| There are more than 20 million patients with chronic hepatitis B(CHB)in China,and the proportion of hepatitis B e antigen(HBe Ag)-negative patients is increasing in the recent years.The average age of HBe Ag negative CHB patients usually is older than that of HBe Ag positive CHB patients,and they also have longer disease durations and more serious hepatic fibrosis.So HBe Ag negative CHB patients are at high risk of cirrhosis and hepatocellular carcinoma.For HBe Ag negative CHB patients,the relapse rate is high if the end points of therapy are virological suppression and biochemical remission.Even extending the consolidation treatment,the relapse rate is not down.However,long-term treatment with nucleos(t)ide analogue(NA)engenders high risk of drug resistance.So recently some treatment guidelines from different countries advise HBe Ag-negative patients to achieve HBs Ag loss,which is really difficult by NA or pegylated interferon(PEG-IFN).It was found that combination of NA with PEG-IFN showed a higher HBs Ag loss rate than monotherapy in a research about combination and prolonged period of treatment.In that research,the population with low HBs Ag levels in week 48 showed high rate of HBs Ag loss in week 96: the HBs Ag loss rate of population with 100 < HBs Ag?1000IU/ml,10 <HBs Ag?100IU/ml and HBs Ag?10IU/ml,whom be named primary advantage population(PAP),middle advantage population(MAP)and super advantage population(SAP),were 3.43%,18.18% and 60%.Based on that research,the new personalize treatment strategy of course-unlimited and target-directed(COSTA)came out.Under the strategy,the patients used NA in long-term and periodically combined with PEG-IFN according to the HBs Ag levels.And this study is a single-center,open-labeled,prospective and clinical cohort study about COSTA.Objective: Evaluating the efficacy and safety of COSTA.Methods:1.Inclusion Criteria:The patients aged from 18 to 60 met the diagnostic criteria for HBe Ag-negative CHB of The Guideline of Prevention and Treatment for Chronic Hepatitis B(2010 version)of China.These patients should have been using NA for more than 24 weeks since the end of treatment with at least 48-week combination of NA and PEG-IFN.And their HBs Ag was less than 1000IU/ml,DNA was less than 100IU/ml and ALT was normal.2.Therapeutic regimen: The patients were divided into group NA and group COSTA According to their wills.In group NA,the patients used ETV in long-term.In group COSTA,the patients used ETV and PEG-IFN in the first 48-week and be divided to 3 populations:(1)SAP continually have combined treatment to week 96.(2)MAP continually have combined treatment to week 72.If they changed to PAP,they could have same drugs to week 96;if not,they stopped PEG-IFN but continually used ETV.(3)PAP stopped PEG-IFN but continually used ETV to week 72.If they changed to MAP or SAP,they could combine PEG-IFN again to week 96;if not,they continually used ETV.All the patients were tested and assessed once every 12 weeks.3.End point of therapy: Once a patient have HBs Ag loss,he or she would receive 24 weeks consolidation treatment.The patient of group NA would have ETV,and that in group COSTA would have combined treatment.If the patient was HBs Ag negative in both next 2 test,he or she can stopped all the drugs.Results:1.A total of 157 patients were involved.103 of them were in group COSTA,and 54 were in group NA.Baseline demographic and other characteristics are similar between the 2 treatment groups.In goup COSTA,2 cases drop out,101 completed 48 weeks and 67 cases completed 96 weeks treat.In group NA,all the cases completed 48 weeks and 41 cases completed 96 weeks treat.There was not drug resistance,clinical relapse or SAE in 96 weeks.2.Efficacy: At the week 48,the percentages of patients with HBs Ag loss and seroconversion in group COSTA were 16.8% and 11.9%,those at week 96 were 35.6% and 29.7%,which were significantly higher than those in group NA(at week 48: 1.6% and 0%;at week 96: 3.2% and 1.6%.P<0.05).Both at week 48 and week 96,the total HBs Ag levels in goup COSTA were significantly lower than those in group NA(P<0.05).The percentage of HBs Ag loss at week 96 of the SAP at week 48 was 60.0%(9/15),and that of MAP was 47.6%(10/21).None of the PAP at week 48 achieved HBs Ag loss at week 96.The SAP and MAP had the significantly better efficacy than PAP(P<0.05).3.Forecast factor analysis: Because there were only 2 cases achieved HBs Ag loss in group NA,the forecast factor analysis about HBs Ag loss contains group COSTA only.(1)For HBs Ag loss at week 48: The lower HBs Ag levels(at baseline,week 12 and week 24),larger HBs Ag decline(at week 12 and week 24)and the abnormal ALT were the single factors that were beneficial to HBs Ag loss at week 48.In multivariate analysis,the HBs Ag levels at week 24 and abnormal ALT had predictive effect.(2)For HBs Ag loss at week96: The analysis only contains 38 cases who used PEG-IFN after week 48.The lower HBs Ag levels and larger HBs Ag decline at week 48 were the single factors that were beneficial to HBs Ag loss at week 96.In multivariate analysis,only the HBs Ag decline at week 48 had predictive effect.Using ROC curve analyzed the HBs Ag decline at week 48,the AUC was 0.681 and the cut-off value was >0.666 log10(sensitivity 84.2%,specificity 31.6%).If HBs Ag declined more than 0.666 log10 at week 48,the rate of HBs Ag loss at week 96 was 61.5%;if not,that was 25.0%.Conclusion:For HBeAg-negative patients,the efficacy under COSTA was significantly better than using long-term NA,the rate of HBs Ag loss in 2 groups had statistical difference(at week 48: 16.8% vs.1.6%;at week 96: 35.6% vs.3.2%.P<0.05).In group COSTA,the patients were divided to 3 populations.The SAP and MAP had continually using PEG-IFN but the PAP stopped.Finally the SAP and MAP had significantly higher rate of HBs Ag loss at week 96 than PAP(60.0% and 47.6% vs.0%).The layering improved the efficacy for the patients with advantage,but it reduced the economic burden and untoward effect of PEG-IFN for the other patients.The analysis above suggests that the patients with lower HBs Ag levels and larger HBs Ag decline are worth to prolong period of combined treatment to pursue the HBs Ag loss.Also,there was not drug resistance,clinical relapse or SAE in 96 weeks.The COSTA strikes balance well between efficacy and safety. |
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