740例HBV感染者血清HBV 逆转录酶区耐药位点分析*

doi:10.3969/j.issn.1672-5069.2014.03.009

实用肝脏病杂志 ›› 2014, Vol. 17 ›› Issue (3): 255-259.doi: 10.3969/j.issn.1672-5069.2014.03.009

740例HBV感染者血清HBV 逆转录酶区耐药位点分析^*

戴明佳, 方圆, 汪莉萍, 武桂萍, 石银月, 颜学兵

221002 江苏省徐州市徐州医学院附属医院感染病科

收稿日期:2013-09-22 出版日期:2014-06-30 发布日期:2016-04-11
通讯作者: 颜学兵,E-mail:yxbxuzhou@126.com
作者简介:戴明佳,女,27岁,硕士研究生。主要从事病毒性肝炎的临床研究。E-mail:daimingjia1009@126.com
基金资助:
国家自然科学基金项目（编号：81371867）; 2011年江苏省“科教兴卫”医学重点人才培养基金（编号：RC2011117）

Mutation of hepatitis B virus DNA reverse transcriptase in 740 patients with hepatitis B and liver cirrhosis

Dai Mingjia, Fang Yuan, Wang Liping

Department of Infectious Disease,Affiliated Hospital,Xuzhou Medical College,Xuzhou221002,Jiangsu Province,China

Received:2013-09-22 Online:2014-06-30 Published:2016-04-11

摘要/Abstract

摘要： 目的了解乙型肝炎病毒（HBV）感染者HBV基因型的构成状况及HBV P区基因变异的特点。方法对2010年8月~2011年10月送检的740份HBV感染者血清,采用ABI基因测序仪检测HBV耐药位点和基因型,应用SPSS15.0软件进行统计分析。结果在740例HBV感染者中,检出HBV B基因型40例（5.41%）,C基因型695例（93.92%）,D基因型5例（0.68%）;与拉米夫定、阿德福韦酯和恩替卡韦耐药明确相关的位点突变377例（50.95%）,其中195例（51.72%）患者既往有明确的应用核苷（酸）类似物（NA）史,在这195例发生耐药的患者中,B基因型12例,C基因型183例,两基因型间耐药发生率无明显差异,他们中包括CHB患者118例,肝硬化患者77例,主要耐药变异模式为M204V+L180M、M204I、M204I+L180M和A181V,两组间ALT、HBV DNA载量和主要耐药变异模式检出率均无统计学差异;HBV DNA载量是影响NA耐药的相关因素（x²=0.496,P<0.001）,但耐药与年龄、性别、疾病严重程度（CHB或肝硬化）和ALT水平无显著性相关;此外,本文还检出多处未知变异位点,如rt64、rt126、rt178和rt129等。结论核苷（酸）类似物的使用将伴随病毒变异的发生,其耐药基因变异位点具有一定的特点及规律性,动态监测HBV DNA载量对早期发现耐药有一定的价值。

关键词: 乙型肝炎, 突变, 核苷（酸）类似物, 耐药

Abstract: Objective Hepatitis B virus （HBV） genotypes and pre-core mutations were studied in patients with HBV infection. Methods Viral DNA was extracted from serum samples of 740 patients with hepatitis B and liver cirrhosis from August 2010 to October 2011,and HBV genotypes and pre-core mutations were detected by ABI sequencing instrument. Results Among 740 patients with HBV infection,40（5.41%） were with HBV genotype B,695 （93.92%） were with genotype C,and 5 （0.68%） were with genotype D infection;377 （50.95%） patients carried mutations related to lamivudine,adefovir dipivoxil and entecavir resistance,among whom 195 patients （51.72%） has a definite history of application of nucleos（t）ide analog （NA）. Out of the 195 patients,there were 12 patients with HBV genotype B and 183 with genotype C infection. Also among these patients with definite NA history,118 patients were with CHB,and 77 patients were with liver cirrhosis,and the major resistant mutations were M204V+L180M,M204,M204I+L180M and A181V;Serum HBV DNA load was related to NA resistance（x²=0.496,P<0.001）,but not age,gender,disease severity （CHB or cirrhosis） and ALT levels;Besides,a number of new mutations,e.g. rt64,rt126,rt178,rt129 and so on were found in this series. Conclusions The administration of NA might results in mutation of hepatitis B virus and drug resistance,and the mutations have certain characteristics. Dynamic monitoring of serum HBV DNA load will help early detection of gene mutation and drug resistance.

