Effect of peginterferon alfa-2b and ribavirin on hepatocellular carcinoma prevention in older patients with chronic hepatitis C.

BACKGROUND AND AIMS: The population of patients chronically infected with hepatitis C virus (HCV) is aging, and the number of older patients with HCV-related hepatocellular carcinoma (HCC) is increasing. The purpose of this study was to elucidate the effects of peginterferon and ribavirin combination therapy on prevention of HCC in older patients with chronic hepatitis C (CH-C). METHODS: We compared the sustained virological response (SVR) and treatment discontinuation rates between older (≥ 65 years) and younger patients (< 65 years) among 1280 CH-C patients treated with peginterferon alfa-2b and ribavirin. Cumulative incidence of HCC was determined by Kaplan-Meier analysis, and factors associated with liver carcinogenesis were analyzed by Cox proportional hazards regression. RESULTS: Older patients had a significantly lower SVR rate and a significantly higher discontinuation rate of treatment than younger patients. Fifty patients developed HCC during median follow-up period of 47 months. Cox proportional hazards regression analysis indicated that the following were independent risk factors associated with the development of HCC: older age, male, advanced fibrosis, non-SVR in all patients: higher gamma-glutamyltranspeptidase, and non-SVR in older patients. Older patients who achieved SVR had a significantly reduced rate of HCC compared with those who did not achieve SVR, especially those who had gamma-glutamyltranspeptidase over 44 IU/L. CONCLUSIONS: The SVR rate was lower and the combination therapy discontinuation rate was higher in older CH-C patients than in younger patients. However, older patients who achieved SVR had a markedly lower rate of HCC development compared with older patients who did not achieve SVR.

Association of interleukin 28B polymorphism and mutations in the NS5A region of hepatitis C virus genotype 2 with interferon responsiveness.

BACKGROUND AND AIM: The single nucleotide polymorphism (SNP) of interleukin 28B (IL28B) and the mutations in the NS5A region of hepatitis C virus (HCV) genotype 1 have been associated with response to interferon (IFN) therapy. However, these relationships in patients with HCV genotype 2 are not well understood. The aim of this study was to investigate whether the SNP of IL28B (rs8099917) and amino acid substitutions in the NS5A region in patients with HCV genotype 2 affect the response to IFN and ribavirin combination therapy. METHODS: The study enrolled 286 patients with chronic hepatitis C genotype 2. Patients received pegylated-IFN-alpha 2b once each week plus oral ribavirin daily for 24 weeks. RESULTS: Of the 286 patients, 215 (75.2%) achieved sustained virologic response (SVR). Rate of SVR was similar in patients with IL28B TT allele (76%) and those with TG or GG alleles (72%). Patients with SVR were younger than those without SVR (P < 0.001). SVR was achieved in 65.9% of patients with wild-type IFN sensitivity-determining region (ISDR) and 83.5% of patients with mutant type (P < 0.001). There were no significant differences in other factors, including sex, alanine aminotransferase, platelet count, HCV viral load, HCV genotype, and IL28B genotype. The factors related to SVR on multivariate analysis were age (P = 0.019) and ISDR (P = 0.003). CONCLUSIONS: ISDR sequence variations are significantly associated with IFN responsiveness in patients with HCV genotype 2. The SNP of IL28B was not associated with SVR in patients with HCV genotype 2.

Comparison of the efficacy of ribavirin plus peginterferon alfa-2b for chronic hepatitis C infection in patients with and without coagulation disorders.

