A substantial proportion of hepatitis C virus (HCV)-1b-infected patients still do not respond to interferon-based therapy. This study aims to explore a predictive marker for the ultimate virological response of HCV-1b-infected patients treated with pegylated interferon/ribavirin (PEG-IFN/RBV) combination therapy. Nonstructural protein 5A (NS5A) sequences of HCV in the pretreated sera of 45 patients infected with HCV-1b were analyzed. The mean number of mutations in the variable region 3 (V3) plus its upstream flanking region of NS5A (amino acid 2334-2379), referred to as IFN/RBV resistance-determining region (IRRDR), was significantly higher for HCV isolates obtained from patients who later achieved sustained virological response (SVR) by PEG-IFN/RBV than for those in patients undergoing non-SVR. The receiver operating characteristic curve analysis estimated six mutations in IRRDR as the optimal threshold for SVR prediction. Indeed, 16 (76%) of 21 SVR, but only 2 (8%) of 24 non-SVR, had HCV with six or more mutations in IRRDR (IRRDR > 6) (P < 0.0001). All of 18 patients infected with HCV of IRRDR of 6 or greater examined showed a significant (>1 log) reduction or disappearance of serum HCV core antigen titers within 24 hours after initial dose of PEG-IFN/RBV, whereas 10 (37%) of 27 patients with HCV of IRRDR of 5 or less did (P < 0.0001). The positive predictive value of IRRDR of 6 or greater for SVR was 89% (16/18; P ‫؍‬ 0.0007), with its negative predictive value for non-SVR being 81% (22/27; P ‫؍‬ 0.0008). Conclusion: A high degree (>6) of sequence variation in IRRDR would be a useful marker for predicting SVR, whereas a less diverse (<5) IRRDR sequence predicts non-SVR. (HEPATOLOGY 2008;48:38-47.) H epatitis C virus (HCV) infection is the major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma in industrialized countries. However, HCV infection is curable, and its complications can be prevented by antiviral therapy. 1,2 Currently, the most effective treatment of chronic HCV infection is based on a combination of pegylated interferon (PEG-IFN) and ribavirin (RBV). 3 Even with this treatment regimen, however, sustained virological response (SVR) rates for those infected with the most resistant genotypes, HCV-1a and HCV-1b, still hover at approximately 50%. 3,4 Considering the high cost and the significant side effects associated with this combination therapy, it is worthy to identify patients most likely to benefit from therapy. 5 Predictors of IFN-based therapy can be classified into two categories, pretreatment and on-treatment factors. Pretreatment factors comprise host factors, such as age, sex, obesity, ethanol consumption, hepatic iron overload, fibrosis, immune responses, and coinfection with other viruses, and viral factors, which mainly include viral genotypes and viral load. On-treatment factors are mainly related to the viral kinetics within

A considerable number of patients infected with Hepatitis C virus subtype 1b (HCV‐1b) do not respond to pegylated interferon/ribavirin combination therapy. In this study we explored a useful factor(s) to predict treatment outcome. A total of 47 HCV‐1b‐infected patients were treated with pegylated interferon/ribavirin for 48 weeks. Sera of the patients were examined for the entire NS5A sequence of the HCV genome, HCV RNA titers and anti‐NS5A antibodies. According to their responses, the patients were divided into two groups, early viral responders who cleared the virus by week 16 (EVR[16w]) and those who did not (Non‐EVR[16w]). The mean number of mutations in the V3 region (aa 2356 to 2379) or that in the V3 region plus its N‐terminally flanking region, which we refer to as interferon/ribavirin resistance‐determining region (IRRDR; aa 2334 to 2379), of NS5A obtained from the pretreatment sera was significantly larger for EVR(16w) compared with Non‐EVR(16w). Moreover, HCV‐1b isolates with ≥5 mutations in V3 or those with ≥6 mutations in IRRDR were almost exclusively found in EVR(16w). Also, the presence of detectable levels of anti‐NS5A antibodies in the pretreatment sera was closely associated with EVR(16w). In conclusion, a high degree of sequence variation in V3 (≥5) or IRRDR (≥6) and the presence of detectable levels of anti‐NS5A antibodies in the pretreatment sera would be useful factors to predict EVR(16w). On the other hand, a less diverse sequence in V3 (≤4) or IRRDR (≤5) together with the absence of detectable anti‐NS5A antibodies could be a predictive factor for Non‐EVR(16w).

Hepatitis C virus (HCV) is a major cause of liver disease worldwide. HCV is able to evade host defense mechanisms, including both innate and acquired immune responses, to establish persistent infection, which results in a broad spectrum of pathogenicity, such as lipid and glucose metabolism disorders and hepatocellular carcinoma development. The HCV genome is characterized by a high degree of genetic diversity, which can be associated with viral sensitivity or resistance (reflected by different virological responses) to interferon (IFN)-based therapy. In this regard, it is of importance to note that polymorphisms in certain HCV genomic regions have shown a close correlation with treatment outcome. In particular, among the HCV proteins, the core and nonstructural proteins (NS) 5A have been extensively studied for their correlation with responses to IFN-based treatment. This review aims to cover updated information on the impact of major HCV genetic factors, including HCV genotype, mutations in amino acids 70 and 91 of the core protein and sequence heterogeneity in the IFN sensitivity-determining region and IFN/ribavirin resistance-determining region of NS5A, on virological responses to IFN-based therapy.

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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. Methods: Pretreatment sequences of NS5A and core regions were analyzed in 68 HCV-1b-infected patients treated with PEG-IFN/RBV. Results: 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 (Gln⁷⁰) was significantly associated with null-response (p < 0.05). Multivariate analysis identified IRRDR≧6 as the only viral genetic factor that independently predicted SVR. Conclusion: 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.