Key words: Hepatitis B, Mutation, Nucleos（t）ide analog, Drug-resistant

戴明佳, 方圆, 汪莉萍, 武桂萍, 石银月, 颜学兵. 740例HBV感染者血清HBV 逆转录酶区耐药位点分析^*[J]. 实用肝脏病杂志, 2014, 17(3): 255-259.

Dai Mingjia, Fang Yuan, Wang Liping. Mutation of hepatitis B virus DNA reverse transcriptase in 740 patients with hepatitis B and liver cirrhosis[J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2014, 17(3): 255-259.

参考文献

[1] Holomn J,Glasa J. EASL clinical practice guidelines. J Hepatol,2009,51（3）:821-822.
[2] Lok AS,Zoulim F,Locarnini S,et al. Antiviral drug-resistant HBV:standardization of nomenclature and assays and recommendations for management. Hepatology,2007,46（1）:254-265.
[3] 中华医学会传染病与寄生虫病学分会,肝病学分会. 慢性乙型肝炎防治指南,实用肝脏病杂志,2006,9（1）：8-18.
[4] Shaw T,Bartholomeusz A,Locamini S. HBV drug resistance: mechanisms,detection and interpretation. J Hepatol,2006（2）,44:593-606.
[5] Tan YW,Ge GH,Zhao W,et al. YMDD motif mutations in chronic hepatitis B antiviral treatment naive patients:a multi-center study. Braz J Infect Dis,2012,16（3）:250-255.
[6] 徐秋仙,张振纲,田德英,等. 阿德福韦酯相关性HBV潜在耐药变异位点研究进展. 传染病信息,2012,6（25）：186-189.
[7] Bartholomeusz A,Locarnini S. Hepatitis B virus mutations associated hepatitis B. Korean J Hepatol,2006,12（4）:484-492.
[8] Zhong Y,Lv J,Li J,et al. Prevalence virology and antiviral drugs susceptibility of hepatitis B virus rtN238H polymerase mutation from 1865 Chinese patients with chronic hepatitis B. Antiviral Res,2012,93（1）:185-190.
[9] Gerolami R,Bourliere M,Colson P,et al. Unusual selection of rtA181V HBV mutants cross-resistant to adefovir following prolonged lamivudine monotherapy:report of two cases. Antivir Ther, 2006,11:1103-1106.
[10] Villet S,Pichoud C,Billioud G,et al. Impact of hepatitis B virus rtA181V/T mutants on hepatitis B treatment failure. J Hepatol,2008,48（5）:747-755.
[11] Yokosuka O,Takaguchi K,Fujioka S,et al. Long-term use of entecavir in nucleoside-naive Japanese patients with chronic hepatitis B infection. J Hepatol,2010,52（6）:791-799.
[12] Gish RG,Lok AS,Chang TT,et al. Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B. Gastroenterology,2007,133（5）:1437-1444.
[13] Sherman M,Yurdaydin C,Sollano J,et al. Entecavir for treatment of lamivudine-refractory,HBeAg-positive chronic hepatitis B. Gastroenterology,2006,130（7）:2039-2049.
[14] 薛瑞霞,张缭云,杨松,等. 恩替卡韦治疗失败的慢性乙型肝炎患者耐药分析20例. 世界华人消化杂志,2009,17（12）：1260-1263.
[15] 杨方,张明香,魏倪,等. 核苷（酸）类似物导致乙型肝炎病毒聚合酶区基因耐药变异的影响因素. 中华肝脏病杂志,2010,18（10）：789-790.
[16] Liu BM,Li T,Xu J,et al. Characterization of potential antiviral resistance mutations in hepatitis B virus reverse transcriptase sequences in treatment-naive Chinese patients. Antiviral Res,2010,85:512-519.
[17] Wang YD,Zhao CY,Wang W,et al. Improved efficacy by individualized combination therapy with Peg IFN-α 2a and ADV in HBeAg positive chronic hepatitis B patients. Hepatogastroenterology,2012,59（115）:680-686.

740例HBV感染者血清HBV 逆转录酶区耐药位点分析^*

Mutation of hepatitis B virus DNA reverse transcriptase in 740 patients with hepatitis B and liver cirrhosis

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