title: Randomized study of danoprevir/ritonavir-based therapy for HCV genotype 1 patients with prior partial or null responses to peginterferon/ribavirin.
abstract: OBJECTIVE
  Chronic hepatitis C treatment for prior non-responders to peginterferon (PegIFN)/ribavirin remains suboptimal. The MATTERHORN study evaluated regimens containing ritonavir-boosted danoprevir (danoprevir/r) in prior PegIFN alfa/ribavirin non-responders.
  
  
  METHODS
  Prior partial responders (N=152) were randomized to 24 weeks of twice-daily danoprevir/r 100/100mg, mericitabine 1000 mg and ribavirin 1000/1200 mg (IFN-free); danoprevir/r plus PegIFN alfa-2a/ribavirin (triple); or danoprevir/r, mericitabine and PegIFN alfa-2a/ribavirin (Quad). Prior null responders (N=229) were randomized to 24 weeks of IFN-free therapy, or quad alone (Quad 24) or quad plus 24-weeks of PegIFN alfa-2a/ribavirin (Quad 48). The primary endpoint was sustained virological response (HCV RNA <25 IU/ml) 24 weeks after end-of-treatment (SVR24). Due to high relapse rates, genotype (G) 1a patients in IFN-free arms were offered additional PegIFN alfa-2a/ribavirin.
  
  
  RESULTS
  Among prior partial responders, SVR24 rates were 46.2%, 51.0%, and 86.0%, in the IFN-free, Triple and Quad arms, respectively; among prior null responders, SVR24 rates were 45.5%, 80.5%, and 83.8% respectively. Relapse rates were lower and SVR24 rates higher in G1b-infected than G1a-infected patients. SVR24 rates in G1a and G1b patients randomized to Quad were 75.0% and 96.2%, respectively, in the partial Quad arm, and 68.1% and 100%, respectively, in the null Quad 24 arm. Treatment failure was associated with resistance to danoprevir, but not to mericitabine, and was more common in G1a infected patients. Treatment was well-tolerated.
  
  
  CONCLUSIONS
  Danoprevir/r, mericitabine plus PegIFN alfa-2a/ribavirin was well-tolerated and produced high overall SVR24 rates in prior partial and null responders to PegIFN alfa/ribavirin. In contrast, IFN-free regimens were associated with unacceptably high relapse rates.
authors.affiliation: Toronto Centre for Liver Disease, McLaughlin-Rotman Centre for Global Health, Toronto, ON, Canada. Electronic address: jordan.feld@uhn.ca.
authors.forename: Jordan J
authors.initials: JJ
authors.lastname: Feld
authors.affiliation: Center for the Study of Hepatitis C, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Ira M
authors.initials: IM
authors.lastname: Jacobson
authors.affiliation: Center for Liver Diseases, University of Chicago Hospitals, Chicago, IL, USA.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Jensen
authors.affiliation: Queen Mary, University of London, Institute of Cellular and Molecular Sciences, London, UK.
authors.forename: Graham R
authors.initials: GR
authors.lastname: Foster
authors.affiliation: Hôpital Cochin, Université Paris Descartes and INSERM U1610, Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Pol
authors.affiliation: LAIR Centre, Vancouver, BC, Canada.
authors.forename: Edward
authors.initials: E
authors.lastname: Tam
authors.affiliation: Medical University of Lodz, Lodz, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Jablkowski
authors.affiliation: Hospital of Infectious Diseases, Warsaw, Poland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Berak
authors.affiliation: Baylor College of Medicine, Houston, TX, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Vierling
authors.affiliation: University of British Columbia, Vancouver, BC, Canada.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Yoshida
authors.affiliation: Hospital Civil de Guadalajara, Instituto de Patologia Infecciosa, Universidad de Guadalajara, Guadalajara, Mexico.
authors.forename: Héctor R
authors.initials: HR
authors.lastname: Perez-Gomez
authors.affiliation: Roche Products Ltd, Welwyn, UK.
authors.forename: Astrid
authors.initials: A
authors.lastname: Scalori
authors.affiliation: Roche Products Ltd, Welwyn, UK.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Hooper
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Tavel
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Mercidita T
authors.initials: MT
authors.lastname: Navarro
authors.affiliation: Roche Products Ltd, Welwyn, UK.
authors.forename: Saba
authors.initials: S
authors.lastname: Shahdad
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Rohit
authors.initials: R
authors.lastname: Kulkarni
authors.affiliation: Hoffmann-La Roche Inc, Nutley, NJ, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Le Pogam
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Isabel
authors.initials: I
authors.lastname: Nájera
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Eng
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Chin Yin
authors.initials: CY
authors.lastname: Lim
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Shulman
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Ellen S
authors.initials: ES
authors.lastname: Yetzer
mesh_terms: D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D003521:Cyclopropanes; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004337:Drug Carriers; D004359:Drug Therapy, Combination; D005500:Follow-Up Studies; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000821:virology; D016898:Interferon-alpha / Q000008:administration & dosage; D054833:Isoindoles; D007769:Lactams / Q000008:administration & dosage; D047029:Lactams, Macrocyclic; D011092:Polyethylene Glycols / Q000008:administration & dosage; D011392:Proline / Q000031:analogs & derivatives; D011994:Recombinant Proteins / Q000008:administration & dosage; D012189:Retrospective Studies; D012254:Ribavirin / Q000008:administration & dosage; D019438:Ritonavir / Q000008:administration & dosage; D012367:RNA, Viral / Q000235:genetics; D013449:Sulfonamides / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D003521:Cyclopropanes; D065692:Cytochrome P-450 CYP3A Inhibitors; C553752:danoprevir; D004337:Drug Carriers; D016898:Interferon-alpha; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; C100416:peginterferon alfa-2a; D011092:Polyethylene Glycols; D011392:Proline; D011994:Recombinant Proteins; D012254:Ribavirin; D019438:Ritonavir; D012367:RNA, Viral; D013449:Sulfonamides
keywords: Danoprevir; Genotype 1; HCV; Mericitabine; Non-responders; Peginterferon/ribavirin; Quad therapy