Mutations in E2-PePHD, NS5A-PKRBD, NS5A-ISDR, and NS5A-V3 of Hepatitis C Virus Genotype 1 and Their Relationships to Pegylated Interferon-Ribavirin Treatment Responses

<jats:title>ABSTRACT</jats:title><jats:p>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,<jats:italic>n</jats:italic>= 47; 1a,<jats:italic>n</jats:italic>= 13) but with different treatment outcomes, those with sustained virologic responses (SVR;<jats:italic>n</jats:italic>= 36) or nonresponders (NR;<jats:italic>n</jats:italic>= 24). Additionally, the sequence of the PKR/eIF-2α 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 (<jats:italic>P</jats:italic>= 0.001) and early virologic responses (EVR; 12 weeks) (<jats:italic>P</jats:italic>= 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;<jats:italic>P</jats:italic>= 0.07). The V3 region had a very high genetic variability, but this was not related to SVR. Finally, the E2-PePHD (<jats:italic>n</jats:italic>= 23) region was well conserved. The presence of >4 mutations in the PKRBD region (odds ratio [OR] = 9.9;<jats:italic>P</jats:italic>= 0.006) and an age of ≤40 years (OR = 3.2;<jats:italic>P</jats:italic>= 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 (<jats:italic>P</jats:italic>= 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.</jats:p>