatment. VEL, SOF and GS-331007 (the inactive metabolite of SOF) in plasma were measured using validated UPLC-MS/MS assays. PK parameters were determined using non-compartmental methods (Phoenix v8.3) and geometric mean ratios and 90% CI compared to historical intensive PK data in non-pregnant women from registrational trials. Maternal adverse events, delivery outcomes, and the sustained virologic response 12 weeks after therapy (SVR12) were also determined.

Results:

Fourteen participants were screened, 3 were excluded due to declining participation, having a fetal anomaly and spontaneous HCV clearance, and 11 participants enrolled. One participant discontinued treatment after two doses due to worsening of hyperemesis. VEL exposures and SOF maximum concentration (Cmax) were similar to historic data, but SOF area under the curve (AUC) was 38% higher and GS-331007 AUC and Cmax were 38% and 43% lower, respectively (Table). All 10 participants that completed treatment had undetectable HCV RNA at delivery. All participants that completed the SVR12 visit were cured (n=7) and all the infants that followed up had an undetectable HCV RNA (n=7). Nine maternal participants experienced adverse events related to SOF/VEL; however, only one was greater than grade 2 (vomiting) and resulted in discontinuation of SOF/VEL. Two infants delivered preterm at 35- and 36-weeks’ gestation.

Conclusions:

SOF/VEL exposures were not clinically different in pregnancy. Consistent with SOF/ledipasvir in pregnant women, lower GS-331007 exposures were observed and possibly due to increased glomerular filtration rate during pregnancy. A multicenter study to evaluate SOF/VEL safety and efficacy in pregnancy is underway (NCT05140941).

SOF/VEL PK parameters during pregnancy compared to non-pregnant women