Department of Medical and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
Treatment of genotype 1b chronic hepatitis C virus (HCV) infection has been improved by extending peg-interferon plus ribavirin combination therapy to 72 weeks, but predictive factors are needed to identify those patients who are likely to respond to long-term therapy.
We analyzed amino acid (aa) substitutions in the core protein and the interferon sensitivity determining region (ISDR) of nonstructural protein (NS) 5A in 840 genotype 1b chronic hepatitis C patients with high viral load. We used logistic regression and classification and regression tree (CART) analysis to identify predictive factors for sustained virological response (SVR) for patients undergoing 72 weeks of treatment.
When patients were separately analyzed by treatment duration using multivariate logistic regression, several factors, including sex, age, viral load, and core aa70 and ISDR substitutions (P = 0.0003, P = 0.02, P = 0.01, P = 0.0001, and P = 0.0004, respectively) were significant predictive factors for SVR with 48 weeks of treatment, whereas age, previous interferon treatment history, and ISDR substitutions (P = 0.03, P = 0.01, and P = 0.02, respectively) were the only significant predictive factors with 72 weeks of treatment. Using CART analysis, a decision tree was generated that identified age, cholesterol, sex, treatment length, and aa70 and ISDR substitutions as the most important predictive factors. The CART model had a sensitivity of 69.2% and specificity of 60%, with a positive predictive value of 68.4%.
Complementary statistical and data mining approaches were used to identify a subgroup of patients likely to benefit from 72 weeks of therapy.
"Nonetheless, supporting this assumption is the significantly greater enrichment in gt-1 patients of both cold-precipitating material with IgM molecules showing RF activity and HCV-Cp, as in this form of MCG, the RNA-to-Cp ratio is higher. It is well known that the genetic variability of HCV affects the metabolism of infected liver cells and influences the outcome of infection . In addition, the RNA chaperone activity of core protein includes genomic RNA dimerization, which may constitute the regulatory switch determining translation/replication versus replication/packaging of viral RNA . "
[Show abstract][Hide abstract] ABSTRACT: In Hepatitis C virus (HCV)-related mixed cryoglobulinemia (MCG), the non-enveloped HCV core protein (HCV-Cp) is a constituent of the characteristic cold-precipitating immune complexes (ICs). A possible correlation between HCV-Cp, virological, laboratory and clinical parameters in both untreated MCG patients and those undergoing specific treatment was explored.
HCV-Cp was quantified by a fully automated immune assay. Correlations between HCV-Cp and HCV RNA, cryocrit, and virus genotype (gt) were investigated in 102 chronically HCV-infected MCG patients.
HCV-Cp concentrations strongly correlated with HCV RNA levels in baseline samples. An average ratio of 1,425 IU and 12,850 IU HCV RNA per pg HCV-Cp was estimated in HCV gt-1 and gt-2 patients, respectively. This equation allowed to estimate that, on average, HCV-Cp was associated with viral genome in only 3.4% of the former and in 35% of the latter group of patients. The direct relationship between HCV-Cp and the cryocrit level suggests that the protein directly influences the amount of cryoprecipitate. Although the therapy with rituximab (RTX) as a single agent resulted in the enhancement of HCV-Cp levels, in patients treated with RTX in combination with a specific antiviral therapy (pegylated interferon-alpha plus ribavirin) the prompt and effective clearance of HCV-Cp was documented.
Our data provide evidence that HCV-Cp has a direct effect on cold-precipitation process in a virus genotype-dependence in HCV-related MCG patients.
"supported by cases in which spontaneous clearance of the virus occurs without treatment in approximately 25% of acutely infected individuals . In general, rates of success of combination therapy depend on various factors, including age and gender  , with younger women experiencing higher success rates than older men. This observation is in line with the more general observation indicating that women have a more active immune system than men, a factor that also predisposes women to autoimmune diseases  . "
[Show abstract][Hide abstract] ABSTRACT: We report a gene expression study aimed at the identification of genes differentially expressed in the livers of Hispanic patients infected with hepatitis C virus (HCV). Six uninfected controls were compared with 14 HCV(+) patients in which the liver biopsies were obtained at the time of diagnosis. Among the latter, five patients were also analyzed 4 weeks after the onset of standard anti-HCV therapy (pegylated interferon-α + ribavirin). We identified many genes up- or down-regulated by the infection with HCV in the human livers. When these genes were subjected to pathway analysis, several prominent pathways were revealed including many interferon (IFN)-inducible pathways as well as immune cell trafficking, inflammation, anti-microbial responses, and even cancer. We detected expression of many genes that have previously been associated with HCV infection, as well as several novel genes including CD47. The genes induced by HCV infection showed large expression changes, whereas the genes induced by the IFN-α combination therapy were relatively few (including MX2, ORMDL3, GPAM, KOPX18, TMEM56, and HBP1) and they reflected relatively small expression changes. This is the first study to identify changes in gene expression in livers of HCV(+) Hispanic patients and the first to identify genes induced by anti-HCV combination therapy in the human liver.
[Show abstract][Hide abstract] ABSTRACT: Aim: Effect of re-treatment for pegylated interferon (PEG-IFN) plus ribavirin was not fully evaluated. We examined the effects of re-treatment with PEG-IFN plus ribavirin in patients with high viral loads of genotype 1 hepatitis C virus who failed to achieve a sustained virological response (SVR) with combination therapy.
Methods: We examined 38 patients who were re-treated with PEG-IFN α2a plus ribavirin for more than 60 weeks, among whom 14 were non-responders and 24 were relapsers after previous treatment with PEG-IFN α2b plus ribavirin. IL28B genotyping was done in 21 patients.
Results: The overall SVR rate was 34%. Analysis of baseline characteristics showed that the relapsers had a significantly higher SVR rate than the non-responders (50.0%, 12/24 vs. 7.1%, 1/14, respectively, P = 0.012) The SVR rates of re-treated patients who had turned hepatitis C virus (HCV) RNA-negative at weeks 8, 12, 24, and 48 of the previous therapy were 67% (4/6), 67% (4/6), 29% (2/7), and 25% (1/4), respectively. Re-treatment achieved an SVR in five of 12 patients with IL28B major alleles and three of nine patients with IL28B minor alleles. During the re-treatment, patients with complete viral suppression at week-12 achieved a significantly higher SVR rate (P = 0.001).
Conclusions: Re-treatment with PEG-IFN α2a plus ribavirin therapy is effective in patients who relapse after a course of PEG-IFN α2b plus ribavirin therapy. Re-treatment is a particularly useful option for patients who achieve early viral clearance during previous therapy.
Hepatology Research 09/2011; 41(12):1169-77. DOI:10.1111/j.1872-034X.2011.00887.x · 2.74 Impact Factor
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