dc.description.abstract | Background Hepatitis C virus (HCV) infection is an important cause of liver cirrhosis and hepatocellular carcinoma(HCC)worldwide. HCV belongs to the Hepacivirus genus of the Flaviviridae family. It is a spherical particle, 55 to 65 nm in diameter, with an envelope, and consists of the genome of a 9.6-kb plus strand RNA. It has short untranslated regions at both the 5’- and 3’- termini, and the middle region, which accounts for about 95% of the whole genome, encodes a precursor protein consisting of ~3,010 amino acid residues. The coding regions of viral structural proteins such as core as well as E1 and E2 are located at the N-terminus, while the non-structural proteins NS2, NS3, NS4A, NS4B, NS5A, and NS5B are situated at the middle region near the C-terminus. Among these viral proteins, core protein reacts with human proteins and bears multiple regulatory functions including the influence on inflammation and induction of HCC. Besides, it can induce insulin resistance in transgenic mice studies. Previous clinical studies from Japan suggested that patient with amino acid substitutions in HCV core region 70 of Glutamine for Arginine(R70Q)and 91 of Methionine for Leucine(L91M)have lower rates of rapid virologic response (RVR) and sustained virologic response (SVR), and HCV core gene polymorphisms are related to the development of insulin resistance in patients with chronic HCV infection.
Materials and Methods We collected 42 Taiwanese chronic hepatitis C patients with genotype 1b infection. All of them received combination therapy of pegylated interferon alfa-2a plus ribavirin for 24 weeks. Blood samples were collected for complete blood count, fasting glucose, fasting insulin and liver enzymes, pre-treatment HCV RNA. Liver biopsy was also performed to determine the stage of hepatic fibrosis and steatosis. Serum HCV RNA level was assayed at week 4 and 24 of therapy to identify RVR and SVR. HCV core gene polymorphisms of amino acid 70 and 91 were analysed by direct sequencing after PCR amplification. Statistical analysis on the relationship among virologic response to antiviral therapy, insulin resistance and HCV core gene polymorphisms were done.
Results Patients with HCV core gene R70Q/H substitution had a higher frequency of more severe insulin resistance(HOMA-IR≧3.5)than those without(60% vs. 26%,P=0.047). Patients with L91M substitution also had similar results(56% vs. 25%,P=0.059). Patients with double wild-type sequences had a higher SVR rate(77.8% vs. 62.5%,P=0.333) and lower insulin resistance(HOMA-IR 2.19±1.26 vs. 7.02±7.43)than those with non-double wild-type sequences. Multivariate analysis suggested that patients with lower viral load tended to achieve a higher SVR rate. In addition, HCV core gene L91M and/or R70Q/H substitution tended to have more severe insulin resistance(Odds ratio 15.598, 95%CI 2.202-110.480, P=0.006.)
Conclusions HCV core gene R70Q and /or L91M substitutions are associated with more severe insulin resistance. HCV genotype 1b patients with lower viral load, younger age and lower fibrosis score have a higher likelihood to achieve SVR to combination therapy. | en |