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.

• Authors: Anuoluwapo Osinusi, Eric G Meissner, Yu-Jin Lee, Dimitra Bon, Laura Heytens, Amy Nelson, Michael Sneller, Anita Kohli, Lisa Barrett, Michael Proschan, Eva Herrmann, Bhavana Shivakumar, Wenjuan Gu, Richard Kwan, Geb Teferi, Rohit Talwani, Rachel Silk, Colleen Kotb, Susan Wroblewski, Dawn Fishbein, Robin Dewar, Helene Highbarger, Xiao Zhang, David Kleiner, Brad J Wood, Jose Chavez, William T Symonds, Mani Subramanian, John McHutchison, Michael A Polis, Anthony S Fauci, Henry Masur, Shyamasundaran Kottilil
• Journal: JAMA (JAMA) Vol. 310 Issue 8 Pg. 804-11 (Aug 28 2013) ISSN: 1538-3598 [Electronic] United States
• PMID: 23982366 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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