Mutations in the interferon sensitivity determining region and virological response to combination therapy with pegylated-interferon alpha 2b plus ribavirin in patients with chronic hepatitis C-1b infection

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
Journal of Gastroenterology (Impact Factor: 4.52). 06/2010; 45(6):656-65. DOI: 10.1007/s00535-009-0195-7
Source: PubMed


Pegylated-interferon-alpha 2b (PEG-IFN) plus ribavirin (RBV) therapy is currently the de-facto standard treatment for hepatitis C virus (HCV) infection. The aims of this study were to analyze the clinical and virological factors associated with a higher rate of response in patients with HCV genotype 1b infection treated with combination therapy.
We analyzed, retrospectively, 239 patients with chronic hepatitis C-1b infection who received 48 weeks of combination therapy. We assessed clinical and laboratory parameters, including age, gender, pretreatment hemoglobin, platelet counts, HCV RNA titer, liver histology, the number of interferon sensitivity determining region (ISDR) mutations and substitutions of the core amino acids 70 and 91. Drug adherence was monitored in each patient. We carried out univariate and multivariate statistical analyses of these parameters and clinical responses.
On an intention-to-treat (ITT) analysis, 98 of the 239 patients (41%) had sustained virological responses (SVRs). Patients with more than two mutations in the ISDR had significantly higher SVR rates (P<0.01). Univariate analyses showed that stage of fibrosis, hemoglobin, platelet counts, ISDR mutations, serum HCV RNA level, and adherence to PEG-IFN plus RBV were significantly correlated with SVR rates. Multivariate analysis in subjects with good drug adherence extracted the number of ISDR mutations (two or more: odds ratio [OR] 5.181).
The number of mutations in the ISDR sequence of HCV-1b (>or=2) is the most effective parameter predicting a favorable clinical outcome of 48-week PEG-IFN plus RBV therapy in patients with HCV genotype 1b infection.

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    • "None of the mutation sites overlapped with a region in NS5A (encompassing amino acids 237–276) referred to as the IFN sensitivity determining region (ISDR). HCV variants with mutations in this putative ISDR central region of NS5A were previously reported to influence the outcome of IFN therapy, suggesting a role for the HCV protein in IFN resistance (Nakagawa et al., 2010; Tran et al., 2011). No amino acid substitutions were identified in the NS4A and NS4B coding regions of the various IFN-resistant replicon cell lines. "
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    • "The mean number of mutations within the ISDR that differ from resistant prototype genotype 1a, 1b and 3a strains increases The natural history of acute HCV in HIV+ve MSM the likelihood of SVR (a mean two to four mutations difference confers protection; Pascu et al., 2004; MacQuillan et al., 2004; Nakagawa et al., 2010). A mutation within HCV core – the R70Q substitution is also strongly associated with resistance and lack of early virological response (EVR; Enomoto & Maekawa, 2010). "
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    • "The association of variability in the ISDR with non-response has been consistently found in Japanese patients infected with subtype 1b, but is weak in other contexts [49,50]. The sequence at the ISDR remains an independent predictor of outcome for Japanese genotype 1b patients even when normalized for the effect of IL28B polymorphisms [51,52]. "
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