Antiviral action of ribavirin in chronic hepatitis C.
OBJECTIVE
In the patients with chronic hepatitis C, the addition of ribavirin to interferon (IFN)-alpha significantly increases the virologic responses. Our aim was to assess the antiviral action of ribavirin on hepatitis C virus (HCV) as a function of ribavirin pharmacokinetics and to evaluate the influence of this antiviral effect on IFN-alpha efficacy.


METHODS
Forty-five patients with chronic hepatitis C (genotype 1b) received various schedules of IFN-alpha and/or ribavirin administration. Frequent blood sampling was performed for HCV RNA kinetics and ribavirin pharmacokinetics assessment.


RESULTS
Ribavirin monotherapy induced a significant, moderate, early, and transient viral load decrease in approximately half of the patients. The occurrence of this effect was associated with longer ribavirin clearance half-lives and higher serum ribavirin concentrations. Ribavirin antiviral effect partly reduced the rebound preceding the second IFN-alpha injection in patients receiving standard IFN-alpha 3 times per week plus ribavirin. The magnitude of the rebound was inversely related to ribavirin concentrations. These patients subsequently experienced a slow, but significant, second slope of viral decrease and cleared HCV RNA. The addition of ribavirin to daily IFN-alpha monotherapy did not have any impact on the second phase of viral decline.


CONCLUSIONS
Ribavirin exerts a significant, moderate, and transient antiviral effect in a significant proportion of patients with chronic hepatitis C. The antiviral effect of ribavirin correlates with ribavirin pharmacokinetics and is partly responsible for the improved efficacy of the combination of standard IFN-alpha and ribavirin compared with IFN-alpha monotherapy by increasing the incidence of the initial response.
Department of Virology, INSERM U635, Hôpital Henri Mondor, Université Paris XII, Créteil, France. jean-michel.pawlotsky@hmn.ap-hop-paris.fr
Jean-Michel
JM
Pawlotsky
Harel
H
Dahari
Avidan U
AU
Neumann
Christophe
C
Hezode
Georgios
G
Germanidis
Isabelle
I
Lonjon
Laurent
L
Castera
Daniel
D
Dhumeaux
D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016022:Case-Control Studies; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009994:Osmolar Concentration; D012367:RNA, Viral / Q000378:metabolism; D012254:Ribavirin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load
D000998:Antiviral Agents; D016898:Interferon-alpha; D012367:RNA, Viral; D012254:Ribavirin