title: Low virological response and high relapse rates in hepatitis C genotype 1 patients with advanced fibrosis despite adequate therapeutic dosing.
abstract: OBJECTIVE
  The impact of fibrosis stage on chronic hepatitis C virus (HCV) treatment response was explored in CHARIOT, a study of high dose peginterferon alfa-2a (PEG-IFNalpha-2a) induction therapy in treatment naïve genotype 1 infection.
  
  
  METHODS
  Eight hundred and ninety-six patients were randomised 1:1 to 360 microg (n=448) or 180 microg (n=448) PEG-IFNalpha-2a weekly with RBV 1000-1200 mg/day for 12 weeks followed by 36 weeks of 180 microg PEG-IFNalpha-2a weekly plus RBV 1000-1200 mg/day. Virological responses were assessed at week 4, 8, 12, 24, 48 (end of therapy), and 24 weeks following therapy (sustained virological response, SVR). As previously reported, there was no significant difference in SVR in the induction (53%) and standard (50%) arms, therefore the pooled study population was used for analysis of SVR and relapse.
  
  
  RESULTS
  A marked step-wise decline in SVR was evident by fibrosis stage: F0 (70%); F1 (60%); F2 (51%); F3 (31%); F4 (10%) (p<0.0001). Early virological responses were lower among F3/4 patients, including rapid virological response (RVR) (21% vs. 34% for F3/4 and F0-2, respectively) (p=0.0072), and the RVR positive predictive value was also lower (63% vs. 80%). Virological relapse rates were similar in early disease stages (F0, 16%; F1, 23%; F2, 26%), but increased markedly in advanced fibrosis (F3, 50%; F4, 80%) (p<0.0001). Cumulative PEG-IFNalpha-2a and ribavirin doses were similar among patients with F3/4 and F0-2 within treatment arms through week 4, 8, 12, and week 24.
  
  
  CONCLUSIONS
  Low virological response in hepatitis C genotype 1 patients with advanced fibrosis is not explained by inadequate cumulative PEG-IFN and ribavirin doses.
authors.affiliation: Royal Perth Hospital, Perth, Australia.
authors.forename: Wendy S C
authors.initials: WS
authors.lastname: Cheng
authors.forename: Stuart K
authors.initials: SK
authors.lastname: Roberts
authors.forename: Geoffrey
authors.initials: G
authors.lastname: McCaughan
authors.forename: William
authors.initials: W
authors.lastname: Sievert
authors.forename: Martin
authors.initials: M
authors.lastname: Weltman
authors.forename: Darrell
authors.initials: D
authors.lastname: Crawford
authors.forename: William
authors.initials: W
authors.lastname: Rawlinson
authors.forename: Philippa S
authors.initials: PS
authors.lastname: Marks
authors.forename: James
authors.initials: J
authors.lastname: Thommes
authors.forename: Bishoy
authors.initials: B
authors.lastname: Rizkalla
authors.forename: Motoko
authors.initials: M
authors.lastname: Yoshihara
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Dore
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage*; D005260:Female; D005838:Genotype; D006526:Hepatitis C / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage*; D008103:Liver Cirrhosis / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D011994:Recombinant Proteins; D012008:Recurrence; D012254:Ribavirin / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a