title: Daclatasvir plus peginterferon and ribavirin is noninferior to peginterferon and ribavirin alone, and reduces the duration of treatment for HCV genotype 2 or 3 infection.
abstract: OBJECTIVE
  Twenty-four weeks of treatment with peginterferon and ribavirin for chronic hepatitis C virus (HCV) genotype 2 or 3 infection produces a sustained virologic response (SVR) in 70%-80% of patients. We performed a randomized, double-blind, phase 2b study to assess whether adding daclatasvir, a nonstructural protein 5A (NS5A) inhibitor that is active against these genotypes, improves efficacy and shortens therapy.
  
  
  METHODS
  Patients with HCV genotype 2 or 3 infection (n = 151), enrolled at research centers in North America, Europe, or Australia, were assigned randomly to groups given 12 or 16 weeks of daclatasvir (60 mg once daily), or 24 weeks of placebo, each combined with peginterferon alfa-2a and ribavirin. Treatment was extended to 24 weeks for recipients of daclatasvir who did not meet the criteria for early virologic response. The primary end point was SVR at 24 weeks after treatment (SVR24).
  
  
  RESULTS
  Baseline characteristics were similar among patients within each HCV genotype group. However, the 80 patients with HCV genotype 3, compared with the 71 patients with HCV genotype 2, were younger (mean age, 45 vs 53 y, respectively), and a larger proportion had cirrhosis (23% vs 1%, respectively). Among patients with HCV genotype 2 infection, an SVR24 was achieved by 83%, 83%, and 63% of those in the daclatasvir 12-week group, the daclatasvir 16-week group, or the placebo group, respectively; among patients with HCV genotype 3 infection, an SVR24 was achieved by 69%, 67%, and 59% of patients in these groups, respectively. Differences between genotypes largely were attributable to the higher frequency of post-treatment relapse among patients infected with HCV genotype 3. In both daclatasvir arms for both HCV genotypes, the lower bound of the 80% confidence interval of the difference in SVR24 rates between the daclatasvir and placebo arms was above -20%, establishing noninferiority. Safety findings were similar among groups, and were typical of those expected from peginterferon alfa and ribavirin therapy.
  
  
  CONCLUSIONS
  Twelve or 16 weeks of treatment with daclatasvir, in combination with peginterferon alfa-2a and ribavirin, is a well tolerated and effective therapy for patients with HCV genotype 2 or 3 infections. Daclatasvir-containing regimens could reduce the duration of therapy for these patients. Clinicaltrials.gov number: NCT01257204.
authors.affiliation: Kirby Institute, University of New South Wales and St Vincent's Hospital, Sydney, Australia. Electronic address: gdore@kirby.unsw.edu.au.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Dore
authors.affiliation: The Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.affiliation: Department of Hepatology, Hôpital Henri Mondor, Créteil, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Hézode
authors.affiliation: Division of Infectious Diseases, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Shafran
authors.affiliation: Department of Gastroenterology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Alnoor
authors.initials: A
authors.lastname: Ramji
authors.affiliation: Options Health Research, Tulsa, Oklahoma.
authors.forename: Harvey A
authors.initials: HA
authors.lastname: Tatum
authors.affiliation: Department of Clinical Medicine, Sapienza Università di Roma, Rome, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Taliani
authors.affiliation: Faculty of Medicine, Hôpital De L'Archet 2, Nice, France.
authors.forename: Albert
authors.initials: A
authors.lastname: Tran
authors.affiliation: Hepatology Unit, University Hospital, Pisa, Italy.
authors.forename: Maurizia R
authors.initials: MR
authors.lastname: Brunetto
authors.affiliation: University Division of Infectious and Tropical Diseases, Azienda Ospedaliera Spedali Civili, Brescia, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Zaltron
authors.affiliation: AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia.
authors.forename: Simone I
authors.initials: SI
authors.lastname: Strasser
authors.affiliation: Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark.
authors.forename: Nina
authors.initials: N
authors.lastname: Weis
authors.affiliation: Vancouver Island Health Authority and University of British Columbia, Victoria, British Columbia, Canada.
authors.forename: Wayne
authors.initials: W
authors.lastname: Ghesquiere
authors.affiliation: Liver Unit, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Lee
authors.affiliation: Département d'Hépato-Gastroentérologie et Transplantation, Hôpital Saint Eloi, Montpellier, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Larrey
authors.affiliation: Université Paris Descartes, Unité d'Hépatologie, Hôpital Cochin, Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Pol
authors.affiliation: Department of Gastroenterology and Hepatology, Royal Adelaide Hospital and University of Adelaide, Adelaide, Australia.
authors.forename: Hugh
authors.initials: H
authors.lastname: Harley
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Westmead Hospital, Sydney, Australia.
authors.forename: Jacob
authors.initials: J
authors.lastname: George
authors.affiliation: Divisions of Gastroenterology and General Internal Medicine, Toronto General Hospital, Toronto, Ontario, Canada.
authors.forename: Scott K
authors.initials: SK
authors.lastname: Fung
authors.affiliation: Department of Hepatology and Gastroenterology, Hôpital Haut-Lévêque, Pessac, France.
authors.forename: Victor
authors.initials: V
authors.lastname: de Lédinghen
authors.affiliation: Research and Development, Bristol-Myers Squibb, Braine-l'Alleud, Belgium.
authors.forename: Peggy
authors.initials: P
authors.lastname: Hagens
authors.affiliation: Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut.
authors.forename: Fiona
authors.initials: F
authors.lastname: McPhee
authors.affiliation: Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut.
authors.forename: Dennis
authors.initials: D
authors.lastname: Hernandez
authors.affiliation: Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut.
authors.forename: David
authors.initials: D
authors.lastname: Cohen
authors.affiliation: Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cooney
authors.affiliation: Research and Development, Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Noviello
authors.affiliation: Research and Development, Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Hughes
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D002219:Carbamates; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000145:classification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011759:Pyrrolidines; D012367:RNA, Viral / Q000032:analysis; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014633:Valine / Q000031:analogs & derivatives
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D016898:Interferon-alpha; D011759:Pyrrolidines; D012367:RNA, Viral; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; D014633:Valine; C549273:daclatasvir; C100416:peginterferon alfa-2a
keywords: Antiviral; Combination Therapy; DAA; NS5A Replication Complex Inhibitor