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

• Published in: Gut Vol. 64; no. 6; pp. 948 - 956
• Main Authors: Hézode, Christophe, Hirschfield, Gideon M, Ghesquiere, Wayne, Sievert, William, Rodriguez-Torres, Maribel, Shafran, Stephen D, Thuluvath, Paul J, Tatum, Harvey A, Waked, Imam, Esmat, Gamal, Lawitz, Eric J, Rustgi, Vinod K, Pol, Stanislas, Weis, Nina, Pockros, Paul J, Bourlière, Marc, Serfaty, Lawrence, Vierling, John M, Fried, Michael W, Weiland, Ola, Brunetto, Maurizia R, Everson, Gregory T, Zeuzem, Stefan, Kwo, Paul Y, Sulkowski, Mark, Bräu, Norbert, Hernandez, Dennis, McPhee, Fiona, Wind-Rotolo, Megan, Liu, Zhaohui, Noviello, Stephanie, Hughes, Eric A, Yin, Philip D, Schnittman, Steven
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.06.2015
• Subjects: Adolescent; Adult; Aged; Antiretroviral drugs; Biopsy; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Genotype; Genotype & phenotype; Hepatitis C virus; Hepatitis C, Chronic - classification; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - genetics; Hepatitis C, Chronic - virology; Humans; Imidazoles - administration & dosage; Infections; Interferon-alpha - administration & dosage; Liver cirrhosis; Liver diseases; Male; Medicin och hälsovetenskap; Middle Aged; Polyethylene Glycols - administration & dosage; Recombinant Proteins - administration & dosage; Remission Induction; Ribavirin - administration & dosage; Studies; Treatment Outcome; Viral Load - drug effects; Young Adult
• ISSN: 0017-5749; 1468-3288; 1468-3288
• DOI: 10.1136/gutjnl-2014-307498

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.