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中华实验和临床感染病杂志(电子版) ›› 2022, Vol. 16 ›› Issue (04) : 247 -253. doi: 10.3877/cma.j.issn.1674-1358.2022.04.005

论著

聚乙二醇化干扰素α-2b联合核苷(酸)类似物治疗低水平乙型肝炎病毒表面抗原慢性乙型肝炎患者的临床疗效及影响因素
谢芳1, 熊熙1, 姚传霞1, 孙浩男1, 李平1, 汪茂荣1,()   
  1. 1. 210002 南京市,东部战区总院肝病科
  • 收稿日期:2022-01-07 出版日期:2022-08-15
  • 通信作者: 汪茂荣
  • 基金资助:
    中国慢性乙型肝炎临床治愈(珠峰)工程项目中国肝炎防治基金会(No. 201791)

Clinical efficacy and influencing factors of pegylated interferon alfa-2b and nucleos(t)ide analogue in chronic hepatitis B patients with low level of hepatitis B virus surface antigen

Fang Xie1, Xi Xiong1, Chuanxia Yao1, Haonan Sun1, Ping Li1, Maorong Wang1,()   

  1. 1. Hepatology Department, Jinling Hospital, Nanjing 210002, China
  • Received:2022-01-07 Published:2022-08-15
  • Corresponding author: Maorong Wang
引用本文:

谢芳, 熊熙, 姚传霞, 孙浩男, 李平, 汪茂荣. 聚乙二醇化干扰素α-2b联合核苷(酸)类似物治疗低水平乙型肝炎病毒表面抗原慢性乙型肝炎患者的临床疗效及影响因素[J/OL]. 中华实验和临床感染病杂志(电子版), 2022, 16(04): 247-253.

Fang Xie, Xi Xiong, Chuanxia Yao, Haonan Sun, Ping Li, Maorong Wang. Clinical efficacy and influencing factors of pegylated interferon alfa-2b and nucleos(t)ide analogue in chronic hepatitis B patients with low level of hepatitis B virus surface antigen[J/OL]. Chinese Journal of Experimental and Clinical Infectious Diseases(Electronic Edition), 2022, 16(04): 247-253.

目的

评估聚乙二醇化干扰素α-2b(PegIFNα-2b)联合核苷(酸)类似物(NAs)治疗低水平乙型肝炎病毒表面抗原(HBsAg)慢性乙型肝炎(CHB)患者的临床疗效及影响因素分析。

方法

本研究为前瞻性、非随机对照的真实世界研究,选取2018年1月至2020年5月东部战区总医院收治的使用NAs治疗1年以上,血清HBsAg ≤ 1 500 IU/ml、HBV DNA < 50 IU/ml的CHB患者,于原NAs治疗基础上联合PegIFNα-2b治疗,收集患者治疗0周、12周、24周、36周及48周丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、HBV血清标志物以及HBV DNA定量等。根据停止注射PegIFNα-2b时HBsAg是否阴转,分为治愈组(13例)和未愈组(32例),运用广义估计方程比较两组患者HBsAg、ALT和AST水平;多因素Logistic回归模型分析HBsAg清除影响因素并绘制受试者工作特征曲线(ROC),评估相关影响因素对HBsAg清除的预测价值。

结果

共纳入CHB患者45例,完成PegIFNα-2b治疗48周患者共21例,其中临床治愈10例(治愈率为47.6%);提前终止PegIFNα-2b治疗患者共24例,其中临床治愈3例(治愈率为12.5%)。治愈组和未愈组患者HBsAg定量较基线水平均显著下降(Z =-2.201、P = 0.028;Z = -3.17、P = 0.011)。入组48周时,治愈组患者ALT水平与基线差异无统计学意义(Z =-1.412、P = 0.158);AST水平与基线差异有统计学意义(Z =-2.90、P = 0.004)。未愈组患者ALT和AST水平与基线差异均无统计学意义(Z =-1.97、P = 0.122,Z = -1.05、P = 0.421)。广义估计方程分析组间比较结果显示,调整年龄及性别后,两组患者在入组48周时,ALT和AST水平差异无统计学意义(χ2 = 0.837、P = 0.36,χ2 = 0.005、P = 0.945),而HBsAg差异具有显著统计学意义(χ2 = 24.161、P < 0.001)。多因素Logistic回归分析显示,基线HBsAg(OR = 0.073、95%CI:0.007~0.803、P = 0.032),年龄(OR = 0.883、95%CI:0.781~0.998、P = 0.047),PegIFNα-2b使用疗程(OR = 1.027、95%CI:1.001~1.053、P = 0.038)均为影响48周HBsAg清除的因素。基线HBsAg、年龄联合PegIFNα-2b疗程对HBsAg清除预测的ROC曲线面积为0.978(95%CI:0.883~0.993),敏感性和特异性分别为96.44%和88.95%。

结论

PegIFNα-2b联合NAs对低水平HBeAg CHB患者具有较好的临床疗效。基线HBsAg、年龄联合PegIFNα-2b疗程对48周HBsAg清除具有一定预测价值。

Objective

To evaluate the clinical efficacy and influencing factors of pegylated interferon (PegIFNα-2b) combined with nucleos(t)ide analogues (NAs) in chronic hepatitis B (CHB) patients with low level of hepatitis B virus surface antigen (HBsAg).

