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中华实验和临床感染病杂志(电子版) ›› 2018, Vol. 12 ›› Issue (04) : 386 -391. doi: 10.3877/cma.j.issn.1674-1358.2018.04.014

所属专题： 文献；

论著

乙型肝炎病毒表面抗原定量检测对恩替卡韦停药后乙型肝炎复发的预测价值
王昌生1,†(), 岳晓荷1, 路淼2   
  1. 1. 5726002　东方市，海南省东方市东方医院检验科
    2. 570100　海口市，海南金域医学检验中心
  • 收稿日期:2018-02-01 出版日期:2018-08-15
  • 通信作者: 王昌生
  • 基金资助:
    海南医学院科研基金资助项目(No. 0020015128)

Predictive value of quantitative detection of hepatitis B virus surface antigen in the relapse of hepatitis B induced by entecavir

Changsheng Wang1,†(), XiaoHe Yue1, Miao Lu2   

  1. 1. Clinical Lab, East Hospital of Dongfang City, Hainan 572600, China
    2. Jinyu Medical Examination Center of Hainan, Haikou 570100, China
  • Received:2018-02-01 Published:2018-08-15
  • Corresponding author: Changsheng Wang
  • About author:
    Corresponding author: Wang Changsheng, Email:
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引用本文：

王昌生, 岳晓荷, 路淼. 乙型肝炎病毒表面抗原定量检测对恩替卡韦停药后乙型肝炎复发的预测价值[J]. 中华实验和临床感染病杂志(电子版), 2018, 12(04): 386-391.

Changsheng Wang, XiaoHe Yue, Miao Lu. Predictive value of quantitative detection of hepatitis B virus surface antigen in the relapse of hepatitis B induced by entecavir[J]. Chinese Journal of Experimental and Clinical Infectious Diseases(Electronic Edition), 2018, 12(04): 386-391.

目的

评价乙型肝炎病毒表面抗原（HBsAg）定量检测对恩替卡韦停药后复发乙型肝炎的诊断效能。

方法

回顾性分析2013年1月至2016年1月于海南省东方市东方医院应用恩替卡韦抗病毒治疗达到停药指征的80例慢性乙型肝炎（CHB）患者的临床资料，根据两年内是否发生病毒学复发，分为复发组（60例）和未复发组（20例），比较两组患者停药后的病毒学指标（HBV DNA载量、HBeAg转阴率和HBsAg定量等），应用Cox回归模型探究患者复发的影响因素，以ROC曲线评价治疗后HBsAg定量检测在预测恩替卡韦停药后病情复发中的价值。

结果

入组患者于24个月随访中共发生病毒学复发60例（75.00%），中位复发时间为9.5（5～24）个月。复发组和未复发组患者的年龄、性别比例、体质指数、乙型肝炎病史和甲胎蛋白等临床资料差异无统计学意义（t = 0.854、χ2 = 1.077、t= 0.749、t = 1.354、t = 1.499，P= 0.396、0.299、0.456、0.180、0.138）。复发组患者的HBeAg阳性率、肝硬化、乙型肝炎家族史、治疗前HBV DNA载量、治疗后HBsAg定量和HBsAg阳性率均显著高于未复发组（χ2= 4.364、6.667、4.689，t= 4.096、2.040、8.219、5.760，P= 0.037、0.010、0.030、0.043，< 0.001，0.016），而用药时间显著低于未复发组（t= 2.006、P= 0.048），差异均有统计学意义。多因素Cox回归分析显示，肝硬化（HR= 1.587、P= 0.041）、HBeAg阳性（HR= 1.742、P = 0.044）和治疗后HBsAg定量（HR= 2.606、P= 0.008）均为影响恩替卡韦停药后复发的独立危险因素。ROC曲线显示应用HBsAg定量（AUC= 0.902，P < 0.001）预测恩替卡韦停药后复发的曲线下面积高于半定量检测（AUC= 0.650、P= 0.046），HBsAg定量最佳截点为2.03 log10IU/ml，准确率、灵敏度、特异度、阳性预测值和阴性预测值分别为91.25%、91.67%、90.00%、96.49%和78.26%。

结论

肝硬化、HBeAg阳性和HBsAg高水平均为恩替卡韦停药后复发的独立危险因素，应用HBsAg定量检测预测恩替卡韦停药后乙型肝炎复发具有较高的诊断效能。

关键词: 肝炎，乙型，慢性, 恩替卡韦, 表面抗原，肝炎病毒，乙型, 复发
Objective

To investigate the diagnostic efficacy of quantitative detection of hepatitis B virus surface antigen (HBsAg) in patients with hepatitis B relapse after entecavir withdrawal.

