Factors predictive of sustained virological response following 72 weeks of combination therapy for genotype 1b hepatitis C.
ABSTRACT 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.
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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.Autoimmunity 08/2011; 44(7):532-42. DOI:10.3109/08916934.2011.592881 · 2.75 Impact Factor
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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 · 2.22 Impact Factor
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ABSTRACT: Aim: We evaluated the efficacy of response-guided therapy in patients with hepatitis C virus (HCV) genotype 2. Methods: We studied 105 patients with an HCV genotype 2 load of higher than 5.0 Log IU/mL who received more than 75% of the target dose of pegylated interferon plus ribavirin. Among patients with rapid viral response (RVR; no HCV RNA detected at week 4), 14 selected 16 weeks of therapy (group A), and 28 selected 24 weeks of therapy (group B). Among non-RVR patients, 40 selected 24 weeks of therapy (group C), and 19 selected 48 weeks of therapy (group D). Results: All patients in group A and B achieved a sustained viral response (SVR). Clinical characteristics did not differ significantly between groups C and D. However, the proportion of patients in whom HCV RNA disappeared at a later week after starting treatment was higher in group D (P = 0.0578). SVR rate was 73% in C, and 79% in D. Among patients in whom HCV RNA disappeared between weeks 5 and 8, SVR was achieved in 28 (82%) of 34 patients in C and 10 (91%) of 11 patients in D. Among patients whose HCV RNA disappeared between weeks 9 and 12, SVR was achieved in one (20%) of five patients in C and five (63%) of eight patients in D (not statistically significant). Conclusions: 16 weeks of combination therapy could achieve an adequate antiviral effect for RVR patients. Extending therapy could not significantly improve SVR rate in non-RVR patients.Hepatology Research 02/2012; 42(6):549-57. DOI:10.1111/j.1872-034X.2011.00956.x · 2.22 Impact Factor