血清HBsAg滴度监测对恩替卡韦治疗的HBeAg阳性慢性乙型肝炎患者应答反应的预测价值

doi:10.3969/j.issn.1672-5069.2014.05.014

摘要/Abstract

摘要： 目的探讨HBeAg阳性慢性乙型肝炎（CHB）患者血清HBsAg滴度的动态变化对恩替卡韦（ETV）治疗反应的预测价值。方法选择2011年1月~2012年1月在我肝病中心住院及门诊接受ETV （0.5mg/d）治疗的HBeAg阳性CHB患者78例,随访1年。于抗病毒治疗的0、3、6、9和12 m分别收集患者血清,采用化学发光法定量检测各时间点的HBsAg和HBeAg滴度;采用实时荧光定量PCR法检测血清HBV DNA载量;采用Pearson相关分析分析HBsAg与HBV DNA水平相关性,采用受试者工作特征曲线（ROC）预测患者的病毒学应答和确定最佳临界值。结果在78例患者中,69例（88.5%）患者发生病毒学应答（VR）,9例未发生病毒学应答;VR组患者基线ALT水平[（141.8±27.2） IU/ml]与未发生VR患者[（136.2±29.7） IU/ml]比,无统计学意义（t=0.27,P=0.793）;HBV DNA[（6.7±1.0） lg IU/ml]明显低于未发生VR患者[（7.6±0.8） lg IU/ml,t=-2.27,P=0.033];HBsAg滴度与未发生VR患者比,无统计学意义[（3.8±0.6） lg IU/ml 对(4.0±0.4） lg IU/ml,t=-1.75,P=0.094）];HBsAg与HBV DNA水平呈正相关（r=0.45,P=0.02）;HBsAg在治疗开始的前3个月下降较快,3个月后下降较缓慢,从基线到治疗3个月时,VR组患者较未发生VR患者HBsAg下降更快[（0.3±0.2） lg IU/ml 对（0.2±0.1） lg IU/ml,t=2.245,P=0.035）];在治疗3个月时,lg HBsAg滴度的ROC曲线下面积最大（AUC=0.840,P=0.005）,临界值为3.85 lg IU/ml的Youden指数最大（0.602）,其诊断敏感度为84.2%,特异度为78.7%。结论ETV治疗3个月时lg HBsAg≤3.85 lg IU/ml可作为预测ETV治疗1年发生病毒学应答的指标。

关键词: 慢性乙型肝炎, 乙型肝炎病毒表面抗原, 恩替卡韦, 治疗

Abstract: Objective To investigate the dynamic changes of quantitative hepatitis B surface antigen concentration in predicting virologic response to entecavir（ETV） therapy in patients with HBeAg-positive chronic hepatitis B（CHB）. Methods Seventy-eight treatment-naive patients with HBeAg-positive CHB receiving ETV （0.5 mg/daily） were recruited and followed up for 1 year from January 2011 to January 2012. Serum samples were collected at baseline and every 3 months after ETV treatment. Serum HBsAg and HBeAg concentrations were quantitatively determined by chemiluminescence assay and serum HBV DNA levels were determined by real-time polymerase chain reaction. The correlation of HBsAg and HBV DNA level was analyzed by Pearson correlation analysis. The receiver operating characteristic curve（ROC） was used to predicted HBV virologic response and determine the optimal threshold. Results Sixty-nine（88.5%）patients achieved virologic response（VR）,while 9 did not;there was no significant difference for baseline levels of serum ALT in patients with VR [（141.8±27.2）IU/ml] and without [（136.2±29.7） IU/ml,t=0.27,P=0.793];serum HBV DNA levels in patients with VR[（6.7±1.0）lg IU/ml] was significantly lower than that in patients without[（7.6±0.8）lg IU/ml,t=-2.27,P=0.033];there was no significant difference in HBsAg concentration between patients with VR and without[（3.8±0.6） lg IU/ml vs.（4.0±0.4）lg IU/ml,t=-1.75,P=0.094]. HBsAg and HBV DNA levels were positively correlated（r=0.45,P=0.02）. there was a rapid decline in HBsAg concentration during the first 3 months of therapy,followed by a much slower decline in the subsequent periods;from the baseline to month 3,the reduction of HBsAg concentration in patients with VR was faster than in patients without[（0.3±0.2） lg IU/ml vs.（0.2±0.1） lg IU/ml,t=2.245,P=0.035]. The lg HBsAg concentration at month 3 showed the biggest area under the curve （AUC）（AUC=0.840,P=0.005）,and the max Youden index（0.602） was appeared at the cut-off value of 3.85 lg IU/ml,with a diagnostic sensitivity and specificity of 84.2% and 78.7%,respectively. Conclusions lg HBsAg≤3.85 lg IU/ml after 3 months of ETV treatment can be used as an indicator to predict the virologic response of patients with CHB 1-year after ETV treatment.

