长期应用恩替卡韦治疗拉米夫定耐药的慢性乙型肝炎患者临床疗效及安全性分析*

doi:10.3969/j.issn.1672-5069.2018.02.010

摘要/Abstract

摘要： 目的分析长期应用恩替卡韦治疗拉米夫定耐药的慢性乙型肝炎患者的临床疗效及安全性。方法 2007年1月~2009年1月我科收治的98例对拉米夫定耐药的慢性乙型肝炎患者,应用恩替卡韦1.0 mg口服,1次/d,长期治疗至今。对27例在治疗期间患者出现病毒学反弹者,则停药,使用阿德福韦酯联合拉米夫定治疗。观察患者临床疗效、病毒学反弹、治疗后HBV DNA阴转、HBsAg和HBeAg血清阴转、ALT复常和不良反应发生情况。结果在治疗24周,应答率达到88.8%,随着治疗时间的延长,临床应答率逐渐升高,在192周时,为92.9%,之后其水平保持稳定;在治疗8周和24周时,未出现病毒学反弹情况,在治疗48周时,6例出现病毒学反弹,随着治疗时间的延长,病毒学反弹发生率逐渐升高,到8年观察结束时达到27.6%;在治疗8周时,出现HBV DNA阴转,在治疗96周时,血清HBV DNA阴转率达到46.9%,之后在治疗过程中阴转情况升高,到观察结束时血清HBV DNA阴转率为60.2%;在治疗48周之前无血清HBeAg和HBsAg阴转,在治疗48周时出现了血清HBeAg和HBsAg阴转情况,并且随着治疗时间的延长,出现的例数在逐渐增多,到观察结束时共出现31例（31.6%）血清HBeAg阴转,12例（12.2%）血清HBsAg阴转;随着治疗时间的延长,98例患者血清ALT水平明显下降,到治疗12周时 ALT水平逐渐恢复正常,直到观察结束;在治疗过程中,25例（25.5%）出现不良反应,其中8例患者出现乏力,6例患者出现心动过速,10患者出现恶心,1例患者尿液中检出白细胞。结论长期应用恩替卡韦治疗对拉米夫定耐药的慢性乙型肝炎患者具有显著的临床疗效,且治疗后未出现明显的不良反应,但用量需加倍。

关键词: 慢性乙型肝炎, 恩替卡韦, 拉米夫定耐药, 挽救治疗

Abstract: Objective To investigate the clinical efficacy and safety of long-term application of entecavir for patients with lamivudine-resistant chronic hepatitis B. Methods 98 patients with lamivudine resistant chronic hepatitis B in our hospital between January 2007 and January 2009 were recruited and were treated with entecavir at dose of 1 mg daily. The application of adefovir dipivoxil combination with lamivudine were given in 27 patients because of virological rebound. The clinical efficacy,virologic rebound rate,HBV DNA negative rate,HBsAg and HBeAg nageive rate,ALT normalization and adverse reactions were observed. Results At the end of 24 weeks of treatment,the total response rate was 88.8%,as the prolongation of treatment,the total response gradually increased,and at the end of 192 weeks of treatment,the total response rate reached to 92.9%;there was no virologic rebound at 24 weeks,there was 6 cases with virologic rebound at 48 weeks of treatment,and the virological rebound rate increased gradually with the prolongation of treatment and at the end of the 8-year observation,the virological rebound rate was up to 27.6%;serum HBV DNA negative rate were up to 46.9% at 96 weeks after treatment,serum HBV DNA negative rate increased slowly and it reached to 60.2% at the end of the observation;there was no serum HBeAg or HBsAg turn to negative before 48 weeks of treatment,and there were 31 cases with serum HBeAg negativity and 12 got serum HBsAg negative at the end of the observation; serum ALT levels decreased with the prolonged treatment,and at the end of 12 weeks of treatment,serum ALT levels gradually returned to normal;there were 25 cases （25.5%） with adverse reactions including 8 cases with fatigue,6 cases with tachycardia,10 cases with nausea and 1 cases with a white blood cell detection in urine. Conclusion Long-term application of entecavir in the treatment of patients with lamivudine-resistant chronic hepatitis B has significant clinical efficacy with no obvious adverse reaction,which warrants further investigation.

Key words: Hepatitis B, Entecavir, Lamivudine-resistant, Rescued therapy

邱英锋, 王淑英. 长期应用恩替卡韦治疗拉米夫定耐药的慢性乙型肝炎患者临床疗效及安全性分析*[J]. 实用肝脏病杂志, 2018, 21(2): 196-199.

Qiu Yingfeng, Wang Shuying. Clinical efficacy and safety of long-term application of entecavir in the treatment of patients with lamivudine-resistant chronic hepatitis B[J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2018, 21(2): 196-199.

