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.
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.
Background and Aims Although patients infected by genotype-1b hepatitis C virus (HCV) with Q70 and/or M91 core gene mutations have an almost five-fold increased risk of developing hepatocellular carcinoma (HCC) and increased insulin resistance, the absence of a suitable experimental system has precluded direct experimentation on the effects of these mutations on cellular gene expression. Methods Huh-7 cells were treated long-term with human serum to induce differentiation and to produce a model system for testing high-risk and control HCV. For clinical validation, profiles of infected cells were compared to each other and to those of liver biopsies of patients with early-stage HCV-related cirrhosis followed prospectively for up to 23 years (n=216). Results Long-term culture in human serum produced growth-arrested, hepatocyte-like cells whose gene profile overlapped significantly with that of primary human hepatocytes. High-risk (Q70/M91) and control (R70/L91) viruses had dramatically different effects on gene expression of these cells. The high-risk virus enhanced expression of pathways associated with cancer and type II diabetes, while the control virus enhanced pathways associated with oxidative phosphorylation. Of special clinical relevance, the transcriptome of cells replicating the high-risk virus correlated significantly with an HCC high-risk profile in patients (Bonferroni-corrected P=0.03), whereas no such association was observed for non-HCC-related clinical outcomes. Conclusions The cell-based system allowed direct head-to-head comparison of HCV variants and provided experimental support for previous clinical data indicating an oncogenic effect of core gene mutations. This simple experimental system distinguished HCV variants and will enable future mechanistic analysis and exploration of interventional approaches.
Viral mutations acquired during the course of chronic hepatitis B virus (HBV) infection are known to be associated with the progression and severity of HBV-related liver disease. This study of HBV-infected Saudi Arabian patients aimed to identify amino acid substitutions within the precore/core (preC/C) region of HBV, and investigate their impact on disease progression toward hepatocellular carcinoma (HCC). Patients were categorized according to the severity of their disease, and were divided into the following groups: inactive HBV carriers, active HBV carriers, liver cirrhosis patients, and HCC patients. Two precore mutations, W28* and G29D, and six core mutations, F24Y, E64D, E77Q, A80I/T/V, L116I, and E180A were significantly associated with the development of cirrhosis and HCC. Six of the seven significant core mutations that were identified in this study were located within immuno-active epitopes; E77Q, A80I/T/V, and L116I were located within B-cell epitopes, and F24Y, E64D, and V91S/T were located within T-cell epitopes. Multivariate risk analysis confirmed that the core mutations A80V and L116I were both independent predictors of HBV-associated liver disease progression. In conclusion, our data show that mutations within the preC/C region, particularly within the immuno-active epitopes, may contribute to the severity of liver disease in patients with chronic hepatitis. Furthermore, we have identified several distinct preC/C mutations within the study population that affect the clinical manifestation and progression of HBV-related disease. The specific identity of HBV mutations that are associated with severe disease varies between different ethnic populations, and so the specific preC/C mutations identified here will be useful for predicting clinical outcomes and identifying the HBV-infected patients within the Saudi population that are at high risk of developing HCC.
Hepatocellular carcinoma (HCC) is one of the common sequelae of hepatitis C virus (HCV) infection. It remains controversial, however, whether HCV itself plays a direct role in the development of HCC. Although HCV core, NS3, and NS5A proteins were reported to display tumorigenic activities in cell culture and experimental animal systems, their clinical impact on HCC development in humans is still unclear. In this study we investigated sequence polymorphisms in the core protein, NS3, and NS5A of HCV genotype 1b (HCV‐1b) in 49 patients who later developed HCC during a follow‐up of an average of 6.5 years and in 100 patients who did not develop HCC after a 15‐year follow‐up. Sequence analysis revealed that Gln at position 70 of the core protein (core‐Gln70), Tyr at position 1082 plus Gln at 1112 of NS3 (NS3‐Tyr1082/Gln1112), and six or more mutations in the interferon/ribavirin resistance‐determining region of NS5A (NS5A‐IRRDR≥6) were significantly associated with development of HCC. Multivariate analysis identified core‐Gln70, NS3‐Tyr1082/Gln1112, and α‐fetoprotein (AFP) levels (>20 ng/L) as independent factors associated with HCC. Kaplan‐Meier analysis revealed a higher cumulative incidence of HCC for patients infected with HCV isolates with core‐Gln70, NS3‐Tyr1082/Gln1112 or both than for those with non‐(Gln70 plus NS3‐Tyr1082/Gln1112). In most cases, neither the residues at position 70 of the core protein nor positions 1082 and 1112 of the NS3 protein changed during the observation period. Conclusion: HCV isolates with core‐Gln70 and/or NS3‐Tyr1082/Gln1112 are more closely associated with HCC development compared to those with non‐(Gln70 plus NS3‐Tyr1082/Gln1112). (HEPATOLOGY 2013;58:555‐563)
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.
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