Abstract
Pegylated-interferon plus ribavirin (PEG-IFN/RBV) therapy is a current standard treatment for chronic hepatitis C. We previously reported that the viral sequence heterogeneity of part of NS5A, referred to as the IFN/RBV resistance-determining region (IRRDR), and a mutation at position 70 of the core protein of hepatitis C virus genotype 1b (HCV-1b) are significantly correlated with the outcome of PEG-IFN/RBV treatment. Here, we aimed to investigate the impact of viral genetic variations within the NS5A and core regions of other genotypes, HCV-2a and HCV-2b, on PEG-IFN/RBV treatment outcome. Pretreatment sequences of NS5A and core regions were analyzed in 112 patients infected with HCV-2a or HCV-2b, who were treated with PEG-IFN/RBV for 24 weeks and followed up for another 24 weeks. The results demonstrated that HCV-2a isolates with 4 or more mutations in IRRDR (IRRDR[2a]≥4) was significantly associated with rapid virological response at week 4 (RVR) and sustained virological response (SVR). Also, another region of NS5A that corresponds to part of the IFN sensitivity-determining region (ISDR) plus its carboxy-flanking region, which we referred to as ISDR/+C[2a], was significantly associated with SVR in patients infected with HCV-2a. Multivariate analysis revealed that IRRDR[2a]≥4 was the only independent predictive factor for SVR. As for HCV-2b infection, an N-terminal half of IRRDR having two or more mutations (IRRDR[2b]/N≥2) was significantly associated with RVR, but not with SVR. No significant correlation was observed between core protein polymorphism and PEG-IFN/RBV treatment outcome in HCV-2a or HCV-2b infection. Conclusion: The present results suggest that sequence heterogeneity of NS5A of HCV-2a (IRRDR[2a]≥4 and ISDR/+C[2a]), and that of HCV-2b (IRRDR[2b]/N≥2) to a lesser extent, is involved in determining the viral sensitivity to PEG-IFN/RBV therapy.
Highlights
Hepatitis C virus (HCV) is a major cause of chronic liver disease, such as chronic hepatitis, liver cirrhosis and hepatocellular carcinoma, with180 million people being currently infected with HCV worldwide
Of the 61 patients infected with HCV-2a, 46 (75%) patients cleared HCV viremia by week 4, and all the patients (100%) by week 12 and at week 24 (Table 1)
To investigate the impact of NS5A heterogeneity on the clinical outcome of pegylated interferon alpha (PEG-IFN)/RBV therapy, we first performed a sliding window analysis with a window size of 20 residues over the fulllength NS5A sequences obtained from 23 rapid virological response at week 4 (RVR) and 7 non-RVR patients infected with HCV-2a along with the consensus sequence, as described previously [8]
Summary
Hepatitis C virus (HCV) is a major cause of chronic liver disease, such as chronic hepatitis, liver cirrhosis and hepatocellular carcinoma, with180 million people being currently infected with HCV worldwide. It is estimated that 70% of acute infections become persistent [1]. As a consequence of the long-term persistence of HCV infection, the number of patients with hepatocellular carcinoma is expected to increase further over the 20 years. More than two decades have passed since the discovery of HCV, and yet therapeutic options remain limited. Standard regimens for treatment of chronic hepatitis C include pegylated interferon alpha (PEG-IFN) and ribavirin (RBV) [2]. S. Food and Drug Administration (FDA) for clinical use in combination with PEG-IFN/RBV to treat chronic hepatitis C patients with HCV genotype 1 [3,4]
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