Polymorphisms of Hepatitis C Virus Non-Structural Protein 5A and Core Protein and Clinical Outcome of Pegylated-Interferon/Ribavirin Combination Therapy

Division of Microbiology, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Japan.
Intervirology (Impact Factor: 1.77). 02/2011; 55(1):1-11. DOI: 10.1159/000322219
Source: PubMed

ABSTRACT Objective: Hepatitis C virus (HCV genome) polymorphisms are thought to influence the outcome of pegylated-interferon/ribavirin (PEG-IFN/RBV) therapy. This study aimed to examine non-structural protein 5A (NS5A) polymorphisms, e.g. IFN/RBV resistance-determining region (IRRDR) and IFN sensitivity-determining region (ISDR), and core protein polymorphism as predictive therapeutic markers.
Pretreatment sequences of NS5A and core regions were analyzed in 68 HCV-1b-infected patients treated with PEG-IFN/RBV.
Of 24 patients infected withHCV having an IRRDR with 6 or more mutations (IRRDR≥6), 18 (75%) patients achieved sustained virological response (SVR), whereas only 11 (25%) of 44 patients infected with HCV having IRRDR≤5 did. IRRDR≥6 was significantly associated with SVR (p < 0.0001). On the other hand, ISDR≥2 was significantly associated with relapse (either before [breakthrough] or after end-of-treatment response [ETR[-]relapse]) (p < 0.05) and a point mutation of the core protein from Arg to Gln at position 70 (Gln(70)) was significantly associated with null-response (p < 0.05). Multivariate analysis identified IRRDR≥6 as the only viral genetic factor that independently predicted SVR.
NS5A (IRRDR and ISDR) and core protein polymorphisms are associated with the outcome of PEG-IFN/RBV therapy for chronic hepatitis C. In particular, IRRDR≥6 is a useful marker for prediction of SVR.

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    • "Previous studies have shown that there is a significant correlation between mutations in the core protein and poor treatment outcome. In particular, patients who had substitutions of Arg70 to Gln70 and/or Leu91 to Met91 showed lower response to PEG-IFN/RBV combined therapy [19,20]. However, most of these studies have been conducted on Asian populations, especially Japanese patients, who were diagnosed with HCV genotype 1b. "
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    • "According to recent clinical studies of patients with CH-C genotype-1b, mutation of amino acids 70 and 91 in the core region of HCV-1b, as a virus-related factor, and genomic variation of the IL28B gene (rs8099917), as a host-related factor, are strong predictors of the outcome of peg-IFN plus ribavirin combination therapy [76–79]. Within the core protein, substitution of amino acid 70 seems to be more influential on the outcome than substitution of amino acid 91 [79–81]. At present, our trial has yielded several important findings (unpublished data). "
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