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

TY - JOUR

T1 - Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection

T2 - a randomised study

AU - Hézode, Christophe

AU - Hirschfield, Gideon M

AU - Ghesquiere, Wayne

AU - Sievert, William

AU - Rodriguez-Torres, Maribel

AU - Shafran, Stephen D

AU - Thuluvath, Paul J

AU - Tatum, Harvey A

AU - Waked, Imam

AU - Esmat, Gamal

AU - Lawitz, Eric J

AU - Rustgi, Vinod K

AU - Pol, Stanislas

AU - Weis, Nina

AU - Pockros, Paul J

AU - Bourlière, Marc

AU - Serfaty, Lawrence

AU - Vierling, John M

AU - Fried, Michael W

AU - Weiland, Ola

AU - Brunetto, Maurizia R

AU - Everson, Gregory T

AU - Zeuzem, Stefan

AU - Kwo, Paul Y

AU - Sulkowski, Mark

AU - Bräu, Norbert

AU - Hernandez, Dennis

AU - McPhee, Fiona

AU - Wind-Rotolo, Megan

AU - Liu, Zhaohui

AU - Noviello, Stephanie

AU - Hughes, Eric A

AU - Yin, Philip D

AU - Schnittman, Steven

N1 - 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.

PY - 2015/6/1

Y1 - 2015/6/1

N2 - 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, placebocontrolled 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 peginterferonalfa: 2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCVRNA< 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.

AB - 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, placebocontrolled 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 peginterferonalfa: 2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCVRNA< 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.

KW - Adolescent

KW - Adult

KW - Aged

KW - Double-Blind Method

KW - Drug Administration Schedule

KW - Drug Therapy, Combination

KW - Female

KW - Genotype

KW - Hepatitis C, Chronic

KW - Humans

KW - Imidazoles

KW - Interferon-alpha

KW - Male

KW - Middle Aged

KW - Polyethylene Glycols

KW - Recombinant Proteins

KW - Remission Induction

KW - Ribavirin

KW - Treatment Outcome

KW - Viral Load

KW - Young Adult

U2 - 10.1136/gutjnl-2014-307498

DO - 10.1136/gutjnl-2014-307498

M3 - Journal article

C2 - 25080450

SN - 0017-5749

VL - 64

SP - 948

EP - 956

JO - Gut

JF - Gut

IS - 6

ER -