Accumulation of refractory factors for pegylated interferon plus ribavirin therapy in older female patients with chronic hepatitis C

Abstract

Several host and viral factors have been reported to influence the effectiveness of pegylated interferon plus ribavirin combination therapy for chronic hepatitis C. In Japan, where the age of treated patients is comparatively high, recent studies have reported poor response to treatment in older female patients, but little is known about the relationship between advanced age in women and previously reported factors. Using a database of 1167 patients chronically infected with hepatitis C virus (HCV) genotype 1b, we analyzed the amino acid sequences of the HCV core protein and interferon sensitivity determining region (ISDR) and examined the relationships among predictive factors. The proportion of patients with substitutions at core 70, which is associated with poor response to pegylated interferon plus ribavirin therapy, increased with age only in female patients. A similar trend was observed for ISDR wild type (wt). We also found that core 70 wt is associated with core 91 wt (P = 5.4 × 10(-9) ) as well as ISDR wt (P = 0.025). HCV RNA levels were higher in patients with core and ISDR wt (P < 0.001). Furthermore, core amino acid mutations were associated with advanced fibrosis and higher inflammatory activity (P = 0.028 and 0.048, respectively) as well as higher gamma-glutamyltranspeptidase, alanine aminotransferase and low-density lipoprotein cholesterol levels (P < 0.001, 0.006 and 0.001, respectively). A combination of factors account for poor response rate in older female patients in Japan. Elucidating the relationship between amino acid substitutions and metabolic alteration is an important step in understanding the mechanism of HCV interferon resistance.