| Part 1 Evaluation of the diagnostic efficacy of TREAT-B scores for antiviral therapy in children with chronic HBV infectionObjective: To verify the diagnostic efficacy of the TREAT-B score in screening patients who deserve antiviral therapy in children with chronic hepatitis B(CHB),to analyze its applicability in children of different ages,and to test the reliability of the score in children with CHB.Methods: The clinical data of children with chronic HBV infection who had not received antiviral therapy from March 2018 to August 2021 in the Department of Pediatrics,Tongji Hospital Affiliated to Tongji Medical College,Huazhong University of Science and Technology were retrospectively collected and reviewed,and the patients with completed follow-up in the out-patient clinic or telephone were finally recruited.The reference standard for children with CHB deserving antiviral therapy,namely the Asia Pacific Association for the Study of the Liver(APASL)and the Guidelines for the Prevention and Treatment of Chronic Hepatitis B in my country(2019 edition),were set as the "gold standard",with the clinical data of the children included in our study comprehensively analyzed.By comparing the "gold standard" and the TREAT-B score in evaluating whether antiviral therapy needs to be prescribed,we drew the receiver operating characteristic curve(ROC curve)to verify the efficacy of TREAT-B score and the "gold standard" respectively.Results: A total of 147 patients who met the inclusion criteria were finally recruited in our study.With the careful review of clinical data comprehensively,there were 100 cases who needed to be considered for antiviral therapy according to the recommendations of the guidelines.When the cut-off value of TREAT-B scores was 2,there were 116 cases who needed to be considered for antiviral therapy,with the sensitivity 99%,the specificity63.8% and the area under the ROC curve 0.81(P<0.0001,95% confidence interval0.73-0.90).When the cut-off value of TREAT-B scores was 3,there were 88 cases deserving the antiviral therapy,with the sensitivity 88%,the specificity 100% and the area under the ROC curve 0.89(P<0.0001,95% confidence interval 0.86-0.94).When different cut-off values were applied,the difference in area under the curve was statistically significant(P=0.001).There was no statistically significant difference in the area under the ROC curve of this score between the age of children ≤6 years old and >6 years old(P=0.745).The calibration curve and the ideal curve of TREAT-B score had a good fit,and the difference between the two was not statistically significant(P=0.312);that is,the reliability of the score in all children was good.Conclusion: Compared to the current guidelines,the TREAT-B score,as a simpler scoring tool in children with CHB,still shows good performance in the efficiency and reliability of diagnosis and screening,which is more applicable with low testing costs in regions with higher prevalence of HBV infection among children.The cost of testing identifies potential patients deserving antiretroviral therapy,and can also be used as a simple evaluation indicator during the follow-up of children temporarily not requiring antiretroviral therapy.Part 2 Evaluation of the efficacy of antiviral therapy for CHB in children and analysis of risk factors for diverse clinical outcomesObjective: To evaluate the efficacy of antiviral therapy in children with CHB,to analyze the associated factors of HBeAg seroconversion in the NAs antiviral therapy,and to compare the efficacy of different NAs antiviral therapy,so as to provide fundamental evidence about the efficacy and antiviral drugs in the clinical treatment.Methods: The clinical data about children with CHB,who received antiviral therapy in the Pediatric Outpatient or Inpatient Department of Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology from May 2004 to October 2019 and were equipped with follow-up data from November 2019 to December2021,were retrospectively collected.The inclusion,exclusion and follow-up criteria were formulated based on the antiviral treatment indications recommended by current guidelines.By gathering and reviewing clinical and follow-up data comprehensively,HBeAg seroconversion and HBsAg negative conversion among all NAs antiviral treatment groups were tested via univariate and multivariate logistic regression,COX regression and Kaplan-Meier survival analysis.The cumulative probability of three clinical outcomes,namely negative conversion,HBeAg seroconversion and ALT returning to normal of groups utilizing lamivudine,entecavir and adefovir dipivoxil were constructed via the survival analysis respectively and compared with each other.Results: A total of 79 patients met the inclusion criteria and were finally reviewed in this part.The median duration of antiviral treatment was 128(interquartile range: 89-186)weeks,with the rate of HBV DNA negative 93.7%,HBeAg seroconversion 62.0% and HBsAg negative 24.1%.Genetic examination of HBV resistance detected pre-existing drug-resistant mutations in eight patients prior to treatment(both resistant to lamivudine and entecavir),and another 4 cases of secondary drug-resistant mutations(3 cases of lamivudine resistance and 1 case of adefovir dipivoxil resistance)were detected during treatment.Among 63 cases with NAs monotherapy,multivariate regression analysis suggested that age was an independent predictor of HBeAg seroconversion(P=0.027,OR=0.99,95% confidence interval 0.981-0.999).In particular,≤4-year-old group was more prone to HBeAg seroconversion than the >4-year-old group(P=0.001).The level of HBV DNA at the 12 th week of treatment was associated with the occurrence of HBeAg seroconversion after 12 weeks(P=0.001,OR=0.767,95% confidence interval:0.654-0.900).Compared with the <4 log IU/ml group,lower levels of HBV DNA in 12 weeks in the group of ≥4 log IU/ml was also found(P=0.001).In the analysis