参考文献

[1] Ding F,Yu HG,Li YX,et al.Sequence analysis of the HBV S protein in Chinese patients with coexisting HBsAg and anti-HBs antibodies. J Med Virol,2015,87(12):2067-2073.
[2] 侯春艳,杨永峰.慢性乙型肝炎抗病毒治疗新进展. 实用肝脏病杂志,2017,20(1):124-128.
[3] 奥敦托娅. 拉米夫定联合中草药治疗慢性乙型肝炎疗效观察.实用肝脏病杂志,2016,19(3):343-344.
[4] Liu F,Wang X,Wei F,et al.Efficacy and resistance in de novo combination lamivudine and adefovir dipivoxil therapy versus entecavir monotherapy for the treatment-naive patients with chronic hepatitis B:a meta-analysis.Virol J,2014,28(11):59.
[5] Arends P,Sonneveld MJ,Zoutendi JK,et al.Entecavir treatment does not eliminate the risk of hepatocellular carcinoma in chronic hepatitis B:limited role for risk scores in Caucasians. Gut,2015,64(8):1289-1295.
[6] 姚云洁,杨才兴,巫继. 恩替卡韦联合复方鳖甲软肝片治疗慢性乙型肝炎患者疗效观察.实用肝脏病杂志,2015,18(4):356-359.
[7] 中华医学会肝病学分会和感染病学分会.慢性乙型肝炎防治指南(2015年版).实用肝脏病杂志,2016,19(3):Ⅴ-ⅩⅩⅢ.
[8] 孔令义,佟辉,苏杰. 恩替卡韦与阿德福韦酯对拉米夫定耐药慢性乙肝患者疗效比较. 中国医药导刊,2016,18(1):42-43.
[9] Ott JJ,Stevens GA, Groeger J,et al.Global epidemiology of hepatitis B virus infection:new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine,2012,30(12):2212-2219.
[10] Huang ZB,Zhao SS,Huang Y,et al.Comparison of the efficacy of lamivudine plus adefovir versus entecavir in the treatment of lamivudine-resistant chronic hepatitis B:a systematic review and meta-analysis. J Clin Pharmacol,2014,54(9):959-967.
[11] Bmmel FV,Bartens A,Mysickova A,et al.Serum hepatitis B virus RNA levels as an early predictor of hepatitis B envelope antigen seroconversion during treatment with polymerase inhibitors. Hepatology,2015,61(1):66-76.
[12] Yun BI,Jung EU,Bo HK,et al.Tenofovir monotherapy versus tenofovir plus lamivudine or telbivudine combination therapy in treatment of tamivudine-resistant chronic hepatitis B. Anticrob Agents Ch,2015,59(2):972.
[13] 王峰,王淑英,张红伟. 恩替卡韦治疗阿德福韦酯耐药慢性乙型肝炎患者的临床疗效观察. 中国预防医学杂志,2016,17(7):559-560.
[14] Lai HW,Chang CC,Chen TH,et al.Safety and efficacy of adefovir therapy for lamivudine-resistant hepatitis B virus infection in renal transplant recipients. [J] Formos Med Assoc.2012,111(8):439-444.
[15] Huang ZB,Zhao SS,Huang Y,et al.Comparison of the efficacy of lamivudine plus adefovir versus entecavir in the treatment of lamivudine-resistant chronic hepatitis B:a systematic review and meta-analysis. Clin Ther,2013,35(12):1997-2006.
[16] Wang Y,Liu S,Chen YU,et al.Lamivudine-resistant rtL180M and rtM204I/V are persistently dominant during combination rescue therapy with entecavir and adefovir for hepatitis B.Exp Ther Med,2016,11(6):2293-2299.
[17] Xiong SY.Effect of lamivudine combined with adefovir dipivoxil in the treatment of lamivudine resistant hepatitis B.Drug Dev Pharm,2016,12(21):316-321.
[18] 许建国,王牛牛,戴金津,等.阿德福韦酯联合拉米夫定治疗拉米夫定耐药的慢性乙型肝炎患者48周疗效观察. 实用肝脏病杂志,2015,18(4):407-408.
[19] 刘明坤,吕文良,赵慧慧,等. 慢性乙型肝炎病因病机再探. 长春中医药大学学报,2015,31(4):735-737.
[20] 王欣,石铭,王楠,等. 阿德福韦治疗拉米夫定耐药慢性乙肝患者的疗效. 标记免疫分析与临床,2015,22(11):1107-1109.
[21] 张鹏,聂绍发,Zhang P,等. 2010-2014年湖北省乙型肝炎流行病学特征及发病趋势分析. 公共卫生与预防医学,2016,27(1):33-35.
[22] 赫晓林,黄建炜,许瑞安,等. HBV病毒复制机制及慢性乙型肝炎药物靶点. 中国药理学通报,2015,31(2):152-156.
[23] 徐建明,李兵,游红勇,等. 恩替卡韦联合替诺福韦与恩替卡韦联合阿德福韦治疗拉米夫定耐药性慢性乙型肝炎患者疗效比较. 检验医学与临床,2016,13(13):1788-1791.
[24] 刘秀荣,邓丽宁,侯宏波. 恩替卡韦联用阿德福韦酯治疗拉米夫定耐药的慢性乙型肝炎的系统评价. 临床药物治疗杂志,2017,15(1):43-47.
[25] 李雨,马宁,邓娇,等. 拉米夫定联合阿德福韦酯与恩替卡韦单药治疗拉米夫定耐药慢性乙肝患者疗效的Meta分析. 中国循证医学杂志,2015,15(5):573-580.
[26] Xiong SY.Effect of lamivudine combined with adefovir dipivoxil in the treatment of lamivudine resistant hepatitis B. Drug Dev Pharm,2016,12(21):316-321.