Mutations in several subgenomic regions of hepatitis C virus (HCV) have been implicated in influencing the response to interferon (IFN) therapy. Sequences within HCV NS5A (PKR binding domain [PKRBD], IFN sensitivity-determining region [ISDR], and variable region 3 [V3]) were analyzed for the pretreatment serum samples of 60 HCV genotype 1-infected patients treated with pegylated IFN plus ribavirin (1b, n ‫؍‬ 47; 1a, n ‫؍‬ 13) but with different treatment outcomes, those with sustained virologic responses (SVR; n ‫؍‬ 36) or nonresponders (NR; n ‫؍‬ 24). Additionally, the sequence of the PKR/eIF-2␣ phosphorylation homology domain (E2-PePHD) region was determined for 23 patients (11 SVR and 12 NR). The presence of >4 mutations in the PKRBD region was associated with SVR (P ‫؍‬ 0.001) and early virologic responses (EVR; 12 weeks) (P ‫؍‬ 0.037) but not rapid virologic responses (4 weeks). In the ISDR, the difference was almost statistically significant (68% of SVR patients with mutations versus 45% without mutations; P ‫؍‬ 0.07). The V3 region had a very high genetic variability, but this was not related to SVR. Finally, the E2-PePHD (n ‫؍‬ 23) region was well conserved. The presence of >4 mutations in the PKRBD region (odds ratio [OR] ‫؍‬ 9.9; P ‫؍‬ 0.006) and an age of <40 years (OR ‫؍‬ 3.2; P ‫؍‬ 0.056) were selected in a multivariate analysis as predictive factors of SVR. NS5A sequences from serum samples taken after 1 month of treatment and posttreatment were examined for 3 SVR and 15 NR patients to select treatment-resistant viral subpopulations, and it was found that in the V3 and flanking regions, the mutations increased significantly in posttreatment sera (P ‫؍‬ 0.05). The genetic variability in the PKRBD (>4 mutations) is a predictive factor of SVR and EVR in HCV genotype 1 patients treated with pegylated IFN and ribavirin.

In conclusion, the combination of 3 MU of interferon plus 600 mg of ribavirin is not effective in chronic hepatitis C resistant to interferon.

Our data do not support RBV plasma monitoring as a tool to optimize treatment in patients with CHC genotype-1, but show that a high RBV plasma concentration could improve SVR rates.

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