Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study.

Abstract

OBJECTIVE:

To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin.

DESIGN:

In this Phase 2b double-blind, placebo-controlled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferon-alfa-2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCV-RNA<lower limit of quantitation at Week 4 and undetectable at Week 10) were rerandomised at Week 12 to continue daclatasvir/peginterferon-alfa-2a/ribavirin for 24 weeks total duration or to placebo/peginterferon-alfa-2a/ribavirin for another 12 weeks. Patients without PDR and placebo patients continued peginterferon-alfa/ribavirin through Week 48. Primary efficacy endpoints were undetectable HCV-RNA at Weeks 4 and 12 (extended rapid virologic response, eRVR) and at 24 weeks post-treatment (sustained virologic response, SVR24) among genotype 1-infected patients.

RESULTS:

Overall, eRVR was achieved by 54.4% (80/147) of genotype 1-infected patients receiving daclatasvir 20 mg, 54.1% (79/146) receiving 60 mg versus 13.9% (10/72) receiving placebo. SVR24 was achieved among 87 (59.2%), 87 (59.6%), and 27 (37.5%) patients in these groups, respectively. Higher proportions of genotype 4-infected patients receiving daclatasvir 20 mg (66.7%; 8/12) or 60 mg (100.0%; 12/12) achieved SVR24 versus placebo (50.0%; 3/6). A majority of daclatasvir-treated patients achieved PDR and experienced less virologic failure and higher SVR24 rates with a shortened 24-week treatment duration. Adverse events occurred with similar frequency across all treatment groups.

CONCLUSIONS:

The combination of daclatasvir/peginterferon-alfa/ribavirin was generally well tolerated and achieved higher SVR24 rates compared with placebo/peginterferon-alfa/ribavirin among patients infected with HCV genotype 1 or 4.

TRIAL REGISTRATION NUMBER:

NCT01125189.

• Authors: Christophe Hézode, Gideon M Hirschfield, Wayne Ghesquiere, William Sievert, Maribel Rodriguez-Torres, Stephen D Shafran, Paul J Thuluvath, Harvey A Tatum, Imam Waked, Gamal Esmat, Eric J Lawitz, Vinod K Rustgi, Stanislas Pol, Nina Weis, Paul J Pockros, Marc Bourlière, Lawrence Serfaty, John M Vierling, Michael W Fried, Ola Weiland, Maurizia R Brunetto, Gregory T Everson, Stefan Zeuzem, Paul Y Kwo, Mark Sulkowski, Norbert Bräu, Dennis Hernandez, Fiona McPhee, Megan Wind-Rotolo, Zhaohui Liu, Stephanie Noviello, Eric A Hughes, Philip D Yin, Steven Schnittman
• Journal: Gut (Gut) Vol. 64 Issue 6 Pg. 948-56 (Jun 2015) ISSN: 1468-3288 [Electronic] England
• PMID: 25080450 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Chemical References

• Carbamates
• Imidazoles
• Interferon-alpha
• Pyrrolidines
• Recombinant Proteins
• Polyethylene Glycols
• Ribavirin
• Valine
• daclatasvir
• peginterferon alfa-2a

Topics

• Adolescent
• Adult
• Aged
• Carbamates
• Double-Blind Method
• Drug Administration Schedule
• Drug Therapy, Combination
• Female
• Genotype
• Hepatitis C, Chronic (classification, drug therapy, genetics, virology)
• Humans
• Imidazoles (administration & dosage)
• Interferon-alpha (administration & dosage)
• Male
• Middle Aged
• Polyethylene Glycols (administration & dosage)
• Pyrrolidines
• Recombinant Proteins (administration & dosage)
• Remission Induction
• Ribavirin (administration & dosage)
• Treatment Outcome
• Valine (analogs & derivatives)
• Viral Load (drug effects)
• Young Adult