Effects of ribavirin monotherapy on the viral population in patients with chronic hepatitis C genotype 1: Direct sequencing and pyrosequencing of the HCV regions

摘要

Ribavirin remains essential to chronic hepatitis C treatment. This paper investigates the influence of ribavirin priming to steady state before combined pegylated-interferon/ribavirin treatment on viral kinetics, ribavirin trough concentrations, genetic variability within HCVcore, -NS5B and -NS5A, and response to antiviral therapy. A prospective cohort study was made of 27 chronic hepatitis C genotype 1 na?ve patients who received four weeks of ribavirin followed by pegIFN-α-2a/ribavirin for 48 weeks (Group A). The results obtained were compared with those for a control/historical group (Group B). In addition, direct sequencing and pyrosequencing were applied to determine ribavirin monotherapy-induced sequence changes. The rapid, early, and sustained virological response values obtained were 48%, 89%, and 52%, respectively, in Group A, and 52%, 90%, and 52% in Group B (P0.05). In the four-week combined treatment, the Group A patients showed a greater decrease in HCV-RNA (2.3 log10 IU/ml vs. 1.2 log10 IU/ml; P=0.04), lower alanine aminotransferase levels (23.5±1.33 U/L vs. 60.11±18U/L; P0.001) and higher mean ribavirin trough concentrations (3.28±1.26 mg/L vs. 1.74±0.7 mg/L; P=0.001). No general increase in rates of nucleotide substitutions in the ribavirin monotherapy- treated patients was observed in NS5B, ISDR, or PKRbd, but there was a decrease in silent mutations in the HCV core (P=0.04). This result was confirmed by pyrosequencing in the NS5A region. It is concluded that the ribavirin priming combined treatment with pegIFN-α-2a does not improve sustained virological response rates in HCV genotype 1 na?ve infected patients. However, the greater reductions in viral load and alanine aminotransferase levels, together with the higher ribavirin trough concentration values obtained, could reflect the greater effectiveness of the treatment. Ribavirin does not have a mutagenic effect on the virus in patients with chronic hepatitis C.