153例慢性HBV感染者核苷和核苷酸类药物的耐药变异位点分析

林菲; 姚贝; 胥婕; 徐小元

doi:10.3969/j.issn.1001-5256.2014.03.018

153例慢性HBV感染者核苷和核苷酸类药物的耐药变异位点分析

DOI: 10.3969/j.issn.1001-5256.2014.03.018

1. 北京大学第一医院感染疾病科
2. 北京大学第三医院检验科分子生物室
3. 北京大学第三医院感染疾病科

基金项目:

北京市科委2012年度科技计划重大项目基金资助项目(D121100003912003)；

详细信息

中图分类号: R512.62
计量
- 文章访问数: 2293
- HTML全文浏览量: 9
- PDF下载量: 620
- 被引次数: 0
出版历程
- 出版日期: 2014-03-20

Drug resistance mutations related to nucleos(t)ide analogues in Chinese patients with chronic HBV infection: an analysis of 153 cases

Research funding:

摘要

摘要:
目的通过对153例慢性HBV感染者进行HBV逆转录酶区扩增测序,了解目前上市的核苷和核苷酸类药物耐药位点检出情况,并分析是否存在与替诺福韦耐药可能相关的耐药位点。方法 153例患者分为2组,其中78例是未使用过核苷和核苷酸类药物治疗的HBV携带者,75例是核苷和核苷酸类药物经治的慢性乙型肝炎患者。通过PCR扩增HBV的逆转录酶（RT）区,进行基因测序分析,了解核苷和核苷酸类药物的耐药位点及替诺福韦相关的耐药位点的检出情况。正态分布资料采用t检验,非正态分布的资料采用秩和检验。结果在未治疗组有7例检出核苷和核苷酸类相关的耐药变异,占该组的8.97%,但并无上述替诺福韦耐药相关的位点。治疗组检出16例耐药变异,占该组的21.33%,其中1例为rtA181T+rtN236T,可能与替诺福韦耐药相关。结论未治疗组中有8.97%的患者检出耐药变异。2组患者中耐药变异的检出率与患者的性别、年龄、病毒基因型均无显著相关。所有患者中仅1例检出rtA181T+rtN236T。提示中国慢性HBV感染者体内预存替诺福韦可能耐药位点的比例很低。
- 肝炎病毒,乙型 /
- 核苷类 /
- 核苷酸类 /
- 替诺福韦 /
- 变异(遗传学)
Abstract:
Objective To amplify and determine the hepatitis B virus ( HBV) reverse transcriptase ( RT) sequences of 153 Chinese patients with chronic HBV infection and investigate the drug resistance mutations related to nucleos ( t) ide analogues, and to analyze if there are drug resistance mutations which might lead to tenofovir resistance. Methods A total of 153 patients with chronic HBV infection were divided into two groups: 78 HBV carriers who had never used nucleos ( t) ide analogues ( NAs) and 75 patients with chronic hepatitis B who had been treated with NAs. Their serum samples were used for HBV DNA extraction and RT gene amplification by PCR, and the RT sequences were analyzed to identify the known drug resistance mutations related to NAs and detect the drug resistance mutations related to tenofovir. The obtained data were statistically analyzed using SPSS 19. 0; the Student's t test was used for normally distributed data, and the Wilcoxon's rank sum test for non- normally distributed data. Results Drug resistance mutations related to NAs were detected in 7 cases ( 8. 97%) of the untreated group, but there was no drug resistance mutation related to tenofovir. Drug resistance mutations were detected in 16 cases ( 21. 33%) of the treated group, with rtA181T + rtN236T mutations in one case, which might be related to tenofovir resistance. Conclusion The drug resistance mutation detection rate in untreated group was 8. 97%. The drug resistance mutation detection rate was not significantly correlated with HBV genotype and patient's sex and age in either group. The rtA181T + rtN236T mutations were detected in only one case of the treated group, which indicates a very low rate of pre- existence of tenofovir- related drug resistance mutations in Chinese patients with chronic HBV infection.
- hepatitis B virus /
- nucleosides /
- nucleostides /
- tenofovir /
- variation (Genetics)

HTML全文

参考文献(19)

[1] PATTERSON SJ, GEORGE J, STRASSER SI, et al.Tenofovir disoproxil fumarate rescue therapy following failure of both lamivudine and adefovir dipivoxil in chronic hepatitis B[J].Gut, 2011, 60 (2) :247-254.

[2]LEVRERO M, CIMINO L, LAMPERTICO P, et al.Tenofovir (TDF) for chronic hepatitis B patients with suboptimal response to adefovir (ADV) or ADV/LAM treatment:results of the OPTIB Italian multicenter prospective open label study[J].Hepatology, 2010, 52:92A.

[3] SHELDON J, CAMINO N, RODES B, et al.Selection of hepatitis B virus polymerase mutations in HIV-coinfected patients treated with tenofovir[J].Antivir Ther, 2005, 10 (6) :727-734.