Methods

This study was a prospective, nonrandomized, controlled, real-world study, which selected patients who had been treated with NAs for more than one year in Jinling Hospital from January 2018 to May 2020 and achieved serum HBsAg ≤ 1 500 IU/ml and HBV DNA < 50 IU/ml, they were all treated with NAs and PegIFNα-2b. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), HBV serum markers, and HBV DNA quantification were collected from all patients at 0, 12th, 24th, 36th, and 48th week. Patients were divided into clinically cured group (13 cases) and non-cured group (32 cases) according to whether HBsAg turned negative when injection of PegIFNα -2b was stopped, and differences of HBsAg, ALT and AST between the two groups were compared respectively by generalized estimating equations. The influencing factors of HBsAg clearance were analyzed by multivariate Logistic regression model, and the influencing factors of HBsAg clearance were furtherly plotted into a receiver operating characteristic curve (ROC) to evaluate the predictive value.

Results

Total of 45 patients were finally enrolled, 21 patients were completely treated with PegIFNα-2b for 48 weeks, among whom 10 cases were clinically cured (cure rate was 47.6%); while 24 patients were treated with premature termination of PegIFNα-2b, among whom 3 cases were clinically cured (cure rate was 12.5%). HBsAg decreased significantly compared with baseline of patients in both cured group and non-cured group (Z = -2.201, P = 0.028; Z =-3.17, P = 0.011). At the end of 48 weeks of enrollment, the level of ALT in cured group had no significant change compared with that of baseline (Z =-1.412, P = 0.158); However, there was a significant difference in level of AST compared with that of baseline (Z =-2.90, P = 0.004). The levels of ALT and AST of patients in non-cured group were not significantly different compared with those of baseline (Z =-1.97, P = 0.122; Z = -1.05, P = 0.421). Comparisons between groups: after adjusting of age and gender, there were no significant differences in ALT or AST at the end of 48 weeks of enrollment between patients of the two groups (χ2 = 0.837, P = 0.36; χ2 = 0.005, P = 0.945), but the level of HBsAg was significantly different (χ2 = 24.161, P < 0.001). Multivariate Logistic regression analysis showed that baseline HBsAg (OR = 0.073, 95%CI: 0.007-0.803, P = 0.032), age (OR = 0.883, 95%CI: 0.781-00.998, P = 0.047) and treatment course of PegIFNα-2b (OR = 1.027, 95%CI: 1.001-1.053, P = 0.038) were all influencing factors for HBsAg clearance at 48 weeks. The area under ROC (AUC) for combination of baseline HBsAg, age and PegIFNα-2b was 0.978 (95%CI: 0.883-0.993), with the sensitivity and specificity as 96.44% and 88.95%, respectively.

Conclusions

PegIFNα-2b combination with NAs showed good clinical efficacy for CHB patients with low HBsAg level. Combination of baseline HBsAg, age and treatment course of PegIFNα-2b showed predictive value for HBsAg clearance at 48th week after treatment.

表1 两组CHB患者的基本资料
表2 PegIFNα-2b联合NAs治疗48周HBeAg(-)CHB患者HBsAg、ALT和AST变化
表3 广义估计方程比较两组CHB患者间ALT、AST和HBsAg的变化
表4 CHB患者治疗48周时HBsAg清除的多因素Logistic回归分析
图1 基线HBsAg、年龄及PegIFNα-2b疗程预测HBeAg(-)CHB患者治疗48周时HBsAg清除的ROC曲线注:AUC两两比较:HBsAg vs. 年龄:Z = 0.551、P = 0.582;HBsAg vs. PegIFNα-2b疗程:Z = 0.585、P = 0.559;年龄 vs. PegIFNα-2b疗程;Z = 1.231、P = 0.218;HBsAg vs. 联合:Z = 2.532、P = 0.011;年龄 vs. 联合;Z = 3.404、P = 0.007;PegIFNα-2b疗程 vs. 联合;Z = 2.999、P = 0.003
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