Methods

Total of 80 patients with chronic hepatitis B (CHB) who received antiviral treatment with entecavir in Dongfang Hospital of Hainan Province from January 2013 to January 2016 were analyzed, retrospectively. The patients were divided into recurrence group (60 cases) and non-recurrence group (20 cases). The virological indexes including HBV DNA load and HBsAg determination were compared between the two groups. The influencing factors of relapse after entecavir treatment were analyzed by Cox regression model. The value of quantitative HBsAg detection after treatment in predicting the recurrence of patients with entecavir treatment was evaluated by ROC curve.

Results

A total of 60 cases (75.00%) had virological recurrence during the 24-month follow-up, with the median recurrence time of 9.5 (5-24) months. There was no significant difference in age, sex ratio, body mass index, history of CHB and AFP between recurrent group and non-recurrence group (t= 0.854,χ2= 1.077,t = 0.749,t= 1.354,t= 1.499;P= 0.396, 0.299, 0.456, 0.180, 0.138). The positive rate of HBeAg, cirrhosis, family history of hepatitis B, HBV DNA load before treatment, HBsAg quantification after treatment and HBsAg positive rate in recurrence group were significantly higher than those in the non-recurrence group (χ2= 4.364, 6.667, 4.689,t= 4.096, 2.040, 8.219, 5.760;P= 0.037, 0.010, 0.030, 0.043,< 0.001, 0.016), but the medication time was significantly lower than that of non-recurrence group (t= 2.006,P= 0.048), with significant differences. Multivariate Cox regression analysis showed that cirrhosis (HR= 1.587,P= 0.041), HBeAg positive (HR= 1.742,P= 0.044) and HBsAg quantitative (HR= 2.606,P= 0.008) were independent risk factors for the relapse after entecavir treatment. ROC curve showed that the area under the curve of HBsAg quantification (AUC= 0.902,P< 0.001) was higher than that of semi-quantitative detection (AUC= 0.650,P = 0.046), with significant differences. The best cut-off point of HBsAg quantification was 2.03 log10IU/ml. The accuracy, sensitivity, specificity, positive predictive value and negative predictive value were 91.25%, 91.67%, 90%, 96.49% and 78.26%, respectively.

Conclusions

Liver cirrhosis, HBeAg positive and high HBsAg levels after treatment are independent risk factors for the relapse of hepatitis B after entecavir withdrawal. The quantitative detection of HBsAg for predicting the recurrence of patients with entecavir withdrawal had a high diagnostic efficacy.

Key words: Chronic hepatitis B, Entecavir, Hepatitis B surface antigen, Relapse
图1 CHB患者ETV停药后的病毒学复发和临床复发率
表1 复发组和未复发组患者的临床资料
临床资料 复发组（60例） 未复发组（20例） 统计量 P值
年龄（±s，岁） 43.6 ± 6.3 45.0 ± 6.7 t= 0.854 0.396
性别[例（%）] ? ? χ2= 1.077 0.299
? 男性 35（58.3） 9（45.0） ? ?
? 女性 25（41.7） 11（55.0）
BMI（±s，kg/m2） 23.1 ± 2.7 23.6 ± 2.2 t= 0.749 0.456
治疗前HBeAg定性[例（%）] ? ? χ2= 4.364 0.037
? 阳性 40（66.7） 10（50.0） ? ?
? 阴性 20（33.3） 10（50.0）
用药时间（±s，年） 1.8 ± 0.4 2.0 ± 0.4 t= 2.006 0.048
乙型肝炎病史（±s，年） 4.2 ± 2.4 3.3 ± 2.3 t= 1.354 0.180
肝硬化[例（%）] 25（41.7） 3（15.0） χ2= 4.689 0.030
乙型肝炎家族史[例（%）] 20（33.3） 2（10.0） χ2= 4.096 0.043
治疗前HBV DNA载量（±s，log10IU/ml） 7.1 ± 1.6 6.2 ± 1.5 t= 2.040 0.045
治疗后HBsAg定量（±s，log10IU/ml） 2.9 ± 0.6 1.9 ± 0.4 t= 8.219 < 0.001
? 治疗后HBsAg定性[例（%）] ? ? χ2= 5.760 0.016
? 阳性 27（45.0） 3（15.0） ? ?
? 阴性 33（55.0） 17（85.0）
甲胎蛋白（±s，μg/L） 46.7 ± 7.2 44.1 ± 5.6 t= 1.499 0.138
表2 影响恩替卡韦停药后病情复发的多因素Cox回归分析
变量 B值 标准误差 Wald值 P值 HR值 95%CI
肝硬化 0.581 0.557 3.653 0.041 1.587 1.112～3.766
HBeAg阳性 0.632 0.622 3.502 0.044 1.742 1.096～4.662
治疗后HBsAg 1.018 0.326 6.298 0.008 2.606 1.278～5.911
图2 HBsAg定量与半定量预测恩替卡韦停药后复发的ROC曲线
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