of factors associated with HBsAg negative conversion,there was a statistically significant difference between the HBsAg<150IU/ml group and the ≥150IU/ml group at the 24 th week of treatment(P=0.005),with the <150IU/ml group more prone to HBsAg negative conversion.Also,the ≤4 years old group was more prone to HBsAg negative conversion(P<0.001).In the age group of ≤4 years of age at the time of initiation of antiviral therapy,the HBsAg negative rate(59.1%,13/22)and serological conversion rate(45.5%,10/22)were significantly higher than those in the >4-year-old group(P<0.001).In the group analysis of monotherapy efficacy such as lamivudine(57 cases),entecavir(10 cases)and adefovir dipivoxil(9 cases),it was found that HBeAg seroconversion(P=0.033)and HBV DNA negative conversion(P=0.030)in lamivudine group was significantly different from that in adefovir dipivoxil group.The comparisons of the cumulative probability curve and the corresponding curve of the entecavir group with other two groups were not statistically different.The differences among the curves of ALT returning to normal also did not emerge.Conclusion: Nucleoside analog antiviral therapy in CHB children who meet the antiviral indications can effectively promote HBV DNA negative,HBeAg seroconversion and ALT levels return to normal.HBV DNA levels at week 12 declining ≥4 log IU/ml from baseline of NAs monotherapy were likely to achieve HBeAg seroconversion after 12 weeks.At the 24 th week of treatment,the HBsAg<150IU/ml group was more likely to achieve HBsAg negative conversion later.Differences in the treatment effect of patients among age groups emerge,as patients ≤4 years old are more likely to have HBeAg seroconversion and HBsAg negative conversion than patients >4 years old.The antiviral efficacy of lamivudine is similar to that of entecavir,both of which are better than adefovir dipivoxil in promoting HBV DNA negative conversion and HBeAg seroconversion.Part 3 Analysis of the response of children with chronic hepatitis B after the first antiviral treatment was discontinuedObjective: To observe the clinical outcome of HBeAg-positive CHB patients after the discontinuation of NAs therapy,to analyze the related factors of relapse after discontinuation,so as to provide a basis for evaluating the risk of relapse after discontinuation of antiviral therapy and adjusting the treatment plan,aiming at improving long-term outcomes of antiviral therapy in children with CHB.Methods: Patients who were enrolled in the second part of the study and who completed the first course of antiviral therapy during the follow-up process were enrolled,with the inclusion criteria,exclusion criteria and follow-up criteria according to the indications of antiviral therapy recommended by current guidelines.The clinical data about patients were collected,and thereafter the clinical characteristics of recurrence or persistent response after drug withdrawal were summarized and analyzed.The Kaplan-Meier method was utilized to estimate the cumulative response rate of patients and the sustained response curve after NAs discontinuation.Univariate and multivariate COX regression were applied to evaluate the potential risk factors for the relapse after NAs antiviral treatment discontinuation,and Kaplan-Meier survival curves were used for further comparing the effects of those factors on the cumulative response rate after discontinuation.The log-rank tests were applied to determine whether there were differences among various survival curves.Results: A total of 40 patients who met the inclusion criteria with complete clinical and follow-up data were recruited in this study.The median of follow-up time after drug discontinuation was 30(13.3-48.5)months.A total of 10 patients had recurrence,and all the recurrence occurred within 69 weeks after drug withdrawal.The cumulative response rate for 72 weeks after drug withdrawal was 64.3%.Interestingly,another four patients still got spontaneous HBsAg seroconversion after drug withdrawal.Among ten patients with relapsed symptoms,nine received NAs again obtaining negative HBV DNA subsequently,and the other one had self-limiting negative HBV DNA at 17 weeks after recurrence without NAs therapy.Three of the re-treated patients(3/9)relapsed twice after discontinuation,with the response rate of NAs re-treatment 66.6%.Multivariate COX regression analysis of recurrence after drug withdrawal showed that the duration of consolidation therapy(P=0.013,OR=0.959,95% confidence interval 0.927-0.991)and the occurrence of hypoviremia during treatment(P=0.001,OR=13.568,95% confidence interval 2.841-64.794)were associated with recurrence after NAs discontinuation.The Kaplan-Meier survival curve suggested that the cumulative response rate of patients who started antiviral therapy aged ≤4 years after drug discontinuation was higher than that of patients >4 years old(P=0.026).Similarly,the Kaplan-Meier survival curve also exhibited that the cumulative response rate after drug discontinuation in patients with consolidation treatment duration ≥48 weeks was higher than that those with consolidation therapy duration <48 weeks(P=0.026).Patients with negative HBV DNA also had higher cumulative response rate than patients with positive HBV DNA(P=0.028).Conclusion: There is a certain proportion of virological recurrence,with or without clinical recurrence,after drug discontinuation in CHB recovered from NAs antiviral therapy.The cumulative response rate after drug withdrawal was higher among patients with consolidation treatment duration >48 weeks,patients who were ≤4 years of age at initiation of antiviral therapy and patients who were negative for HBV DNA at the time of HBeAg seroconversion.Long duration of consolidation therapy and low viremia during antiviral therapy can be risk factors for relapse after discontinuation of antiviral therapy. |
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