48周HBsAg低水平的HBeAg阴性慢性乙型肝炎患者是获得HBsAg清除的优势人群

Low-levels of HBsAg quantification at 48-week in HBeAg-negative chronic hepatitis B patients are the advantageous population for HBsAg clearance

目的针对采用聚乙二醇干扰素α-2a联合核苷（酸）类似物治疗的HBeAg阴性慢性乙型肝炎患者进行疗效分析，以期获得预测HBsAg清除的影响因素。方法采用回顾性研究方法，研究对象为HBeAg阴性慢性乙型肝炎优化治疗方案临床研究中采用聚乙二醇干扰素α-2a联合核苷（酸）类似物（拉米夫定／阿德福韦酯）治疗，疗程96周，随访至120周的患者；以120周HBsAg清除为研究目标，通过logistic回归、受试者工作特征曲线分析筛选出影响HBsAg清除的相关因素。计数资料的比较采用x^2检验。结果聚乙二醇干扰素α-2a联合核苷（酸）类似物治疗组共计111例患者，107例完成预定疗程及随访。120周HBsAg清除率为29．0％（31／107）。影响因素分析：（1）性别对HBsAg清除率无影响；年龄及基线HBVDNA、丙氨酸氨基转移酶水平对HBsAg清除影响不明显；基线低水平HBsAg（≤3．0231gIU／ml）有利于HBsAg清除，其受试者工作特征曲线下面积为0．746，阳性预测值为44．4％，阴性预测值为86．8％。（2）疗程24周、48周HBsAg定量或下降幅度均对HBsAg清除具有良好的预测作用，其中48周预测价值高于24周。48周HBsAg定量≤2．070lgIU／ml时，其受试者工作特征曲线下面积为0．931，阳性预测值为52．8％，阴性预测值为94．4％；HBsAg相对基线下降≥0．9911gIU／ml时，其受试者工作特征曲线下面积为0．888，阳性预测值为50．8％，阴性预测值为97．9％。（3）48周HBsAg水平亚组分析结果提示，采用“区间水平”划分人群相对以“节点水平”划分，前者预测HBsAg清除更加精准，48周100IU／ml〈HBsAg≤1000IU／ml、10IU／ml〈HBsAg≤100IU／ml以及HBsAg≤10IU／ml人群的HBsAg清除率分别为6．7％、31．8％和67．7％。（4）疗程中丙氨酸氨基转移酶再异常者也可获得较高的HBsAg清除率（48．0％，12／25）。结论采用96周长疗程聚乙二醇干扰素α-2a联合核苷（酸）类似物治疗HBeAg阴性慢性乙型肝炎，基线及疗程中HBsAg水平均对HBsAg清除具有良好的预测价值。以48周HBsAg的“区间水平”来预测HBsAg清除结果更加精准，提示48周HBsAg低水平的HBeAg阴性慢性乙型肝炎患者是获得HBsAg清除的优势人群，这类患者更值得延长疗程以追求“临床治愈”。

Objective To analyze the therapeutic effect on HBeAg-negative chronic hepatitis B patients treated with Peg-IFNa-2a combined with NAs to obtain the influencing factors for predicting HBsAg clearance. Methods A retrospective study was conducted to investigate the effect of pegylated interferon alpha-2a combined with nucleoside analogues （lamivudine/adefovir dipivoxil） on HBeAg-negative chronic hepatitis B. The treatment course was 96 weeks. Patients were followed up 120 weeks after the treatment. HBsAg clearance at 120 weeks was taken as the objective of the study. Logistic regression and receiver operating characteristic curve analysis screened the related factors affecting HBsAg clearance. x^2 test was used to compare count data. Results 111 patients were treated with pegylated interferon alpha-2a combined with nucleoside analogues, and 107 patients completed the scheduled course of treatment and follow-up. HBsAg clearance rate at120 week was 29.0% （31/107）. The influencing factors for analysis were： （1） gender had no effect on HBsAg clearance rate; age and baseline levels of HBV DNA and alanine aminotransferase had no significant effect on HBsAg clearance; low baseline level of HBsAg （〈 3.023 lglU/ml） was beneficial to HBsAg clearance. The area under the working characteristic cm＇ve of the subjects was 0.746, the positive predictive value was 44.4%, and the negative predictive value was 86.8%. （2） HBsAg quantification or decline in 24 weeks and 48 weeks of treatment had a good predictive effect on HBsAg clearance, and the 48 weeks predicted value was higher than 24 weeks. When the HBsAg quantification was ≤ 2.070 lgIU/ml at 48 weeks, the area under the receiver operating characteristic curve was 0.931, the positive predictive value was 52.8%, and the negative predictive value was 94.4%. When HBsAg decreased from baseline to/〉 0.991 lglU/ml, the area under the receiver operating characteristic curve was 0.888, the positive predictive value was 50.8%, and the negative predictive value was 97.9%. （3） The analysis of HBsAg subgroup levels at 48 weeks suggested that the ＂interval analysis＂ can forecast HBsAg clearance more exactly than ＂nodal analysis＂.The final HBsAg clearance rate of 100 IU/ml 〈 HBsAg ≤ 1 000 IU/ml, 10 IU/ml 〈 HBsAg ≤ 100 IU/ml and HBsAg ≤ 10 IU/ml groups reached 6.7%, 31.8% and 67.7%, respectively. （4） The ALT abnormal group in the course of treatment obtained a higher HBsAg clearance rate （48.0%, 12/25）. Conclusion 96-weeks long-term treatment with pegylated interferon-alpha -alpha-2a combined with nucleoside analogues for HBeAg-negative chronic hepatitis B has a good predictive value for HBsAg clearance at baseline and during treatment. The ＂interval level＂ of HBsAg at 48-weeks is more accurate in predicting HBsAg clearance, suggesting that HBeAg-negative chronic hepatitis B patients with low HBsAg levels at 48-weeks are the advantageous populations with HBsAg clearance. These patients are worthy of prolonged treatment to pursue ＂clinical cure＂.