[4] AMINI-BAVIL-OLYAEE S, HERBERS U, SHELDON J, et al.The rtA194T polymerase mutation impacts viral replication and susceptibility to tenofovir in hepatitis B e antigen-positive and hepatitis B e antigen-negative hepatitis B virus strains[J].Hepatology, 2009, 49 (4) :1158-1165.

[5] BRUNELLE MN, JACQUARD AC, PICHOUD C, et al.Susceptibility to antivirals of a human HBV strain with mutations conferring resistance to both lamivudine and adefovir[J].Hepatology, 2005, 41 (6) :1391-1398.

[6]KOZIEL MJ, PETERS MG.Viral hepatitis in HIV infection[J].N Engl J Med, 2007, 356 (14) :1445-1154.

[7]GISH RG, LOCARNINI S.Genotyping and genomic sequencing in clinical practice[J].Clin Liver Dis, 2007, 11 (4) :761-795.

[8]ZOULIM F, LOCARNINI S.Management of treatment failure in chronic hepatitis B[J].J Hepatol, 2012, 56 (Suppl 1) :s112-122.

[9]ZHENG J, ZENG Z, ZHANG D, et al.Prevalence and significance of hepatitis B reverse transcriptase mutants in different disease stages of untreated patients[J].Liver Int, 2012, 32 (10) :1535-1542.

[10]RHEE SY, MARGERIDON-THERMET S, NGUYEN MH, et al.Hepatitis B virus reverse transcriptase sequence variant database for sequence analysis and mutation discovery[J].Antiviral Res, 2010, 88 (3) :269-275.

[11]XU Z, LIU Y, XU T, et al.Acute hepatitis B infection associated with drug-resistant hepatitis B virus[J].J Clin Virol, 2010, 48 (4) :270-274.

[12]GAI HP, SUN WX, YUAN DS, et al.The clinical implications of detecting pre-existing resistance to nucleos (t) ide analogue-based antiviral therapy[J].J Clin Hepatol, 2012, 28 (11) :841-844. (in Chinese) 盖洪鹏, 孙伟翔, 袁德胜, 等.预存耐药对核苷 (酸) 类似物抗病毒治疗应答和耐药的影响[J].临床肝胆病杂志, 2012, 28 (11) :841-844.

[13]TAN Y, DING K, SU J, et al.The naturally occurring YMDD mutation among patients chronically infected HBV and untreated with lamivudine:a systematic review and meta-analysis[J].PLoS One, 2012, 7 (3) :e32789.

[14]MIN XC, MIAO XH, ZHAO SM, et al.The spontaneous YMDD mutation rate in chronic hepatitis B patients[J].Chin J Hepatol, 2009, 17 (12) :887-890. (in Chinese) 闵晓春, 缪晓辉, 赵书民, 等.慢性乙型肝炎病毒感染者病毒YMDD的自然变异[J].中华肝脏病杂志, 2009, 17 (12) :887-890.

[15]YANG YL, XIAO P, GAO P, et al.Distribution of HBV genotypes and YMDD mutations in e antigen-positive patients[J].J Clin Hepatol, 2012, 28 (6) :428-430. (in Chinese) 杨彦麟, 肖萍, 高鹏, 等.HBeAg阳性患者中乙肝病毒基因型分布及YMDD变异位点分析[J].临床肝胆病杂志, 2012, 28 (6) :428-430.

[16]YE XG, WANG RL, GUO HB.Detection of YMDD mutant in patients with chronic hepatitis B before treatment[J].Chin J Lab Med, 2002, 25 (4) :248. (in Chinese) 叶晓光, 王若伦, 郭海波.慢性乙型肝炎患者治疗前YMDD变异基因的检测及分析[J].中华检验医学杂志, 2002, 25 (4) :248.

[17]QIN B, BUDEUS B, CAO L, et al.The amino acid substitutions rtP177G and rtF249A in the reverse transcriptase domain of hepatitis B virus polymerase reduce the susceptibility to tenofovir[J].Antiviral Research, 2013, 97 (2) :93-100.

[18]van BMMEL F, de MAN RA, Wedemeyer H, et al.Long-term efficacy of tenofovir monotherapy for hepatitis B virus monoinfected patients after failure of nucleoside/nucleotide analogues[J].Hepatology, 2010, 51 (1) :73-80.

[19]LIANG ZL, LIU Y, SU HL, et al.Mutations possibly associated with tenofovir disoproxil fumarate resistance in 1740 patients with chronic hepatitis B[J].Infect Dis Info, 2009, 22 (4) :207-210. (in Chinese) 梁兆玲, 刘妍, 苏何玲, 等.1740例慢性乙型肝炎患者替诺福韦酯耐药可能相关突变分析[J].传染病信息, 2009, 22 (4) :207-210.

施引文献

资源附件(0)

访问统计