title: Daclatasvir and asunaprevir plus peginterferon alfa and ribavirin in HCV genotype 1 or 4 non-responders.
abstract: OBJECTIVE
  Improved therapies for peginterferon/ribavirin null or partial responders are needed. This study evaluated daclatasvir (NS5A inhibitor) and asunaprevir (NS3 protease inhibitor) plus peginterferon alfa-2a and ribavirin in this patient population.
  
  
  METHODS
  This open-label, phase 3 study (HALLMARK-QUAD; NCT01573351) treated patients with chronic hepatitis C virus (HCV) genotype 1 (n=354) or 4 (n=44) infection who had a prior null or partial response to peginterferon/ribavirin. Patients received daclatasvir 60 mg once-daily plus asunaprevir 100mg twice-daily, with weekly peginterferon alfa-2a and weight-based ribavirin for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12 (SVR12) among genotype 1-infected patients.
  
  
  RESULTS
  Daclatasvir plus asunaprevir and peginterferon/ribavirin demonstrated SVR12 rates of 93% (95% CI 90-96) in prior non-responders infected with HCV genotype 1. SVR12 rates among genotype 4-infected patients were 98% (95% CI 93-100); one patient had a missing post-treatment week-12 HCV-RNA measurement, but achieved an SVR at post-treatment week 24, yielding a 100% SVR rate in genotype 4 patients. Prior peginterferon/ribavirin response, sex, age, IL28B genotype, or cirrhosis status did not influence SVR12 rates. Serious adverse events occurred in 6% of patients; 5% discontinued treatment due to an adverse event. Grade 3/4 laboratory abnormalities included neutropenia (22%), lymphopenia (16%), anemia (6%), thrombocytopenia (4%), and ALT/AST elevations (3% each).
  
  
  CONCLUSIONS
  Daclatasvir plus asunaprevir and peginterferon/ribavirin demonstrated high rates of SVR12 in genotype 1- or 4-infected prior null or partial responders. The combination was well tolerated and no additional safety and tolerability concerns were observed compared with peginterferon/ribavirin regimens.
authors.affiliation: University of Chicago Medical Center, Chicago, IL, USA. Electronic address: djensen110@gmail.com.
authors.forename: Donald
authors.initials: D
authors.lastname: Jensen
authors.affiliation: University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Sherman
authors.affiliation: Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, AP-HP, Université Paris-Est, INSERM U955, Créteil, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Hézode
authors.affiliation: APHP, Université Paris Descartes, INSERM U1016, Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Pol
authors.affiliation: Johann Wolfgang Goethe Universitaet, Frankfurt, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.affiliation: Hepatology Unit, Hôpital Haut-Leveque, CHU Bordeaux and INSERM U1053, Bordeaux University, France.
authors.forename: Victor
authors.initials: V
authors.lastname: de Ledinghen
authors.affiliation: INSERM U1065, Team 8: Hepatic Complications in Obesity and CHU of Nice Digestive Center, Nice, France.
authors.forename: Albert
authors.initials: A
authors.lastname: Tran
authors.affiliation: Toronto Liver Center, Toronto, Canada.
authors.forename: Magdy
authors.initials: M
authors.lastname: Elkhashab
authors.affiliation: Gastro One, Germantown, TN, USA.
authors.forename: Ziad H
authors.initials: ZH
authors.lastname: Younes
authors.affiliation: South Denver Gastroenterology, Denver, CO, USA.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Kugelmas
authors.affiliation: Center for HIV and Hepatogastroenterology, Duesseldorf, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mauss
authors.affiliation: University of Colorado Denver, Aurora, CO, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Everson
authors.affiliation: Virginia Commonwealth University School of Medicine and McGuire Research Institute, McGuire DVAMC, Richmond, VA, USA.
authors.forename: Velimir
authors.initials: V
authors.lastname: Luketic
authors.affiliation: Baylor College of Medicine, Houston, TX, USA.
authors.forename: John
authors.initials: J
authors.lastname: Vierling
authors.affiliation: Hôpital Saint Antoine, Paris, France.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Serfaty
authors.affiliation: Hepatology Unit, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Pisa, Italy.
authors.forename: Maurizia
authors.initials: M
authors.lastname: Brunetto
authors.affiliation: Department of Internal Medicine, Pusan National University School of Medicine and Medical Research Institute, Pusan National University Hospital, Busan, Republic of Korea.
authors.forename: Jeong
authors.initials: J
authors.lastname: Heo
authors.affiliation: North Shore-Long Island Jewish Health System, Manhasset, NY, USA.
authors.forename: David
authors.initials: D
authors.lastname: Bernstein
authors.affiliation: Bristol-Myers Squibb Research and Development, Wallingford, CT, USA.
authors.forename: Fiona
authors.initials: F
authors.lastname: McPhee
authors.affiliation: Bristol-Myers Squibb Research and Development, Braine-l'Alleud, Belgium.
authors.forename: Delphine
authors.initials: D
authors.lastname: Hennicken
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Mendez
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Hughes
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Noviello
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage; D002219:Carbamates; D004279:DNA, Viral / Q000235:genetics*; D004334:Drug Administration Schedule; D004337:Drug Carriers; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D016898:Interferon-alpha / Q000008:administration & dosage*; D007546:Isoquinolines / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D011759:Pyrrolidines; D011994:Recombinant Proteins / Q000008:administration & dosage; D012254:Ribavirin / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage*; D016896:Treatment Outcome; D014633:Valine / Q000031:analogs & derivatives; D019562:Viral Load / Q000235:genetics; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D004279:DNA, Viral; D004337:Drug Carriers; D007093:Imidazoles; D016898:Interferon-alpha; D007546:Isoquinolines; D011759:Pyrrolidines; D011994:Recombinant Proteins; D013449:Sulfonamides; D011092:Polyethylene Glycols; D012254:Ribavirin; D014633:Valine; C549273:daclatasvir; C100416:peginterferon alfa-2a; C571889:asunaprevir
keywords: Asunaprevir; Daclatasvir; Direct-acting antiviral; NS5A; Null; Partial; Peginterferon alfa