| Background:Hepatitis C is an infectious disease caused by hepatitis C virus(HCV).It is a global epidemic.People are generally susceptible to HCV.According to World Health Organization statistics,there are about 180 million people infected with HCV in the world,and about 10 million people infected with HCV in China.HCV infection tends to be chronic.More than 20%of chronic hepatitis C patients can progress slowly to hepatic fibrosis,cirrhosis and even hepatocellular carcinoma.Early antiviral therapy and sustained viral response(SVR)can reduce liver inflammation and necrosis caused by chronic HCV infection,and the risk of progression to liver fibrosis and cirrhosis,thus reducing the risk of hepatocellular carcinoma and greatly improving the prognosis of patients with chronic hepatitis C.The traditional antiviral therapy was the combination of Pegylated interferon(Peg-IFN)and Ribavirin(RBV),which was called PR therapy.The overall efficiency was not high,only 50%-60%of patients can get SVR through this therapy,and there were many taboos,and cases of treatment failure and recurrence after treatment in the traditional PR therapy,with more adverse reactions.The direct-acting antiviral agents(DAA)had achieved good efficacy and safety in clinical trials abroad after they were marketed.However,HCV had significant heterogenous and highly variable,primary drug resistance was found different in different races,regions,genotypes and quasispecies.The occurrence of primary drug resistance had a certain impact on the choice of treatment options and efficacy of DAAs drugs.There are few reports on the efficacy,safety and baseline primary drug resistance of antiviral regimens based on sofosbuvir(SOF)in renal transplantation patients with hepatitis C and general hepatitis C patients.Therefore,we focus on the two aspects,so as to provide theoretical basis for the selection of antiviral treatment options and the adjustment of follow-up treatment for these hepatitis C patients in Shandong region of China.Objective:To observe and compare the efficacy and safety of antiviral therapy based on SOF in general hepatitis C patients and kidney transplantation patients with hepatitis C,anddescribe the distribution characteristics of drug resistance mutations in baseline non-structural genes 5 A(NS5A)region of hepatitis C patients in Shandong region,so as to provide suitable treatment for hepatitis C patients in Shandong region.Methods:In this study,all patients with hepatitis C admitted to hepatology ward and outpatient clinic of the Second Hospital of Shandong University from March 2016 to September 2018 were enrolled.All enrolled patients were divided into general group(group A)and kidney transplant group(group B)according to whether they are kidney transplantrecipients or not.Baseline serum was collected for genotyping and NS5A region sequencing,The antiviral regimens based on SOF was given for 12 weeks or 24 weeks according to the baseline genotype,previous treatment,liver and kidney function,complications and combined drug use,referring to their treatment intention and economic situation,and referring to the recomendation of guidelines.The general data of patients at baseline,and serum at baseline,1,2,4 weeks,end of treatment,12 and 24 weeks after drug withdrawal was collected during the whole study for detection of liver and kidney function,whole blood cell count,HCV RNA quantification,urinary routine,and serum concentration of immunosuppressants such as tacrolimus(FK506)and cyclosporine A at each time point.To observe and compare the efficacy and adverse reactions of antiviral therapy,the changes of estimated glomerular filtration rate(eGFR)level in the two groups and the adjustment of antirejective drugs.To determine the efficacy and safety of SOF-based antiviral therapies in the treatment of generalhepatitis C patients and renal transplantation patients with hepatitis C.Detection of drug resistance sites:HCV NS5A region sequence was amplified by RT-PCR.The PCR products was sequenced by Sanger sequencing,and compared with HCV reference standard strains.According to the known drug resistance sites reported in the past literatures,amino acid mutations at 24.25,28,30,31,54,58,62,92 and 93 sites in NS5A region were mainly observed to understand the basisdistribution of drug resistance mutations in NS5A region of hepatitis C patients in Shandong Province.Results:A total of 94 patients with hepatitis C were enrolled in this study.Among them,43 were males and 51 werefemales,with an average age of 47.78±13.24 years.62 cases(65.96%)were genotype 1b,21 cases(22.34%)were genotype 2a,2 cases(2.13%)were genotype 3a,2 cases(2.13%)were genotype 3b,2 cases(2.13%)were genotype 1a and 5 cases(5.32%)were genotype 6a.50 of the 94 patients in the group detected mutations in drug resistance sites associated with NS5A inhibitors.Among them,21 cases(33.87%)were found to have drug resistance mutations in genotype 1b,7 cases(11.29%)of Y93H mutations were detected,including 5 cases of Y93H single drug resistance,2 cases of Y93H combined with R30Q mutation;One case(1.61%)was resistant to L31site.All serum samples were detected mutations at L31M site for genotype 2a.Three of them were L31M with P58S mutation.Onepatient(50%)with genotype 3a had mutation of A30M site.All the patients with genotype 3b had mutations at A30K and L31M site.F28L site resistance was detected in all 5 patients with genotype 6a,and one case was complicated with T58S mutation.There were 78 patients in general group.Among them,30 were males and 48 were females,with an average age of 47.9±14.09 years.Baseline HCV RNA quantification was 6.11±1.12 Log10 IU/ml.There were 33 cases of cirrhosis and 45 cases of non-cirrhosis.55 patients(70.51%)with genotype 1b;1 9 cases(24.36%)were genotype 2a;In addition,there were 2 cases of genotype 1a,1 case of genotype 3b and 1 case of genotype 6a.Among the 78 patients,51 were initially treated and 27 were treated with PR therapy.58 patients were treated with Sofosbuvir+Daclatasvir ±RBV