Hepatitis C virus (HCV) infection is a dynamic process during which molecular variants are continuously selected as the result of virus adaptation to the host. Understanding the nature of HCV genetic variation is central to current theories of pathogenesis and immune response. We prospectively studied hypervariable region 1 (HVR1) variation in the E2 gene of 36 hepatitis C patients, including 10 asymptomatic carriers, followed up for 1 to 2 years. Sequence changes in single and consecutive serum samples were assessed and correlated with clinical and virological parameters of liver disease. A region of the E1 gene was sequenced for comparison in 3 subjects. HVR1 heterogeneity at single time points widely varied in individual patients, did not increase cumulatively over the follow-up period, and did not correlate with HVR1 evolutionary rates. Conversely, the process of HVR1 sequence diversification, although differed considerably among patients, was stable over time and directly correlated with infections by HCV type 2, lower alanine aminotransferase (ALT) levels, and absence of cirrhosis. HCV carriers showed the highest HVR1 variation rates. Our findings indicate that HVR1 variation has an adaptive significance and is associated with favorable features of liver disease and suggest that prospective, rather than static, observations are required to model the process of HCV variation.

BACKGROUND & AIMS:Viral genotypes have been associated with different severity and outcome of hepatitis C virus (HCV)-related liver disease. The aim of this study was to determine whether HCV genotypes may influence the cirrhosis-related risk of the development of hepatocellular carcinoma (HCC). METHODS:Three groups of patients were studied: 593 patients with chronic hepatitis, 166 patients with HCC and cirrhosis, and 219 patients with cirrhosis but without HCC. A cross-sectional study of frequency distribution and a case-control analysis were performed. HCV genotypes were detected according to Okamoto. RESULTS:HCV type 1b infection was more prevalent among patients with HCC compared with patients with cirrhosis but without HCC (P < 0.01) and chronic hepatitis (P < 0.001). Age, male sex, and HCV type 1b significantly influenced the risk of cancer in cirrhosis by univariate analysis. A pairwise comparison performed on 162 patients with HCC and an equal number of patients with cirrhosis matched by age, sex, and Child's class showed that HCV type 1b was independently associated with HCC (odds ratio, 1.7; P = 0.026). CONCLUSIONS:HCV type 1b is overrepresented in patients with cirrhosis and HCC and significantly influences the risk of HCC in cirrhosis, independent of sex, age, and Child's class.