Key words: Chronic hepatitis B, Hepatitis B surface antigen, Hepatitis B e antigen, Entecavir, Treatment

郑盛, 唐映梅, 杨晋辉. 血清HBsAg滴度监测对恩替卡韦治疗的HBeAg阳性慢性乙型肝炎患者应答反应的预测价值[J]. 实用肝脏病杂志, 2014, 17(5): 502-507.

Zheng Sheng, Tang Yingmei, Yang Jinhui. Predictive value of serum HBsAg titers in virologic response to entecavir treatment in patients with HBeAg-positive chronic hepatitis B[J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2014, 17(5): 502-507.

参考文献

[1] Pan CQ,Trinh H,Yao A,et al. Efficacy and safety of tenofovir disoproxil fumarate in Asian-Americans with chronic hepatitis B in community settings. PLoS One,2014,9（3）:e89789.
[2] Su TH,Hsu CS,Chen CL,et al. Serum hepatitis B surface antigen concentration correlates with HBV DNA level in patients with hepatitis B. Antivir Ther,2010,15（8）:1133-1139.
[3] Nguyen T,Thompson AJ,Bowden S,et al. Hepatitis B surface antigen levels during the natural history of chronic hepatitis B:a perspective on Asia. J Hepatol,2010,52（4）:508-513.
[4] 王临旭,黄长形,李新红,等. 慢性乙型肝炎病毒感染自然史中表面抗原水平的研究. 中华临床医师杂志（电子版）,2011,5（17）:5122-5123.
[5] 郑盛,唐映梅,杨晋辉,等. 恩替卡韦治疗高ALT水平HBeAg阳性慢性乙型肝炎疗效观察. 实用肝脏病杂志,2012,15（2）:140-142.
[6] Jaroszewicz J,Calle SB,Wursthorn K,et al. Hepatitis B surface antigen（HBsAg） levels in the natural history of hepatitis B virus（HBV）-infection:a European perspective. J Hepatol,2010,52（4）:514-522.
[7] Heathcote EJ,Marcellin P,Buti M,et al. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology,2011,140（1）:132-143.
[8] Chan HL,Wong VW,Wong GL,et al. A longitudinal study on the natural history of serum hepatitis B surface antigen changes in chronic hepatitis B. Hepatology,2010,52（4）:1232-1241.
[9] Brunetto MR,Oliveri F,Colombatto P,et al. Hepatitis B surface antigen serum levels help to distinguish active from inactive hepatitis B virus genotype D carriers. Gastroenterology,2010,139（2）:483-490.
[10] Kim YJ,Cho HC,Choi MS,et al. The change of the quantitative HBsAg level during the natural course of chronic hepatitis B. Liver Int,2011,31（6）:817-823.
[11] Park H,Lee JM,Seo JH,et al. Predictive value of HBsAg quantification for determining the clinical course of genotype C HBeAg-negative carriers. Liver Int,2012,32（5）:796-802.
[12] Wurthorn K,Jung M,Riva A,et al. Kinetics of hepatitis B surface antigen decline during 3 years of telbivudine treatment in hepatitis B e antigen-positive patients. Hepatology,2010,52（5）:1611-1620.
[13] Lee JM,Ahn SH,Kim HS,et al. Quantitative hepatitis B surface antigen and hepatitis B e antigen titers in prediction of treatment response to entecavir. Hepatology,2011,53（5）:1486-1493.
[14] Chen EQ,Wang TT,Bai L,et al. Quantitative hepatitis B surface antigen titers in Chinese chronic hepatitis B patients over 4 years of entecavir treatment. Antivir Ther,2013,18（8）:955-965.
[15] Lee MH,Lee da M,Kim SS,et al. Correlation of serum hepatitis B surface antigen level with response to entecavir in naive patients with chronic hepatitis B. J Med Virol,2011,83（6）:1178-1186.
[16] Reijnders JG,Rijckborst V,Sonneveld MJ,et al. Kinetics of hepatitis B surface antigen differ between treatment with peginterferon and entecavir. J Hepatol,2011,54（3）:449-454.
[17] Manesis EK,Hadziyannis ES,Angelopoulou OP,et al. Prediction of treatment-related HBsAg loss in HBeAg-negative chronic hepatitis B:a clue from serum HBsAg levels. Antivir Ther,2007,12（1）:73-82.
[18] Yeh CT. Development of HBV S gene mutants in chronic hepatitis B patients receiveing nucleotide/nucleoside analogue therapy. Antivir Ther,2010,15（3）:471-475.
[19] Moucari R,Mackiewicz V,Lada O,et al. Early serum HBsAg drop:a strong predictor of sustained virological respongse to pegylated interferon alfa-2a in HBeAg-negative patients. Hepatology,2009,49（4）:1151-1157.