| It is estimated that approximately 180 million people worldwide are infected with hepatitis C virus (HCV). Furthermore, approximately 85% of the patients with a HCV infection go on to develop chronic disease, and of these, up to 20% will eventually develop cirrhosis, which may lead to liver failure and hepatocellular carcinoma. HCV infection has become a major public health problem.HCV is a RNA-virus characterized by high genetic heterogeneity,and is classified into six major genotypes and multiple subtypes. HCV genotype has been shown to have unique patterns of geographic distribution and to be a major tool in HCV epidemiological study. In recent years, however, a shift in the prevalence of the predominant HCV genotypes has been observed in a number of European countries, correlation with the changes in mode of HCV acquisition.In China, with the implementation of mandatory HCV screening of blood and blood products in the early 1990s, the number of post-transfusion infections has already dramatically decreased; however, the number of intravenous drug users has increased. Southwest China is adjacent to Southeast Asia, which is one of the world's most important opium planting and drug producing bases. So we presumed that intravenous drug use (IDU) had been the predominant mode of HCV acquisition in southwest China; and following which, genotypes 3 and 6, the major genotypes in Southeast Asia, had been gradually'imported'in this region.Superinfection of patients carrying another HCV strains or infection with multitypic HCV has been repeatedly reported, and multiple exposed patients can be mixed infected with more than one subtypes or genotypes of HCV. There was competition among those infecting strains, which could result in the dominance of a single strain, but the dominant strain might switched in the follow-up sera from multiple exposed patients. And since the first identification of an intergenotypic (2k/1b) HCV recombinant in St.Petersburg, several intergenotypic and intragenotypic recombinants of HCV have been identified. Multitypic HCV infection and following survival states not only present a serious impediment to vaccine development but also to prediction of the response to antiviral therapy. However, the frequency of multitypic HCV infection and the survival rules after multitypic HCV infecting a given individual are still controversial. The overlap in genotype distribution and IDU being the predominant mode of HCV acquisition would increase the chance of multitypic HCV infection and thus the likelihood of intragenotypic and intergenotypic HCV recombination. While to date, there is few data which focused on the multitypic HCV infection in southwest China. So it is very important and emergent to investigate the frequency of multitypic HCV infection and following survival states in this region.Pegylated interferon (PEG-IFN) plus ribavirin is currently the standard treatment for patients with chronic HCV infection, but the optimal duration of treatment and expected response rate depend on the genotype of the infecting virus. HCV genotypes 1–3 are the predominant genotypes in Western Europe and the United States,and these genotypes have been the focus of most clinical trials to date. Forty-eight weeks of therapy are advised for patients with genotype 1, and 24 weeks for those with genotype 2 and 3. However, there is a general paucity of data on treatment response in patients infected with other genotypes, including genotype 6. With HCV genotype 6a being gradually'imported'in southwest China, it is important to study the optimal duration of treatment and expected response rate for patients with HCV genotype 6.To answer these questions, we designed and conducted the experiments as follows: collecting the sera and clinical information of chronically HCV infected patients attending Southwest Hospital between January 2006 and March 2009, analyzing the recent distribution and evolution of HCV genotypes and the modes of HCV acquisition, detecting multitypic HCV infection with the method of colony analysis in the CE1 region among some multiple exposed patients, comparising HCV subtype among follow-up series sera in all multiple exposed patients who had more than one serum specimen, investigating the possible natural intragenotypic and intergenotypic HCV recombination, and also retrospectively analyzing the treatment outcome of PEG-IFN plus ribavirin and the association of on-treatment virological response with sustained virological response (SVR) for patients with HCV 6a. Main Research Results1. Among the 371 patients, subtypes 1a (0.8%), 1b (42.0%), 2a (9.7%), 3a (12.1%), 3b (21.0%), 4a (0.3%), and 6a (14.0%) were found. Genotypes 3 and 6 were significantly more frequent among patients age 40 years or under (63.6%) than older patients (21.6%, P =0.000), among patients infected after 1997 (54.4%) than those infected before 1997 (27.3%, P=0.001), among IDUs (85.4%) than among other subjects (32.5%, P=0.000). Age 40 years or under (P=0.000) and infection via IDU (P=0.000) were independently associated with genotypes 3 and 6 in the multivariate stepwise logistic regression analysis. IDU was detected as a cause of infection in 27.8% of HCV cases; it was more frequent among younger patients (40.4%) than older ones (7.1%, P=0.000), among patients infected after 1997 (40.3%) than those infected before 1997 (16.2%, P=0.000).2. Multitypic HCV infection was identified in 9 (47.4%) of the 19 subjects, and 11 (45.8%) of the 24 specimens. There were 26 repeatedly exposed patients who had more than one HCV RNA positive sera at different time points, but neither of their HCV subtypes had switched over time. And there was no discrepancy between genotyping results based on the NS5B and CE1 regions in 243 sera from 222 patients, including 107 samples from 92 IDU patients, 26 samples from 20 hemodialysis patients, and 110 samples from 110 patients who had neither a history of IDU nor hemodialysis. It is worth to note that patients ZQ and YLB were infected with multitypic HCV for more than 5 and 12 months respectively, while there was no evidence for possible intergenotypic HCV recombinant or genotype switching in these two patients.3. Patients with genotype 6a, as those with genotype 2 or 3 were treated with PEG-IFN and ribavirin for 24 weeks, and those with genotype 1b were treated for 48 weeks. The rate of SVR in patients with HCV 6a (81.8%) was similar to that in patients with HCV 2 or 3 (83.3%, P=0.879), and was higher than that in patients infected with HCV 1b (59.0%, P=0.068). The rates of rapid virological response (RVR), early virological response (EVR) and end-of-treatment virological response (ETVR) in patients with genotype 6a were 83.3%, 95.5% and 90.9%, respectively. They were all similar to those in patients with genotype 2 or 3, and were higher than those with genotype 1b. A lower relapse rate was seen in patients with HCV 6a (10.0%) comparison with HCV 2 or 3 (12.5%), as well as HCV 1b infections (23.3%), although there were no significant difference (P=0.344). The positive predictive values of RVR and EVR for patients with HCV genotype 6a were comparable with those for patients with genotype 2 or 3 (86.7% vs. 90.0%, P=0.683 and 85.7% vs. 86.8%, P=0.904, respectively). Of the 3 patients with genotype 6a who did not achieve a RVR, after completing the 24 weeks treatment, two went on to achieve an EVR and a SVR follow-up; in contrast, the only 1 patient who did not achieve an EVR, did not achieve a SVR either.From these results, we draw conclusions as below1. IDU has been the predominant mode of HCV acquisition in southwest China, and following which, genotypes 3 and 6 have been gradually'imported'in this region.2. Although a high frequency of multitypic HCV infection was identified in patients with multiple exposures, HCV subtype switching over time and intergenotypic or intragenotypic recombination remain infrequent events.3. The virological response of 24 weeks treatment with PEG-IFN plus ribavirin for HCV genotype 6 is similar to that for genotype 2/3, and is superior to that of 48 weeks for genotype 1. |
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