Many patients with coagulation disorders are infected with hepatitis C virus (HCV) that advances to end stage liver disease, resulting in an increased number of deaths. The efficacy of ribavirin and peginterferon combination therapy for chronic HCV infection in patients with coagulation disorders has not been clarified fully. The aim of this study was to evaluate the efficacy and tolerability of combination therapy in this patient population compared with patients who are infected with HCV and do not have coagulation disorders. A total of 226 consecutive chronic hepatitis C patients were treated with combination therapy and divided into two groups: patients with (n = 23) and without coagulation disorders (n = 203). Clinical characteristics, sustained virological response rates obtained by an intention-to-treat analysis, and combination therapy discontinuation rates were compared between the two groups. The sustained virological response rates did not differ significantly between patients with and without coagulation disorders (65.2% vs. 47.8% by intention-to-treat analysis). According to a multivariate analysis, age, alanine aminotransferase, gamma-glutamyltransferase, and HCV genotype were associated significantly with a sustained virological response, whereas whether a patient had a coagulation disorder did not affect the sustained virological response. In conclusion, combination therapy for chronic hepatitis C was comparably effective between patients with and without coagulation disorders and did not result in adverse bleeding.

Prevalence of hepatitis C virus genotype 1a in Japan and correlation of mutations in the NS5A region and single-nucleotide polymorphism of interleukin-28B with the response to combination therapy with pegylated-interferon-alpha 2b and ribavirin.

Hepatitis C virus (HCV) genotype 1a is rare in Japanese patients and the clinical characteristics of this genotype remain unclear. The interferon (IFN) sensitivity-determining region (ISDR) and single-nucleotide polymorphisms (SNPs) of interleukin-28B (IL28B) among patients with HCV genotype 1b are associated with IFN response, but associations among patients with genotype 1a are largely unknown. This study investigated the clinical characteristics of genotype 1a and examined whether genomic heterogeneity of the ISDR and SNPs of IL28B among patients with HCV genotype 1a affects response to combination therapy with pegylated-IFN-α2b and ribavirin. Subjects comprised 977 patients infected with HCV genotype 1, including 574 men and 412 women (mean age, 55.2 ± 10.6 years). HCV was genotyped by direct sequencing of the 5'-untranslated region and/or core regions and confirmed by direct sequencing of the NS5A region. HCV genotypes 1a (n = 32) and 1b (n = 945) were detected. Twenty-three (71.9%) of the 32 patients with genotype 1a were patients with hemophilia who had received imported clotting factors. Prevalence of genotype 1a after excluding patients with hemophilia was thus 0.9%. Of the 23 patients with genotype 1a who completed IFN therapy, 11 (47.8%) were defined as achieving sustained virological response. Factors related to sustained virological response by univariate analysis were IL28B and ISDR. In conclusion, HCV genotype 1a is rare in Japan. The presence of IL28B genotype TT, and more than two mutations, in the ISDR are associated with a good response to IFN therapy in patients with HCV genotype 1a.

Relationship between polymorphisms of the inosine triphosphatase gene and anaemia or outcome after treatment with pegylated interferon and ribavirin.

BACKGROUND: A genome-wide association study revealed an association between variants of the inosine triphosphatase (ITPA) gene and ribavirin (RBV)-induced anaemia. The aim of this study was to replicate this finding in an independent Japanese cohort and to define a method to allow pretreatment prediction of anaemia in combination with other factors. METHODS: Genotype 1b chronic hepatitis C patients (n=132) treated with pegylated interferon (PEG-IFN)-α and RBV for 48 weeks were genotyped for ITPA rs1127354 and examined for anaemia and treatment outcome. RESULTS: Variants of the ITPA gene protected against severe anaemia throughout the 48-week treatment period and were associated with lower incidence of anaemia-related RBV dose reduction. A combination of the ITPA genotype with baseline haemoglobin (Hb) and creatinine clearance (CLcr) levels predicted severe anaemia with high accuracy (90% sensitivity and 62% specificity). Among a subset of patients with the IL28B genotype of TT at rs8099917, patients with variants of the ITPA gene were associated with a higher rate of receiving >80% of the expected RBV dose, a higher rate of sustained virological response (SVR), and a lower rate of relapse. CONCLUSIONS: The variants of the ITPA gene, which could protect against haemolytic anaemia and RBV dose reduction, were associated with a high rate of SVR by standard PEG-IFN and RBV therapy in a subset of Japanese patients with the favourable TT genotype at rs8099917 of IL28B. A combination of ITPA genetic polymorphisms with baseline Hb and CLcr levels further improves the predictive accuracy of severe anaemia.