Therapy Efficacy Prediction And Relapse In The Management Of Treatment Of Chronic Hepatitis C

Background and objective:Hepatitis C virus (HCV) infection inflicts about42million population in China,increasing about3~4million every year. Spontaneous clearance of HCV occurs in10-20%of patients with acute infection, about80%of patients develop chronic infection, thendevelop into progressive fibrosis that leads to liver cirrhosis and hepatocellular carcinoma(HCC). Therefore, HCV infection is emerging as a global concern of public health problem.The current standard of care for patients with chronic hepatitis C is the combination ofpegylated interferon (pegIFN) alpha and ribavirin. End-of-treatment viral response (ETR）was defined as seronegative for HCV RNA at the end of treatment. Sustained viral response(SVR) defined as seronegative for HCV RNA at24-week after ETR(treatment completion).SVR is associated with histological improvement and the prevention of complications, suchas the development of liver cirrhosis and HCC. Thus, SVR is deemed as an important factorfor long-term favourable prognosis.Based on population data, several key host and viral factors are able to predictresponse to treatment of CHC. Host factors include race, gender, age, body massindex(BMI), advanced degree of liver fibrosis and hepatic steatosis. Viral factors includeHCV genotype, pretreatment HCV RNA load, amino-acid mutations in the core and NS5Agene and on-treatment viral kinetics. Among them, HCV genotype is an independent factorfor SVR. According to HCV genotype, the duration of treatment are48weeks for genotype1HCV and24weeks for genotype Non-1HCV. Approximately54-63%of patients achieveSVR after the treatment. Therapy was also frequently complicated by treatment-limitingside effects. In addition, African-American patients were less likely to respond to treatmentthan East-Asian patients. It suggested that other factors may contribute to the response totreatment of CHC.In three recent genome-wide association studies (GWAS), a single nucleotide polymorphism (rs12979860)3kilobases upstream of the IL28B gene, which encodes thetype Ⅲ interferon IFN-λ3, was shown to associate strongly with spontaneous clearance andresponse to HCV treatment in patients infected with genotype1HCV in three separateethnic populations. Patients with the CC genotype were three times more likely to clearHCV relative to patients with the CT and TT. The CC genotype can contribute to the abilityto clear HCV in individuals of African and European ancestry. Thus, IL28B SNP may be animportant factor deciding Curative effect of treatment for CHC. So it is of importantsignificance for making individualizing therapy to explore the distribution ofSNP(rs12979860) and the potential effect of rs12979860variation on outcome to HCVinfection in Chinese patients.Despite favourable long-term prognosis for patients with SVR, relapse after SVR hasbeen found in Clinical practice. However, Clinical data in the long-term management andfollow-up of patients with SVR is limited.The retrospective study was conducted on608of chronic hepatitis C patients fromsouthwest of China. The SNPs(rs12979860) was genotyped and the distribution ofSNP(rs12979860) was analysed. Then, the predictive effect of SNPs (rs12979860) andHCV genotype on response to treatment of CHC in two cohorts of201and179of CHCpatients were investigated. Meanwhile, to understand the viral relapse and its risk factorsduring long-term follow-up in chronic hepatitis C (CHC) patients with ETR after interferonand ribavirin therapy, clinical data of146of CHC patients treated with the combination ofpegylated interferon-alfa or conventional interferon and ribavirin for24(Non-genotype1b)or48(genotype1b) weeks was analysed.Results:1. The frequency of the SNP(rs12979860) C allele and T allele was respectively94.16%（1145/1216）and5.84%(71/1216) in Chinese HAN CHC patients from southwest ofChina. The MAF was5.84%. Three genotypes CC, CT and TT were identified in the study.The predominant genotype was CC (88.65%，539/608）and the proportion of TT genotypewas extremely low(0.33%，2/608) in our cohort.2. SNP rs12979860CC was uniformly the predominant genotype accounted for greaterthan86%in CHC patients with different HCV genotype infection. There was no significantdifference between the frequency of C allele in patients with HCV genotype1b and Non-1b(93.14%vs90.91%，P=0.223).3．