Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial

Abstract

Importance: The efficacy of directly acting antiviral agents in interferon-free regimens for the treatment of chronic hepatitis C infections needs to be evaluated in different populations.

Objective: To determine the efficacy and safety of sofosbuvir with weight-based or low-dose ribavirin among a population with unfavorable treatment characteristics.

Design, setting, and patients: Single-center, randomized, 2-part, open-label phase 2 study involving 60 treatment-naive patients with hepatitis C virus (HCV) genotype 1 enrolled at the National Institutes of Health (October 2011-April 2012).

Interventions: In the study's first part, 10 participants with early to moderate liver fibrosis were treated with 400 mg/d of sofosbuvir and weight-based ribavirin for 24 weeks. In the second part, 50 participants with all stages of liver fibrosis were randomized 1:1 to receive 400 mg of sofosbuvir with either weight-based or low-dose 600 mg/d of ribavirin for 24 weeks.

Main outcomes and measures: The primary study end point was the proportion of participants with undetectable HCV viral load 24 weeks after treatment completion (sustained virologic response of 24 weeks [SVR24]).

Results: In the first part of the study, 9 participants (90%; 95% CI, 55%-100%) achieved SVR24. In the second part, 7 participants (28%) in the weight-based group and 10 (40%) in the low-dose group relapsed after treatment completion leading to SVR24 rates of 68% (95% CI, 46%-85%) in the weight-based group and 48% (95% CI, 28%-69%; P = .20) in the low-dose group. Twenty individuals participated in a pharmacokinetic-viral kinetic substudy, which demonstrated a slower loss rate of infectious virus in relapsers than in participants who achieved SVR (clearance, 3.57/d vs 5.60/d; P = .009). The most frequent adverse events were headache, anemia, fatigue, and nausea. There were 7 grade 3 events including anemia, neutropenia, nausea, hypophosphatemia, and cholelithiasis or pancreatitis. No one discontinued treatment due to adverse events.

Conclusion and relevance: In a population of patients with a high prevalence of unfavorable traditional predictors of treatment response, a 24-week regimen of sofosbuvir and weight-based or low-dose ribavirin resulted in SVR24 rates of 68% and 48%, respectively.

Trial registration: clinicaltrials.gov Identifier: NCT01441180.

Figure 1A. Enrollment and treatment outcomes (ITT analysis)

*SVR rates based on all randomized participants (ITT analysis) † cumulative relapsers. This analysis includes all participants who were taken off study drug/lost to follow up. part 1: One patient at week 3 was taken off due to non-adherence and lost to follow up part 2: One patient on weight based RBV: self discontinued at week 3 and lost to follow up. Three patients on low dose RBV (1 lost to follow up at week 8, 2 participants taken off due to non-adherence at week 8 and remain in follow up). Figure 1B Treatment response in all randomized subjects (ITT analysis) In the WBR arm: relapses were as follows: 3 participants 2 weeks after treatment; 3 participants at 4 weeks after treatment while the last patient was 8 weeks after treatment. In the LDR arm: relapses were as follows: 7 participants at 2 weeks after treatment; 1 subject at 4 weeks after treatment, 1 subject at 8 weeks after treatment and 1 was detectable 12 weeks after treatment. Roche assay was used for these time points. LOQ: Level of quantification; SVR: Sustained virologic response.

Figure 2. Viral kinetic (VK), pharmacokinetic (PK) and pharmacodynamics (PD) curves

Fitted curves for hepatitis C viral kinetics (VK) in 50 randomized participants (a and b), pharmacokinetics and pharmacodynamics (PK-PD) in 20 randomized participants (c), and pharmacodynamics and viral kinetic (PD-VK) in 20 randomized participants (d). Median fitted curves are plotted for viral decay (VK) (a); median viral decay curves were rapid and independent of ribavirin dosing(b); median efficiency of drug blocking viral production (PK-PD model) was similar in SVR vs. relapsers (c) PK-VK model for viral decay in SVR vs. relapsers (d) SVR: Sustained virologic responders; Weight-based ribavirin: 1000-1200mg/day, Low-dose ribavirin: 600mg/day.