title: Ritonavir-boosted danoprevir-based regimens in treatment-naive and prior null responders with HCV genotype 1 or 4 and compensated cirrhosis.
abstract: OBJECTIVE
  Effective and safe antiviral treatment regimens are needed for patients with chronic hepatitis C (CHC) and cirrhosis.
  
  
  METHODS
  An international open-label trial was conducted in CHC patients with genotype (G)1/4 infection, compensated cirrhosis, HCV RNA ≥ 50,000 IU/mL and body mass index 18-35 kg/m(2). Treatment-naive patients (Cohort 1) received a triple therapy regimen [danoprevir/r 100/100 mg twice daily (bid), ribavirin 1000/1200 mg/day and peginterferon alfa-2a 180 µg/week] for 24 weeks. Prior null responders (Cohort 2) received a quadruple therapy regimen (danoprevir/r 100/100 mg bid, mericitabine 1000 mg bid and peginterferon alfa-2a/ribavirin). The primary efficacy outcome was sustained virological response (HCV RNA < limit of quantification, target not detected) at end of the 24-week follow-up period (SVR24).
  
  
  RESULTS
  In Cohort 1 (n = 23), 73.9 and 65.2 % of patients had a virological response at Weeks 4 and 24, respectively; 39.1 % achieved SVR24 (G1a = 1/13; G1b = 8/9; G4 = 0/1). In Cohort 2 (n = 20), 100 % achieved virological response at Weeks 4 and 24; 65 % achieved SVR24 (G1a = 4/8; G1b = 7/10; G4 = 2/2). Treatment failure was more common in G1a than G1b-infected patients and less common in patients receiving quadruple therapy. Treatment failure was associated with emergence of resistance to danoprevir, but not mericitabine. The safety profile was typical of that associated with peginterferon alfa-2a/ribavirin. No deaths/episodes of hepatic decompensation occurred.
  
  
  CONCLUSIONS
  Treatment with danoprevir/r-based regimens for 24 weeks is safe and well tolerated in CHC patients with compensated cirrhosis. A quadruple therapy regimen (danoprevir/r, mericitabine, peginterferon alfa/ribavirin) produced high SVR24 rates in prior null responders, particularly among G1b patients.
authors.affiliation: Auckland Clinical Studies, Grafton, New Zealand. edgane@adhb.govt.nz.|Auckland City Hospital, Auckland, 1442, New Zealand. edgane@adhb.govt.nz.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Gane
authors.affiliation: Centre Cap, Centre Médical Odysséum, Montpellier, France.
authors.forename: Régine
authors.initials: R
authors.lastname: Rouzier
authors.affiliation: Southern California Liver Centers, Coronado, CA, USA.
authors.forename: Tarek
authors.initials: T
authors.lastname: Hassanein
authors.affiliation: Christchurch Clinical Studies and University of Otago, Christchurch, New Zealand.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Stedman
authors.affiliation: Department of Infectious Diseases, Medical University of Silesia, Katowice, Poland.
authors.forename: Wlodzimierz
authors.initials: W
authors.lastname: Mazur
authors.affiliation: Medical Faculty of Comenius University, Dérer's Hospital, Bratislava, Slovakia.
authors.forename: Viera
authors.initials: V
authors.lastname: Kupcova
authors.affiliation: Hoffmann-La Roche Inc, Nutley, NJ, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Le Pogam
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Eng
authors.affiliation: Roche Products Ltd, Welwyn, UK.
authors.forename: Athina
authors.initials: A
authors.lastname: Voulgari
authors.affiliation: Hoffmann-La Roche Inc, Nutley, NJ, USA.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Morcos
authors.affiliation: Hoffmann-La Roche Inc, Nutley, NJ, USA.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Brennan
authors.affiliation: Roche Products Ltd, Welwyn, UK.
authors.forename: Astrid
authors.initials: A
authors.lastname: Scalori
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Thommes
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D003521:Cyclopropanes; D004334:Drug Administration Schedule; D005260:Female; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006526:Hepatitis C / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use; D054833:Isoindoles; D007769:Lactams / Q000008:administration & dosage / Q000627:therapeutic use*; D047029:Lactams, Macrocyclic; D008103:Liver Cirrhosis / Q000209:etiology* / Q000821:virology; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use; D011392:Proline / Q000031:analogs & derivatives; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012254:Ribavirin / Q000008:administration & dosage / Q000627:therapeutic use; D019438:Ritonavir / Q000008:administration & dosage / Q000627:therapeutic use*; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D017211:Treatment Failure
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D016898:Interferon-alpha; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D011994:Recombinant Proteins; D013449:Sulfonamides; D011092:Polyethylene Glycols; D012254:Ribavirin; C553752:danoprevir; D011392:Proline; D019438:Ritonavir; C100416:peginterferon alfa-2a
keywords: Chronic hepatitis C; Direct acting antiviral; Microsoftericitabine; Quadruple therapy; Sustained virological response; Triple therapy