The patients with IL28B rs12979860CC genotype got higher rates of ETR and SVRthan the patients with CT/TT(Non-CC) genotypes.（ETR:93.1%vs64.3%，P﹤0.0001；SVR:83.8%vs36.0%，P﹤0.0001).4．Under the background of HCV genotype1b, the patients with IL28B rs12979860CC genotype got higher rates of ETR and SVR than the patients with CT/TT(Non-CC)genotype（ETR：89.9%vs46.7%，P﹤0.0001；SVR：77.2%vs13.3%，P﹤0.0001）；But under the background of HCV genotype non-1b, there was no significant differencebetween the rate of ETR （89.9%vs84.6%，P=0.17）and SVR （87.6%vs70%，P=0.13）in the patients with CC genotype and CT/TT(Non-CC) genotypes.5．Under the background of IL28B rs12979860CC genotype, there was no significantdifference between the rate of ETR （89.9%vs95.2%，P=0.18）and SVR （77.2%vs87.6%，P=0.09）in patients with HCV genotype1b and Non-1b. But under the backgroundof rs12979860CT/TT genotype, the patients HCV genotype Non-1b got higher rates ofETR and SVR than the patients with genotype1b（ETR：84.6%vs46.7%，P=0.04；SVR：70%vs13.3%，P=0.009）；6．In univariate analysis of factors associated with ETR and SVR, HCV genotype andrs12979860genotype was associated with ETR, while HCV genotype, rs12979860genotype, age and baseline viral load was associated with SVR. In multiplelogistic-regression analysis, only the rs12979860genotype was significantly associatedwith ETR （OR:10.1，95%CI:3.325~30.68，P <0.0001） and SVR （OR:17.449，95%CI:5.521~55.15，P <0.0001）than the other factors, including sex, age, HCV genotype andbaseline viral load.7．During a mean follow-up of33.45±16.41months (range:12to85months), thecumulative relapse rate of14.80%was observed in146CHC patients with ETR afterantiviral therapy.8．The relapse rate of8.90%within6months was significantly higher than otherperiods during two years follow-up and no relapse occurred after30months.9．The relapse rate in patients with HCV genotype1b and non-1b deferred little(20.37%vs12.12%,χ~2=1.517, P=0.315).The mean baseline HCV RNA load in relapserswas higher than that of Non-relapsers (t=0.915，P=0.362). Relapse rates were similar in patients treated with PEG-IFNα-2b，PEG-IFNα-2a and IFNα (12.12%vs13.97%vs15.00%，χ~2=0.104, P=0.949).The mean age of relapsers was significantly higher than thatof Non-relapsers (P <0.005).Conclusion:1．The frequency of the SNP(rs12979860) C allele is dominated （94.16%）in HANCHC patients from southwest of china. The MAF is5.84%. Three genotypes CC,CT andTT were identified in the study. The predominant genotype is CC and the proportion of TTgenotype is extremely low in our cohort.2．SNP rs12979860CC is uniformly the predominant genotype in CHC patients withdifferent HCV genotypes. There is no association between rs12979860genotype andinfection of different HCV genotype, that is, probability of different HCV genotypeinfection in different background of patients with CC or CT/TT genotype is similar.3．IL28B rs12979860CC genotype is advantageous to response to treatment for CHCin Chinese HAN patients as reported globally. rs12979860SNP exert significant effect onresponse to treatment in patients with HCV genotype1b, but not in HCV genotype non-1b.4．Under the standard antiviral therapy guided by HCV genotype (eliminating theinfluence of HCV genotype on response to treatment), IL28B rs12979860SNP issignificantly associated with ETR and SVR. IL28B rs12979860genotype could be apredictor for ETR and SVR in Chinese Han patients with HCV infection.5．The maximum probability of relapse occurred within6months of follow-up inpatients with ETR, but thereafter there is still a risk for relapse. Therefore, it is import topay attention for at least2-year follow-up after cessation of antiviral therapy. The patientcould be clinically considered to be cure if HCVRNA sustained negative2yearspost-treatment.6．Under the standard antiviral therapy guided by HCV genotype (eliminating theinfluence of HCV genotype on response to treatment), the older patient has a higher risk forrelapse.