title: High dose daily interferon-alpha induction and secondary adjunction of ribavirin in treatment-naive patients with chronic hepatitis C. A multicentric, randomised, controlled trial.
abstract: OBJECTIVE
  To evaluate in naive patients with chronic hepatitis C 1- the efficacy and safety of one month interferon alpha (IFN-alpha) induction regimen; 2- the potential virological benefit of a secondary adjunction of ribavirin among HCV RNA negative patients after 20 weeks of IFN therapy, with or without an initial 4-week IFN induction.
  
  
  METHODS
  151 naive HCV-RNA positive patients presenting with biopsy- proven chronic hepatitis C and elevated ALT were randomised in a 2: 1 ratio in two arms: IFN-alpha 3 MU thrice a week (tiw) for 24 weeks (non-induced patients); IFN-alpha 6 MU daily for two weeks, then 3 MU daily for two weeks then 3 MU tiw for 20 weeks (induced patients). At week 24, HCV-RNA negative patients were randomised to receive in addition or not ribavirin 1-1.2 g daily for 24 additional weeks. Induction efficacy was assessed on the early viral response (EVR) defined as undetectable HCV RNA at week 4 then week 20. Ribavirin efficacy was assessed on the proportion of maintained complete response until the end of follow-up, 24 weeks after discontinuation of treatment. Data were analysed on an intent-to-treat basis.
  
  
  RESULTS
  Efficacy of IFN-alpha induction: 104 patients were randomised to the non-induction group, 47 to the induction group. Gender, age, genotype distribution and HCV viral load at baseline did not differ significantly between the two groups. There was one treatment discontinuation because of adverse events in induced patients versus four in non-induced patients (P > 0.05). The 4 week EVR was significantly greater in induced patients in patients with HCV genotype 1, 4 or 5 (47% vs 12%, P=0.0002) only. There was no impact of induction in patients with HCV genotype 2 or 3. Efficacy of ribavirin: at week 24, 28 and 26 HCV-RNA negative patients were randomised to addition of ribavirin or not, respectively. Patients randomised to secondary additive ribavirin were more often HCV-RNA negative at the end of follow-up than patients treated with IFN-alpha alone: 18/28 (64%) vs 10/26 (39%); P=0.06. Among patients randomised to bitherapy, the relapse rate was significantly lower in patients with genotype 2 or 3 (0/12 vs 6/13, P=0.01) and not in those with genotype 1, 4 or 5 (5/11 vs 3/6, P=0.99).
  
  
  CONCLUSIONS
  A 4 week IFN-alpha induction significantly increases the EVR rate in patients with HCV genotype 1, 4 or 5. Late secondary adjunction of ribavirin to IFN-alpha for 6 months in HCV-RNA negative patients after 6 months of IFN-alpha significantly decreases the relapse rate in patients with HCV genotype 2 or 3, but not in patients with genotypes 1, 4 or 5.
authors.affiliation: Centre Hospitalier du Pays d'Aix, Service d'Hépato-Gastroentérologie, Avenue des Tamaris, 13616 Aix en Provence Cedex. cwartelle@ch-aix.fr
authors.forename: Claire
authors.initials: C
authors.lastname: Wartelle-Bladou
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Arpurt
authors.forename: Christophe
authors.initials: C
authors.lastname: Renou
authors.forename: Alexandre
authors.initials: A
authors.lastname: Pariente
authors.forename: Didier
authors.initials: D
authors.lastname: Pillon
authors.forename: Bernard
authors.initials: B
authors.lastname: Nalet
authors.forename: Magali
authors.initials: M
authors.lastname: Picon
authors.forename: André
authors.initials: A
authors.lastname: Glibert
authors.forename: Michel
authors.initials: M
authors.lastname: Chousterman
authors.forename: Denis
authors.initials: D
authors.lastname: Grasset
authors.forename: Thierry
authors.initials: T
authors.lastname: Morin
authors.forename: Pierre
authors.initials: P
authors.lastname: Bernard
authors.forename: Daniel
authors.initials: D
authors.lastname: Fischer
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ramdani
authors.forename: Evelyne
authors.initials: E
authors.lastname: Lagier
authors.forename: Michel
authors.initials: M
authors.lastname: Rotily
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D012367:RNA, Viral / Q000032:analysis / Q000097:blood; D012254:Ribavirin / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D012367:RNA, Viral; D012254:Ribavirin