title: 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.
  
  
  METHODS
  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.
  
  
  BACKGROUND
  NCT01125189.
authors: Hôpital Henri Mondor, AP-HP, Université Paris-Est, Inserm U955, Créteil, France.
authors: Christophe
authors: C
authors: Hézode
authors: Centre for Liver Research and NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK.
authors: Gideon M
authors: GM
authors: Hirschfield
authors: Vancouver Island Health Authority & University of British Columbia, Victoria, British Columbia, Canada.
authors: Wayne
authors: W
authors: Ghesquiere
authors: Monash University and Monash Health, Melbourne, Australia.
authors: William
authors: W
authors: Sievert
authors: Fundacion De Investigacion, San Juan Bautista School of Medicine, San Juan, Puerto Rico.
authors: Maribel
authors: M
authors: Rodriguez-Torres
authors: University of Alberta Hospital, Edmonton, Canada.
authors: Stephen D
authors: SD
authors: Shafran
authors: Mercy Medical Center, Baltimore, Maryland, USA.
authors: Paul J
authors: PJ
authors: Thuluvath
authors: Options Health Research, LLC, Tulsa, Oklahoma, USA.
authors: Harvey A
authors: HA
authors: Tatum
authors: National Liver Institute, Shebin Elkom, Egypt.
authors: Imam
authors: I
authors: Waked
authors: Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt.
authors: Gamal
authors: G
authors: Esmat
authors: Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas, USA.
authors: Eric J
authors: EJ
authors: Lawitz
authors: Metropolitan Research, Fairfax, Virginia, USA.
authors: Vinod K
authors: VK
authors: Rustgi
authors: Inserm U1016 and Liver Unit, Université Paris Descartes, Hôpital Cochin, Paris, France.
authors: Stanislas
authors: S
authors: Pol
authors: Copenhagen University Hospital, Hvidovre, Denmark.
authors: Nina
authors: N
authors: Weis
authors: Scripps Clinic, La Jolla, California, USA.
authors: Paul J
authors: PJ
authors: Pockros
authors: Hôpital Saint Joseph, Marseille, France.
authors: Marc
authors: M
authors: Bourlière
authors: Hôpital Saint-Antoine, Paris, France.
authors: Lawrence
authors: L
authors: Serfaty
authors: Baylor College of Medicine, Houston, Texas, USA.
authors: John M
authors: JM
authors: Vierling
authors: University of North Carolina, Chapel Hill, North Carolina, USA.
authors: Michael W
authors: MW
authors: Fried
authors: Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors: Ola
authors: O
authors: Weiland
authors: Hepatology Unit, University Hospital of Pisa, Pisa, Italy.
authors: Maurizia R
authors: MR
authors: Brunetto
authors: University of Colorado Denver, Aurora, Colorado, USA.
authors: Gregory T
authors: GT
authors: Everson
authors: Goethe University, Frankfurt, Germany.
authors: Stefan
authors: S
authors: Zeuzem
authors: Indiana University, Indianapolis, Indiana, USA.
authors: Paul Y
authors: PY
authors: Kwo
authors: Johns Hopkins University, Baltimore, Maryland, USA.
authors: Mark
authors: M
authors: Sulkowski
authors: James J. Peters VA Medical Center, Bronx, New York, USA.
authors: Norbert
authors: N
authors: Bräu
authors: Bristol-Myers Squibb, Clinical Research and Development, Wallingford, Connecticut, USA.
authors: Dennis
authors: D
authors: Hernandez
authors: Bristol-Myers Squibb, Clinical Research and Development, Wallingford, Connecticut, USA.
authors: Fiona
authors: F
authors: McPhee
authors: Bristol-Myers Squibb, Research and Development, Princeton, New Jersey, USA.
authors: Megan
authors: M
authors: Wind-Rotolo
authors: Bristol-Myers Squibb Research and Development, Hopewell, New Jersey, USA.
authors: Zhaohui
authors: Z
authors: Liu
authors: Bristol-Myers Squibb, Research and Development, Princeton, New Jersey, USA.
authors: Stephanie
authors: S
authors: Noviello
authors: Bristol-Myers Squibb, Research and Development, Princeton, New Jersey, USA.
authors: Eric A
authors: EA
authors: Hughes
authors: Bristol-Myers Squibb, Clinical Research and Development, Wallingford, Connecticut, USA.
authors: Philip D
authors: PD
authors: Yin
authors: Bristol-Myers Squibb, Clinical Research and Development, Wallingford, Connecticut, USA.
authors: Steven
authors: S
authors: Schnittman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002219:Carbamates; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000145:classification / Q000188:drug therapy* / Q000235:genetics* / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D016898:Interferon-alpha / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D011759:Pyrrolidines; D011994:Recombinant Proteins / Q000008:administration & dosage; D012074:Remission Induction; D012254:Ribavirin / Q000008:administration & dosage*; D016896:Treatment Outcome; D014633:Valine / Q000031:analogs & derivatives; D019562:Viral Load / Q000187:drug effects; D055815:Young Adult
chemical_list: D002219:Carbamates; D007093:Imidazoles; D016898:Interferon-alpha; D011759:Pyrrolidines; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; D014633:Valine; C549273:daclatasvir; C100416:peginterferon alfa-2a