The team of Prof. Jin Zhong's at Institut Pasteur of Shanghai, Chinese Academy of Sciences，in collaboration with Prof. Qing Xie's team at Shanghai Ruijin Hospital, analyzed HCV genomic sequence evolution in unsuccessfully treated genotype 1b patients before, during and after the interferon based therapy. The study, published online in the Journal of Infection, Genetics and Evolution on Dec 10, 2010, presented evidence that viral factors might have important effects on the outcome of “difficult-to-treat” CHC patients, and the action of interferon and ribavirin might be the major force to drive the evolution of HCV genomic sequences and to select the resistant HCV variants in the breakthrough patients.

Chronic hepatitis C virus (HCV) infection is a major public health burden and a leading cause of chronic liver disease including chronic hepatitis, liver cirrhosis, end-stage liver disease and hepatocellular carcinoma (HCC), and it is one of the most common indications for liver transplantation worldwide. The World Health Organization reports that over 3% of the global population with approximately 180 million individuals is estimated to be infected with HCV. The prevalence was estimated to be over 3.2% with more than 41 million people infected in China. In nearly 85% of the cases, the disease progresses into chronicity. Currently, there is no vaccine to prevent HCV infection, and the only available treatment regimens based on interferon alpha (IFN-α) or pegylated (peg)-IFN-α plus Ribavirin for 24 to 48 weeks lead to a sustained virological response (SVR) in about 39.8-40.9% of patients infected by genotype 1 HCV, which is the prevalent HCV genotype in China, while 75-80% for genotypes 2 and 3. Treatment failure occurs in the following forms: nonresponse, breakthrough, and relapse. Unfortunately, molecular mechanisms underlying the failure of the interferon based therapy for chronic hepatitis C (CHC) patients are still unclear. Since interferon resistant HCV quasispecies might be selected during the therapy, the analysis of the viral genomic sequences before, during and after the therapy may help understand the roles of viral determinants of interferon resistance.

The researchers found that HCV sequences in the breakthrough patient displayed significantly more mutations during the one-year therapy than that in the nonresponse patient, with p7 and NS2 encoding regions having the highest mutation rates. Most of the mutations selected during the therapy phase in the breakthrough patient were maintained and few new mutations arose in the four-year post-therapy phase, suggesting these mutations might not compromise viral fitness. This work received positive comments from peer reviewer: “…The longitudinal sequence data that were obtained … in the manuscript are important information that not readily available in the literature, and therefore the analysis is valuable.”

The first author of the publication is Xiaogang Xiang, a PhD candidate under co-supervision of Shanghai Ruijin Hospital and Institut Pasteur of Shanghai. This work was supported by grants from Chinese National Key Programs on Infectious Diseases, the ‘973’ Program, the National Natural Science Foundation of China, Chinese Academy of Sciences, the Key Basic Research Grant of Science and Technology Commission of Shanghai Municipality, Shanghai Pasteur Health Research Foundation, Shanghai Municipal Health Bureau.

Source: "Viral Sequence Evolution in Chinese Genotype 1b Chronic Hepatitis C Patients Experiencing Unsuccessful Interferon Treatment". Infection, Genetics and Evolution on Dec.13, 2010