title: Randomized trial of asunaprevir plus peginterferon alfa and ribavirin for previously untreated genotype 1 or 4 chronic hepatitis C.
abstract: OBJECTIVE
  Asunaprevir is a selective HCV NS3 protease inhibitor, active against genotypes 1, 4, 5, and 6 in vitro. We evaluated asunaprevir plus peginterferon alfa-2a/ribavirin (PegIFNα/RBV) for genotype 1 and 4 chronic HCV.
  
  
  METHODS
  In this phase 2b, double-blind, placebo-controlled study, treatment-naive adults with genotype 1 (n=213) or 4 (n=25) were randomly assigned (3:1) to asunaprevir 200mg or placebo twice daily plus PegIFNα/RBV. Asunaprevir recipients, achieving protocol-defined response (HCV-RNA below quantification limit at week 4 and undetectable at week 10), were rerandomized at week 12 to continue asunaprevir-based triple therapy or receive placebo plus PegIFNα/RBV for weeks 13-24. Patients without protocol-defined response (PDR) and placebo recipients continued PegIFNα/RBV through week 48. Co-primary end points were undetectable HCV-RNA at week 4 and 12 (eRVR) and 24 weeks posttreatment (SVR24).
  
  
  RESULTS
  Most patients were male (64.3%), white (83.6%), and had non-CC IL28B genotypes (71.3%). Among genotype 1 patients, eRVR rates (asunaprevir vs. placebo) were 67% (80% CI 62, 72) vs. 6% (80% CI 2, 10); corresponding SVR24 rates were 64% (80% CI 59, 68) vs. 44% (80% CI 36, 53). SVR24 among genotype 4 patients was 89% (asunaprevir) vs. 43% (placebo). Rates of rash and haematologic adverse events were similar between treatment groups. Five asunaprevir-treated patients had grade 4 alanine aminotransferase elevations that resolved following discontinuation (n=4) or with continued dosing (n=1).
  
  
  CONCLUSIONS
  Addition of asunaprevir to PegIFNα/RBV in treatment-naive genotype 1- or 4-infected patients improves response rates and is well tolerated, with aminotransferase elevations that were manageable with appropriate monitoring. ClinicalTrials.gov ID: NCT01030432.
authors.affiliation: INSERM U954, Centre Hospitalier Universitaire de Nancy, Université de Lorraine, Vandoeuvre les Nancy, France. Electronic address: jp.bronowicki@chu-nancy.fr.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bronowicki
authors.affiliation: Groupe Hospitalier Pitié Salpêtrière, Université Pierre et Marie Curie, Paris, France.
authors.forename: Vlad
authors.initials: V
authors.lastname: Ratziu
authors.affiliation: Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Adrian
authors.initials: A
authors.lastname: Gadano
authors.affiliation: Mercy Medical Center, Baltimore, MD, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Thuluvath
authors.affiliation: Hospital Provincial del Centenario, University of Rosario School of Medicine, Rosario, Argentina.
authors.forename: Fernando
authors.initials: F
authors.lastname: Bessone
authors.affiliation: The Research Institute, Springfield, MA, USA.
authors.forename: Claudia T
authors.initials: CT
authors.lastname: Martorell
authors.affiliation: Université Paris Descartes, INSERM U-1016, APHP, Hôpital Cochin, Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Pol
authors.affiliation: Universidad del Salvador Hospital de Gastroenterología Bonorino Udaondo, Buenos Aires, Argentina.
authors.forename: Ruben
authors.initials: R
authors.lastname: Terg
authors.affiliation: Gastro One, Germantown, TN, USA.
authors.forename: Ziad
authors.initials: Z
authors.lastname: Younes
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: He
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Eley
authors.affiliation: Bristol-Myers Squibb, Wallingford, CT, USA.
authors.forename: David
authors.initials: D
authors.lastname: Cohen
authors.affiliation: Bristol-Myers Squibb, Wallingford, CT, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Yu
authors.affiliation: Bristol-Myers Squibb, Wallingford, CT, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Hernandez
authors.affiliation: Bristol-Myers Squibb, Wallingford, CT, USA.
authors.forename: Fiona
authors.initials: F
authors.lastname: McPhee
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Mendez
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Hughes
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000378:metabolism; D000998:Antiviral Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D007546:Isoquinolines / Q000627:therapeutic use*; D008099:Liver / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D007546:Isoquinolines; D011994:Recombinant Proteins; D013449:Sulfonamides; D011092:Polyethylene Glycols; D012254:Ribavirin; D000410:Alanine Transaminase; C100416:peginterferon alfa-2a; C571889:asunaprevir
keywords: Hepatitis C virus; NS3 protease inhibitor; Sustained virologic response; Treatment-naïve