Prospective studies of mutations in the E2-PePHD, NS5A-PKRBD, NS5A-ISDR and NS5A-V3 regions of hepatitis C virus genotype 1 and their relationship to peginterferon and ribavirin treatment response

San Cecilio University Hospital, Gastroenterology Unit and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Granada, Spain

^* To whom correspondence should be addressed. Email: fsalmero{at}ugr.es.

	Abstract

Mutations in several subgenomic regions of HCV have been implicated in influencing response to IFN therapy. Sequences within the HCV NS5A (PKR bainding domain (PKRBD), IFN sensitivity-determining region (ISDR) and variable region 3 (V3)), were analyzed in pretreatment serum of 60 patients genotype 1 treated with pegIFN plus ribavirin (1b, n=47 and 1a, n=13) with different treatment outcome: sustained virologic response (SVR, n=36) or non responders (NR, n=24). Additionally, the sequence of the PKR/eIF2 phosphorylation homology domain region (E2-PePHD) was determined in 23 patients (11 SVR and 12 NR). >4 mutations in PKRBD region was associated with SVR (P=0.001) and early virological response (EVR, 12 weeks) (P=0.037); but was not related with rapid virological response (RVR, 4 weeks). In ISDR the difference was almost statistically significant (SVR: 68% with mutations vs 45% without mutations, P=0.07). The V3 region had a very high genetic variability, but this was not related with SVR. Finally, E2-PePHD (n=23) region was well conserved. >4 mutations in PKRBD region (OR=9.9; P=0.006) and an age 40 years (OR=3.2; P=0.056) were selected in multivariate analysis as predictive factors of SVR. NS5A sequences from 1 month treatment and post-treatment serum were examined in 3 SVR and 15 NR to select treatment-resistant viral subpopulations, and it was found that in the V3 and flanking regions, the mutations increased significantly in post-treatment sera (P=0.05).The genetic variability in PKRBD (> 4 mutations) is a predictive factor of SVR and EVR in HCV genotype 1 patients treated with peginterferon and ribavirin.