Plasma Ribavirin Assay During Combination Therapy for Chronic Hepatitis C

Background and rational The serum concentrationS of ribavirin commonly range from 1 to 5 in patients during the combination treatment " interferon+ribavirin " (Larrat et al. 2003). However, the bioavailibility of ribavirin is not considered in the current recommendation for this treatment.

The aim of this study is to demonstrate that the adaptation " à la carte " of ribavirin posology according to its serum concentration could improve the efficacy and the tolerance of the hepatitis C combination therapy.

Study design This study is a prospective clinical pharmacology trial in patients on combination treatment for a chronic hepatitis C with genotype 1 or 4 virus.

The evaluation will concern the serum ribavirin concentration during the first three months of treatment and its correlation with the evolution of hemoglobin (toxicity marker) or viral load (efficacy marker).

After the 3 months of the study, a adaptation of posology based on serum ribavirin level will be offer to the patients for the rest of the treatment period. A control of the ribavirin level one month after the dose adaptation will be performed.

Judgement endpoints

There will be intermediate endpoints :

• blood hemoglobin concentration whom reduction during the 4 first weeks of treatment is a marker of toxicicty of the drug (induction of an hemolytic anemiae)
• viral load whom reduction of at least 2 log after 12 weeks of treatment is correlated with the sustained virologic response to treatment
• serum level of ribavirin for which it is expected a correlation with the two previous biological markers

The primary judgement endpoint will be the statistical correlation as following :

• the serum concentration of ribavirine at the plateau of pharmacokinetics (J28(S4))
• the change of the hemoglobin concentration from D0 to D28(S4)
• the change of hemoglobin concentration between D0 and D84(S12)