2025 年第 7 期 第 20 卷

核苷(酸)类似物序贯聚乙二醇干扰素治疗后早期丙氨酸转氨酶跃升联合乙型肝炎表面抗原下降对慢性乙型肝炎患者功能性治愈预测价值的研究

Study on the predictive value of early alanine aminotransferase jump combined with hepatitis B surface antigen decline in chronic hepatitis B patients with nucleotide analogues sequential pegylated interferon therapy

作者：曾凰1杨海清1李岩1彭伟豪1张婧1季芳2

英文作者：Zeng Huang1 Yang Haiqing1 Li Yan1 Peng Weihao1 Zhang Jing1 Ji Fang2

单位：1徐州医科大学研究生院，徐州221004；2徐州医科大学附属医院感染及肝病科，徐州221002

英文单位：1Graduate School of Xuzhou Medical University Xuzhou 221004 China; 2Department of Infection and Hepatology the Affiliated Hospital of Xuzhou Medical University Xuzhou 221002 China

关键词：慢性乙型肝炎；核苷(酸)类似物；聚乙二醇干扰素；功能性治愈；预测模型

英文关键词：ChronichepatitisB;Nucleotideanalogues;Pegylatedinterferon;Functionalcure;Predictionmodel

• 摘要：

• 目的 探索核苷(酸)类似物(NAs)序贯聚乙二醇干扰素(Peg-IFN)治疗后，丙氨酸转氨酶(ALT)跃升联合乙型肝炎表面抗原(HBsAg)下降对慢性乙型肝炎(CHB)患者功能性治愈的预测价值并建立预测模型。方法 回顾性纳入2019年7月至2022年12月在徐州医科大学附属医院就诊、HBsAg阳性超过6个月、乙型肝炎病毒（HBV）DNA≤3.3 log10IU/ml且接受NAs抗病毒治疗至少1年的CHB患者，联合Peg-IFN治疗48周，根据基线至治疗12周ALT跃升(较基线2倍以上升高)及HBsAg下降(较基线下降)情况进行分析。HBsAg应答定义为治疗24周HBsAg＜3.2且下降＞1.0 log10IU/ml。以治疗48周HBsAg＜2.0 log10IU/ml为疗效评价指标，同时分析HBsAg应答的预测因素并构建预测模型。使用受试者工作特征曲线评估模型拟合效果。结果研究共纳入NAs序贯Peg-IFN治疗CHB患者145例。治疗24周时50例HBsAg应答者中有40例在治疗48周时HBsAg＜2.0 log10IU/ml，阳性预测值（PPV）为80.0%，其中19例患者(38.0%)获得了HBsAg清除。多因素Logistic回归分析结果显示：基线HBsAg(比值比=11.306，95%置信区间：3.959～32.288，P＜0.001)、基线至治疗12周ALT跃升(比值比=3.435，95%置信区间：1.107～10.659，P=0.033)及HBsAg下降(比值比=54.775，95%置信区间：5.941～505.028，P＜0.001)是HBsAg应答的独立预测因素，建立预测模型Logit P=2.425×基线HBsAg+4.003×HBsAg下降+1.234×ALT跃升-5.776(BHA模型)，其曲线下面积为0.843，标准误为0.037，95%置信区间：0.769～0.916，根据约登指数计算公式，确定P值的截断值为0.51，其诊断的敏感度为86.70%，特异度为67.30%。结论 基线HBsAg水平、治疗12周ALT跃升联合HBsAg下降与NAs序贯Peg-IFN治疗CHB患者HBsAg应答相关。应用上述指标构建的预测模型可筛选出在联合治疗48周时可能获得功能性治愈的患者。

• Objective  To explore the predictive value of alanine aminotransferase (ALT) jump combined with hepatitis B surface antigen (HBsAg) decline for functional cure in chronic hepatitis B (CHB) patients treated with nucleotide analogues (NAs) sequential pegylated interferon (Peg-IFN) and establish a prediction model. Methods CHB patients who visited the Affiliated Hospital of Xuzhou Medical University from July 2019 to December 2022, were HBsAg positive for more than 6 months, hepatitis B virus (HBV) DNA≤3.3 log10IU/ml and received NAs antiviral therapy for at least 1 year, combined with Peg-IFN for 48 weeks, were retrospectively enrolled. The analysis was based on the baseline to 12 weeks alanine aminotransferase (ALT) jump (2-fold increase from baseline) and HBsAg decline (decrease from baseline). HBsAg response was defined as HBsAg <3.2 and a decrease of >1.0 log10IU/ml at 24 weeks.HBsAg <2.0 log10IU/ml at 48 weeks was used as the efficacy evaluation index, and the predictive factors of HBsAg response were analyzed and a prediction model was constructed. The receiver operating characteristic curve was used to evaluate the model fitting effect. Results A total of 145 CHB patients treated with NAs followed by Peg-IFN were included in the study. Forty of 50 HBsAg responders at 24 weeks had HBsAg <2.0 log10IU/ml at 48 weeks of treatment, with a positive predictive value (PPV) of 80.0%, and 19 of them (38.0%) achieved HBsAg loss. Multivariate Logistic regression analysis showed that baseline HBsAg(odds ratio=11.306, 95% confidence interval: 3.959-32.288, P＜0.001), baseline to week 12 ALT jump (odds ratio=3.435, 95% confidence interval: 1.107-10.659, P=0.033), and HBsAg decreased at 12 weeks (odds ratio=54.775, 95% confidence interval: 5.941-505.028, P＜0.001) were independent predictors of HBsAg response. The prediction model was established as follows: Logit P=2.425× baseline HBsAg +4.003× HBsAg decreased +1.234× ALT flared -5.776(BHA model), its area under the curve was 0.843, the standard error was 0.037, 95% confidence interval: 0.769-0.916, according to the calculation formula of Jorden index, the cutoff value of P value was determined to be 0.51, and the sensitivity and specificity of its diagnosis were 86.70% and 67.30%. Conclusion Baseline HBsAg level, ALT jump combined with HBsAg decline at 12 weeks of treatment are associated with HBsAg response in CHB patients treated with NAs sequential Peg-IFN. The prediction model constructed by the above indicators can screen out patients who are likely to achieve functional cure at 48 weeks of combination therapy.