核苷(酸)类似物经治慢性乙型肝炎患者序贯联合聚乙二醇干扰素α治疗48~96周的疗效及影响因素分析

Analysis of the therapeutic efficacy and factors influencing sequential combination of nucleos(t)ide analogues with pegylated interferon alpha for 48~96 weeks in the treatment of patients with chronic hepatitis B

目的探究核苷(酸)类似物(NAs)经治慢性乙型肝炎(CHB)患者序贯联合聚乙二醇干扰素α(Peg-IFN-α)治疗疗效及其影响因素。方法选取2018年5月-2020年5月在解放军总医院第五医学中心治疗随访的NAs治疗1年以上、HBV DNA<20 IU/ml、乙型肝炎表面抗原(HBsAg)定量<3000 IU/ml的CHB患者144例,给予序贯联合Peg-IFN-α治疗48~96周;采用意向性分析统计96周HBsAg清除率,采用Kaplan-Meier法计算96周HBsAg累积清除率,通过单因素和多因素logistic回归进行序贯联合治疗48周HBsAg清除的影响因素分析,通过单因素和多因素COX比例风险模型进行延长Peg-IFN-α疗程96周HBsAg清除的影响因素分析,采用受试者操作特征曲线评价影响因素对HBsAg清除的预测价值。计量资料组间数据比较采用Mann-Whitney U检验,计数资料组间数据比较采用χ^(2)检验。结果41例(28.47%)患者在序贯联合治疗48周时实现HBsAg清除。意向性分析96周HBsAg清除率为40.28%(58/144),Kaplan-Meier法计算96周HBsAg累积清除率为68.90%。多因素logistic回归分析显示基线HBsAg定量(OR=0.090,95%CI:0.034~0.240,P<0.001)和24周HBsAg下降幅度(OR=7.788,95%CI:3.408~17.798,P<0.001)是NAs经治CHB患者序贯联合Peg-IFN-α治疗48周实现HBsAg清除的独立预测因素。受试者操作特征曲线分析显示基线HBsAg定量[受试者操作特征曲线下面积(AUC)为0.911,95%CI:0.852~0.952]与24周HBsAg下降幅度(AUC=0.881,95%CI:0.814~0.930)均具有较好的48周HBsAg清除预测价值,但两者差异无统计学意义(Z=0.638,P=0.523)。基线HBsAg定量与24周HBsAg下降幅度联合(AUC=0.981,95%CI:0.941~0.997)预测48周HBsAg清除率的价值均高于单一的基线HBsAg定量(Z=3.017,P=0.003)或24周HBsAg下降幅度(Z=3.214,P=0.001)。多因素COX比例风险模型分析显示48周HBsAg定量(HR=0.364,95%CI:0.176~0.752,P=0.006)是延长Peg-IFN-α疗程96周HBsAg清除的独立预测因素。结论基线HBsAg定量联合24周HBsAg下降幅度可以有效预测NAs经治CHB患者序贯联合Peg-IFN-α治疗48周HBsAg清除率;延长Peg-IFN-α疗程能够提高HBsAg清除率;序贯联合治疗48周时HBsAg定量是延长Peg-IFN-α疗程96周HBsAg清除的独立预测因素。

Objective To explore the therapeutic efficacy and factors influencing the sequential combination of nucleos(t)ide analogues(NAs)with pegylated interferon alpha(Peg-IFN-α)in the treatment of patients with chronic hepatitis B(CHB).Methods 144 CHB cases with NAs treatment for more than 1 year,HBV DNA<20 IU/ml,hepatitis B surface antigen(HBsAg)quantification<3000 IU/ml,treated with a sequential combination of Peg-IFN-αtreatment for 48 to 96 weeks,and followed up were selected from the Fifth Medical Center of the PLA General Hospital between May 2018 and May 2020.Intention-to-treat analysis was used to measure the HBsAg clearance rate at 96 weeks.The Kaplan-Meier method was used to compute the cumulative HBsAg clearance rate at 96 weeks.Univariate and multivariate logistic regression were used to analyze the factors influencing HBsAg clearance at 48 weeks of sequential combination therapy.Univariate and multifactorial COX proportional hazard models were used to analyze the factors influencing HBsAg clearance following 96 weeks of prolonged PEG-IFN-α treatment.The receiver operating characteristic curve was used to assess the predictive value of factors influencing HBsAg clearance.A Mann-Whitney U test was used to compare the measurement data between groups.The count data was compared using the χ^(2) test between groups.Results 41(28.47%)cases achieved HBsAg clearance at 48 weeks of sequential combination therapy.The HBsAg clearance rate at 96 weeks was 40.28%(58/144)by intention-to-treat analysis.The Kaplan-Meier method computed that the cumulative HBsAg clearance rate at 96 weeks was 68.90%.Multivariate logistic regression analysis showed that HBsAg quantification at baseline(OR=0.090,95%CI:0.034-0.240,P<0.001)and a 24-week drop in HBsAg level(OR=7.788,95%CI:3.408-17.798,P<0.001)were independent predictors of HBsAg clearance in CHB patients treated sequentially in combination with NAs and Peg-IFN-α for 48 weeks.Receiver operating characteristic curve analysis showed that the baseline HBsAg quantification[area under the receiver operating characteristic curve(AUC),0.911,95%CI:0.852-0.952]and 24-week drop in HBsAg level(AUC=0.881,95%CI:0.814-0.930)had equally good predictive value for 48-week HBsAg clearance,but there was no statistically significant difference between the two(Z=0.638,P=0.523).The value of the combination of baseline HBsAg quantification and 24-week drop in HBsAg level(AUC=0.981,95%CI:0.941-0.997)was superior to that of single baseline HBsAg quantification(Z=3.017,P=0.003)and 24-week drop in HBsAg level(Z=3.214,P=0.001)in predicting HBsAg clearance rate at 48 weeks.Multivariate COX proportional hazards model analysis showed that HBsAg quantification at 48 weeks(HR=0.364,95%CI:0.176-0.752,P=0.006)was an independent predictor of HBsAg clearance with a prolonged course to 96 weeks of Peg-IFN-α treatment.Conclusion The HBsAg clearance rate can be accurately predicted with baseline HBsAg quantification combined with a 24-week drop in HBsAg level in patients with CHB who are treated with a sequential combination of NAs and Peg-IFN-αtherapy for 48 weeks.Prolonging the course of Peg-IFN-α treatment can enhance the HBsAg clearance rate's capability.An independent predictor of HBsAg clearance is HBsAg quantification at 48 weeks of sequential combination therapy with a prolonged course of 96 weeks of Peg-IFN-αtreatment.