regimen,of which 9 needed combined RBV treatment.17 patients were treated with Sofosbuvir/Veruprevir regimen.3 patients were treated with Sofosbuvir+PR regimen.There were 16 patients in kidney transplant group.Among them,13 were males and 3 were females,with an average age of 47.19±8.21 years.The time after kidney transplant was 55(3,168)months.Among them,one case was after KT twice.All patients were treated for the first time.There were 4 cases of cirrhosis,12 cases of non-cirrhosis,7 cases of genotype 1 b,2 cases of genotype 2a,2 cases of genotype 3a,1 case of genotype 3b and 4 cases of genotype 6a.Baseline HCV RNA quantification was 6.41±0.99 Log10 IU/ml.Thirteen patients were treated with Sofosbuvir+Daclatasvir ±RBV regimen.Three patients were treated with Sofosbuvir/Veruprevir regimen.Four patients(25%)in the renal transplantation group were negative for hepatitis C antibody test,while all patients in the general hepatitis C group were positive for hepatitis C antibody.Among the94 patients,15/16 patients completed the treatment in the kidney transplantation group;And the complete virological response rate was 12.5%(2/1 6)at 1 week,68.75%(11/16)at 2 weeks,93.33%(14/15)at 4 weeks,100%(15/15)at the end of treatment,and 14/15 cases(93.33%)reached SVR 12 and SVR 24.In general group,78/78 patients completed the treatment;And the complete virological response rate was 52.56%(41/78)at 1 week,75.64%(59/78)at 2 weeks,97.44%(76/78)at 4 weeks,100%(78/78)at the end of treatment,and 77 cases(77/77,100%)reached SVR 12 and SVR 24.The complete virological response rate of kidney transplantation group was lower than that of general hepatitis C group at 1 week of treatment.In addition,there was significant difference in complete virological response rate between chronic hepatitis C patients and cirrhosis patients at 2 weeks of treatment.There was also significant difference in complete virological response rate between initially treated patients and treated patients at 2 weeks.All patients achieved SVR by SOF-based regimens for general hepatitis C patients and kidney transplantation patients combined with hepatitis C,except for one patient with genotype 3b who relapsed.The SVR rates of other different genes are higher.At the same time,the biochemical response of recruited patients was good after antiviral treatment,and the hepatic inflammation improved significantly after treatment.In group A,the baseline creatinine level and eGFR level were 58.1±15.02?mol/L and 100.62±19.8 ml/min/1.73 m2,respectively.The creatinine level and eGFR level at the end of treatment were 60.48±14.46?mol/L and 99.46±20.96 ml/min/1.73 m2,respectively.And the creatinine level and eGFR level at 12 weeks after drug withdrawal were 60.12±13.79?mol/Land 101.76±19.51 ml/min/1.73 m2,respectively.In group B,the baseline creatinine level and eGFR level were 114.32±35.53?mol/L and 50.81±18.23 ml/min/1.73m2,respectively.The creatinine level and eGFR level at the end of treatment were 128.61±38.90?mol/L and 49.19±16.61ml/min/1.73m2,respectively.And the creatinine level and eGFR level at 12 weeks after drug withdrawal were 129.54±39.97±mol/L and 50.79±16.66 ml/min/1.73m2,respectively.There was no significant difference in the levels of creatinine and eGFR in kidney transplantation group at baseline,1 week,2 weeks,4 weeks,time of withdrawal,12 weeks and 24 weeks of withdrawal.The same was true for the general group.In addition,headache was the most common adverse reaction,accounting for 9.57%;blood pressure was transient unstable in 8 cases,accounting for 8.51%;hair loss was 6.38%;7 patients suffered from fatigue,nausea,heartburn,gastric discomfort,diarrhea and other gastrointestinal symptoms.7 cases(7.45%)had dizziness,tinnitus,dry eyes,abdominal distention and rash.The overall rate of adverse reactions was low,and most of them were tolerable,and no serious adverse reactions were observed.One patient in group A was treated with sofobuvir and daclatasvir,and died of lymph node metastasis of colon cancer about 10 weeks after discontinuation.Primary hepatocellular carcinoma was detected in 3 patients with cirrhosis during follow-up after drug withdrawal and treated accordingly.One patient in group B stopped taking drugs because his eGFR decreased from 41.2 ml/min/1.73 m2 to 29.1 ml/min/1.73 m2 due to the increase of creatinine at 2 weeks of treatment.No other serious adverse events were observed during the whole treatment.Among the 16 patients in group B,12 patients were treated with FK506+Mycophenolate mofetil(MMF)+Prednisone(Pred)as an immunosuppressive regimen at basement.Cyclosporine(CsA)+MMF+Pred was used in 4 cases.The blood concentrations of FK506,MMF and CSA in most patients changed within the target Valley level during the whole treatment,immunosuppressive agent was adjusted in only 4 patients during treatment.About 50%of patients may have transient decrease of eGFRwithin 2 weeks of treatment.However,follow-up observation showed that the lowest eGFR was found in about 31.25%of patients at 24 weeks of follow-up after withdrawal.It was presumed that the change of eGFR was not necessarily related to SOF and other drugs,but may be related to the transplanted kidney itself.Conclusions:1.SOF-based antivirus regimens are effective in the treatment of general hepatitis C patients and renal transplantation patients with hepatitis C,with fewer adverse reactions,good safety and high compliance.There is no need for early detection of HCV RNA.If the patients have obvious hepatic fibrosis at the baseline of treatment,regular liver imaging review is necessary.2.The distribution of drug resistance mutations in NS5A region of different genotypes of HCV is different at baseline,but SVR can be obtained by SOF-based antivirus regimens.Most of genotype 3b had mutations of A30K combined with L31 Msites in NS5A region,which might be related to its recurrence.3.HCV RNA should be routinely monited in kidney transplant patients to prevent missed diagnosis and treatmentof hepatitis C. |
PDF Full Text Request