title: Efficiency and Safety of an Early Dose Adjustment of Ribavirin in Patients Infected With Hepatitis C Underexposed to the Drug and Treated With Peginterferon Ribavirin.
abstract: Ribavirin exposure after the first dose (D0AUC0-4h) >1755 mcg·h·L is predictive of sustained virological response (SVR) in patients with hepatitis C treated with peginterferon and ribavirin. The aim of this study was to test the benefit of ribavirin early dose adjustment based on this target in naïve patients infected with genotype 1.
  
  
  
  A multicenter randomized controlled trial with two parallel groups; fixed-dose (FD) group: standard of care in 2010-2011, ie, peginterferon-α2a 180 mcg·wk and weight-based ribavirin 1000-1200 mg/d during 48 weeks; adapted-dose (AD) group: increase of ribavirin dose if D0AUC0-4h <1755 mcg·h·L.
  
  
  
  A total of 221 patients were included, 110 in the AD group and 111 in the FD group with similar baseline characteristics. In the perprotocol analysis, SVR was higher in the AD group (55.1% versus 40.4%; P = 0.042), especially in patients with D0AUC0-4h <1755 mcg·h·L (54.3% versus 31.9%; P = 0.029). In the intention-to-treat analysis, the difference was not significant (50% versus 41%; P = 0.197). Ribavirin trough concentrations (C0s) at week 4 of treatment (intention-to-treat analysis) were higher in patients achieving SVR (2.06 versus 1.72 mg/L, P = 0.003). In the subgroup of patients with AUC0-4h <1755 mcg·h·L, 46% of patients with AD achieved a C0 >2.0 mg/L versus 22% of patients with FD (P = 0.013). Grade 1 anemia (but not other grades) was more frequent in the AD group (70% versus 48%, P = 0.001). The number of dose reductions or discontinuation of ribavirin was similar in both groups.
  
  
  
  Early ribavirin dose adjustment increases SVR in patients underexposed to ribavirin without increasing grade II-IV anemia. Such a strategy could be useful in patients with no access to new antiviral drugs.
authors: *Service d'Hépatogastroentérologie, Hôpital Dupuytren, Limoges; †INSERM, U850, Université de Limoges, F-87000 Limoges; ‡Service d'Hépatologie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon; §INSERM, U1092, Université de Limoges, F-87000 Limoges; ∥Laboratoire de Pharmacologie Spécialisée, Hôpital E. Herriot, Hospices Civils de Lyon, Lyon; ¶U1052, INSERM, Lyon; **Pôle de Référence Hépatite C, Hôpital Archet 2, Nice; ††Service d'Hépato-gastro-entérologie et nutrition, Hôpital de la Côte de Nacre, CAEN; ‡‡Service d'Hépato-gastro-entérologie, Centre Hospitalier Universitaire de Poitiers; §§Département Biologie des agents infectieux et pharmacotoxicologie-Virologie, Centre Hospitalier Universitaire d'Angers, Angers; ‖‖Direction de la Recherche Clinique et de l'Innovation, Hospices Civils de Lyon, Lyon, France; and ¶¶Laboratoire de Pharmacologie Médicale, Université de Limoges.
authors: Véronique
authors: V
authors: Loustaud-Ratti
authors: Marianne
authors: M
authors: Maynard
authors: Sylvie
authors: S
authors: Thevenon
authors: Pierre
authors: P
authors: Pradat
authors: Annick
authors: A
authors: Rousseau
authors: Sophie
authors: S
authors: Alain
authors: Paul
authors: P
authors: Deny
authors: Marie-Claude
authors: MC
authors: Gagnieu
authors: Albert
authors: A
authors: Tran
authors: Thông
authors: T
authors: Dao
authors: Christine
authors: C
authors: Silvain
authors: Françoise
authors: F
authors: Lunel-Fabiani
authors: Nicolas
authors: N
authors: Picard
authors: Irène
authors: I
authors: Zublena
authors: Pierre
authors: P
authors: Marquet
authors: Christian
authors: C
authors: Trepo
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D007372:Interferons / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D064792:Pragmatic Clinical Trials as Topic; D011994:Recombinant Proteins / Q000008:administration & dosage*; D012254:Ribavirin / Q000008:administration & dosage* / Q000009:adverse effects*
chemical_list: D000998:Antiviral Agents; D011994:Recombinant Proteins; D012254:Ribavirin; D007372:Interferons