Hepatitis C virus genotype 1a NS5A pretreatment sequence variation and viral kinetics in African American and white patients.
ABSTRACT In hepatitis C virus (HCV) infection, race is a determinant of treatment response and interferon (IFN) effectiveness. Here, we investigated whether there were differences in the pretreatment viral strains between African American patients and white patients and whether these differences correlated with viral kinetics. IFN effectiveness was calculated using a viral kinetic model. The HCV NS5A region from 21 treated patients with HCV genotype 1a was sequenced and analyzed. White patients displayed more mutations in the V3 region (mean+/-SD, 4.5+/-1.4 vs. 2.9+/-1.6; P=.016), and treatment responders tended to have more mutations in this region than did nonresponders. There was a significant positive correlation between IFN effectiveness and the number of mutations in the V3 region (P=.03). There was no clustering of strains by race, treatment response, or IFN effectiveness in phylogenetic analyses. The results of this study, in conjunction with those of a previous study illustrating the impaired IFN effectiveness in African Americans, suggest a role for host-related factors.
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ABSTRACT: Hepatitis C virus (HCV) is considered a significant risk factor in HCV-induced liver diseases and development of hepatocellular carcinoma (HCC). Nucleotide substitutions in the viral genome result in its diversification into quasispecies, subtypes and distinct genotypes. Different genotypes vary in their infectivity and immune response due to these nucleotide/amino acid variations. The current combination treatment for HCV infection is pegylated interferon α (PEG-IFN-α) with ribavirin, with a highly variable response rate mainly depending upon the HCV genotype. Genotypes 2 and 3 are found to respond better than genotypes 1 and 4, which are more resistant to IFN-based therapies. Different studies have been conducted worldwide to explore the basis of this difference in therapy response, which identified some putative regions in the HCV genome, especially in Core and NS5a, and to some extent in the E2 region, containing specific sequences in different genotypes that act differently with respect to the IFN response. In the review, we try to summarize the role of HCV proteins and their nucleotide sequences in association with treatment outcome in IFN-based therapy.Archives of Virology 07/2013; · 2.28 Impact Factor
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ABSTRACT: AIM: Previous studies have suggested that patients with chronic hepatitis C with a low pretreatment hepatitis C virus (HCV) level have a high sustained virological response (SVR) rate, and that there would be a subpopulation of patients in which HCV can be eradicated with pegylated interferon (PEG IFN) alone without a decrease in SVR. However, the efficacy of PEG IFN monotherapy in patients with low HCV RNA levels is unclear. Several studies have reported that interferon sensitivity-determining region (ISDR) and the single-nucleotide polymorphism (SNP) of interleukin-28B (IL-28B) contribute to IFN response, but these relationships are controversial. The aim of this study was to determine whether the SNP of IL-28B (rs8099917) and amino acid substitutions in the ISDR among patients with low HCV levels affect the response to PEG IFN monotherapy. METHODS: One hundred and four patients with low-level HCV infection were studied. Low HCV level was defined as 100 KIU/mL or less. RESULTS: SVR was achieved in 94 patients (92.2%). HCV levels (≤50 KIU/mL) and ISDR (≥2 mutations) were associated with SVR on univariate analysis. The rates of SVR in the patients with IL-28B genotypes TT, TG and GG were 94.5%, 77.8% and 100%, respectively. The G allele tended to be associated with poor response to IFN therapy (P = 0.0623). On multivariate analysis, the ISDR was the factor predictive of SVR (P = 0.004). CONCLUSION: The ISDR is significantly associated with a good response to PEG IFN monotherapy in patients with low HCV levels.Hepatology Research 10/2012; · 2.07 Impact Factor
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ABSTRACT: Heterogeneity of subgenomic regions of hepatitis C virus (HCV) may be associated with response to interferon (IFN) therapy. The amino acid sequences of the PKR/eIF-2α phosphorylation homology domain (pePHD), IFN sensitivity determining region (ISDR), PKR binding domain (PKRBD), and variable region 3 (V3) were studied in 19 patients before and after 4 weeks of treatment. All patients were infected with HCV genotype 1a and were treated with pegylated-IFN and ribavirin. Thirteen patients achieved sustained viral response (responders) and six failed to clear viral RNA (nonresponders). The amino acid sequences in the pePHD and ISDR were identical in responders and nonresponders. However, amino acid substitution at position 2252 of PKRBD was significantly different between responders and nonresponders (P = 0.044). A larger number of mutations were observed in the V3 region of responders (P < 0.001). In this region, the amino acid in position 2364 differed between responders and nonresponders (responders: aspartic acid and serine, nonresponders: asparagine, P = 0.018). The amino acid sequences in the regions which were studied did not change after 4 weeks of treatment. It is concluded that the presence of specific amino acids in position 2252 of PKRBD and position 2364 of V3 might be associated with clinical response to IFN.Journal of Medical Virology 08/2011; 83(8):1332-7. · 2.37 Impact Factor