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

JAMA. 2013 Aug 28;310(8):804-11. doi: 10.1001/jama.2013.109309.

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.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / administration & dosage*
  • Antiviral Agents / adverse effects
  • Antiviral Agents / pharmacokinetics
  • Body Weight
  • Female
  • Hepacivirus / classification
  • Hepacivirus / genetics*
  • Hepacivirus / isolation & purification
  • Hepatitis C / drug therapy*
  • Hepatitis C / genetics
  • Humans
  • Interferons
  • Interleukins / genetics
  • Male
  • Middle Aged
  • Prognosis
  • Ribavirin / administration & dosage*
  • Ribavirin / adverse effects
  • Ribavirin / pharmacokinetics
  • Sofosbuvir
  • Treatment Outcome
  • Uridine Monophosphate / administration & dosage
  • Uridine Monophosphate / adverse effects
  • Uridine Monophosphate / analogs & derivatives*
  • Uridine Monophosphate / pharmacokinetics
  • Viral Load

Substances

  • Antiviral Agents
  • IFNL3 protein, human
  • Interleukins
  • Ribavirin
  • Interferons
  • Uridine Monophosphate
  • Sofosbuvir

Associated data

  • ClinicalTrials.gov/NCT01441180