Polymorphisms of Hepatitis C Virus Non-Structural Protein 5A and Core Protein and Clinical Outcome of Pegylated-Interferon/Ribavirin Combination Therapy
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.
- SourceAvailable from: Fatimah S. Alhamlan
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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. "
ABSTRACT: Hepatitis C virus (HCV) shows a remarkable genetic diversity, contributing to its high persistence and varied susceptibilities to antiviral treatment. Previous studies have reported that the substitution of amino acids in the HCV subgenotype 1b core protein in infected patients is associated with a poor response to pegylated interferon and ribavirin (PEG-IFN/RBV) combined therapy.Objectives: Because the role of the core protein in HCV genotype 4 infections is unclear, we aimed in this study to compare the full-length core protein sequences of HCV genotype 4 between Saudi patients who responded (SVR) and did not respond (non-SVR) to PEG-IFN/RBV therapy.Study design: Direct sequencing of the full-length core protein and bioinformatics sequence analysis was utilized. Our data revealed that there is a significant association between core protein mutations, particularly at position 70 (Arg70Gln), and treatment outcome in HCV subgenotype 4d patients. However, HCV subgenotype 4a showed no significant association between core protein mutations and treatment outcome. In addition, amino acid residue at position 91 was well-conserved among studied patients where Cys91 is the dominant amino acid residue. These findings provide a new insight into HCV genotype 4 among affected Saudi population where the knowledge of HCV core gene polymorphisms is inadequate.Journal of Translational Medicine 04/2014; 12(1):91. DOI:10.1186/1479-5876-12-91 · 3.99 Impact Factor
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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). "
ABSTRACT: It has been reported that hepatitis C virus (HCV) infection is closely associated with hepatic metabolic disorders. Hepatic steatosis and insulin resistance are both relatively common in patients with chronic hepatitis C. Recent investigations suggest that HCV infection changes the expression profile of lipid-metabolism-associated factors in the liver, conferring advantages to the life cycle of HCV. Moreover, insulin resistance and steatosis are independent predictors of impaired response to antiviral treatment in chronic hepatitis C. In this paper, we summarize our current knowledge of hepatic metabolic disorders and describe how HCV leads to and exploits these hepatic disorders. We also discuss the clinical significance of insulin sensitizers used to improve insulin resistance and lipid modulators used to manage lipid metabolism as potential treatment options for chronic hepatitis C.06/2012; 2012:264017. DOI:10.1155/2012/264017
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ABSTRACT: Hepatitis C virus (HCV) is a rapidly-evolving RNA virus that establishes chronic infections in humans. Despite the virus' public health importance and a wealth of sequence data, basic aspects of HCV molecular evolution remain poorly understood. Here we investigate three sets of whole HCV genomes in order to directly compare the evolution of whole HCV genomes at different biological levels: within- and among-hosts. We use a powerful Bayesian inference framework that incorporates both among-lineage rate heterogeneity and phylogenetic uncertainty into estimates of evolutionary parameters. Most of the HCV genome evolves at ~0.001 substitutions/site/year, a rate typical of RNA viruses. The antigenically-important E1/E2 genome region evolves particularly quickly, with correspondingly high rates of positive selection, as inferred using two related measures. Crucially, in this region an exceptionally higher rate was observed for within-host evolution compared to among-host evolution. Conversely, higher rates of evolution were seen among-hosts for functionally relevant parts of the NS5A gene. There was also evidence for slightly higher evolutionary rate for HCV subtype 1a compared to subtype 1b. Using new statistical methods and comparable whole genome datasets we have quantified, for the first time, the variation in HCV evolutionary dynamics at different scales of organisation. This confirms that differences in molecular evolution between biological scales are not restricted to HIV and may represent a common feature of chronic RNA viral infection. We conclude that the elevated rate observed in the E1/E2 region during within-host evolution more likely results from the reversion of host-specific adaptations (resulting in slower long-term among-host evolution) than from the preferential transmission of slowly-evolving lineages.BMC Evolutionary Biology 05/2011; 11(1):131. DOI:10.1186/1471-2148-11-131 · 3.41 Impact Factor