乙型肝炎病毒逆转录酶区多位点预存耐药变异研究
摘要
目的研究宁德地区乙型肝炎病毒(HBV)预存耐药变异情况及相关影响因素,为临床制订个体化抗病毒治疗方案提供理论依据。方法采用基因芯片法,对未经核苷(酸)类似物治疗的慢性乙型肝炎患者及慢性HBV携带者进行多位点耐药突变检测,分析预存耐药变异与年龄、性别、谷氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、乙型肝炎e抗原(HBeAg)、HBV-DNA载量之间的关系。结果 401例患者共检出预存耐药变异79例,检出率为19.70%。突变位点主要集中在rtN236T、rtM204I、rtL180M。突变模式以rtN236T、rtN236T+rtM204I+rtM204V、rtN236T+rtM204为主。相关药物前3位为阿德福韦(15.96%)、拉米夫定(7.48%)、恩曲他滨(7.48%)。年龄<20岁及>60岁,肝酶>10ULN,病毒载量>10~7 IU/mL,HBeAg阳性的患者,其预存耐药变异检出率较高。结论宁德地区慢性乙型肝炎患者及慢性HBV携带者的预存耐药变异率较高,以rtN236T突变最为常见,相关药物阿德福韦应慎用。替诺福韦、恩替卡韦的预存耐药变异检出率低,抗病毒治疗时可首选。抗病毒治疗前进行多位点耐药突变检测,对指导个体化用药具有重要的临床意义。
引文
[1]钟艳丹,杨永峰.关于乙型肝炎病毒预存耐药变异的认识[J/CD].中华临床医师杂志(电子版),2012,6(20):6215-6216.
[2]饶友义,寇国先,马庆阳,等.慢性乙型肝炎患者预存耐药和抗病毒治疗后耐药情况分析[J].肝脏,2014,19(7):507-510.
[3]中华医学会肝病学分会,中华医学会感染病学分会.慢性乙型肝炎防治指南(2015年更新版)[J].临床肝胆病杂志,2015,31(12):1941-1960.
[4]CHOI Y M,LEE S Y,KIM B J.Naturally occurring hepatitis B virus reverse transcriptase mutations related to potential antiviral drug resistance and liver disease progression[J].World J Gastroenterol,2018,24(16):1708-1724.
[5]ZHANG H,PAN C Q,PANG Q,et al.Telbivudine or lamivudine use in late pregnancy safely reduces perinatal transmission of hepatitis B virus in real-life practice[J].Hepatology,2014,60(2):468-476.
[6]KIM J E,LEE S Y,KIM H,et al.Naturally occurring mutations in the reverse transcriptase region of hepatitis B virus polymerase from treatment-naive Korean patients infected with genotype C2[J].World J Gastroenterol,2017,23(23):4222-4232.
[7]陈灿峰,徐传彬,黄雪辉.深圳地区乙型肝炎病毒基因分型和预存耐药变异的研究[J].国际检验医学杂志,2014,35(23):3190-3191.
[8]薛彩花,吴玮,安俊丽,等.987例乙型肝炎患者HBVDNA P区多位点耐药突变分析及临床意义[J].胃肠病学和肝病学杂志,2014,23(10):1187-1190.
[9]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.
[10]孙静怡,贾蓓,黄文祥.乙型肝炎病毒相关性原发性肝癌术后患者对核苷(酸)类似物预存耐药变异的研究[J].牡丹江医学院学报,2017,38(1):35-39.
[11]许正锯,潘兴南,杨环文,等.乙型肝炎病毒RT区原发性耐药变异的研究[J].胃肠病学和肝病学杂志,2012,21(10):927-929.
[12]林菲,姚贝,胥婕,等.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[J].临床肝胆病杂志,2014,30(3):269-273.
[13]罗新月,韩峰,张琳.乙型肝炎病毒逆转录酶区预存耐药研究[J].中国实用内科杂志,2015,35(9):786-789.
[14]SCHINAZI R F,BASSIT L,CLAYTON M M,et al.E-valuation of single and combination therapies with tenofovir disoproxil fumarate and emtricitabine in vitro and in a robust mouse model supporting high levels of hepatitis Bvirus replication[J].Antimicrob Agents Chemother,2012,56(12):6186-6191.
[15]MURRAY K F,SZENBORN L,WYSOCKI J,et al.Randomized,placebo-controlled trial of tenofovir disoproxil fumarate in adolescents with chronic hepatitis B[J].Hepatology,2012,56(6):2018-2026.
[16]CHAN H L,CHAN C K,HUI A J,et al.Effects of tenofovir disoproxil fumarate in hepatitis B e antigen-positive patients with normal levels of alanine aminotransferase and high levels of hepatitis B virus DNA[J].Gastroenterology,2014,146(5):1240-1248.
[17]慢性乙型肝炎核苷(酸)类似物经治患者抗病毒治疗专家委员会.慢性乙型肝炎核苷(酸)类似物经治患者抗病毒治疗专家共识(2016年更新)[J/CD].中华实验和临床感染病杂志(电子版),2016,10(5):527-533.
[2]饶友义,寇国先,马庆阳,等.慢性乙型肝炎患者预存耐药和抗病毒治疗后耐药情况分析[J].肝脏,2014,19(7):507-510.
[3]中华医学会肝病学分会,中华医学会感染病学分会.慢性乙型肝炎防治指南(2015年更新版)[J].临床肝胆病杂志,2015,31(12):1941-1960.
[4]CHOI Y M,LEE S Y,KIM B J.Naturally occurring hepatitis B virus reverse transcriptase mutations related to potential antiviral drug resistance and liver disease progression[J].World J Gastroenterol,2018,24(16):1708-1724.
[5]ZHANG H,PAN C Q,PANG Q,et al.Telbivudine or lamivudine use in late pregnancy safely reduces perinatal transmission of hepatitis B virus in real-life practice[J].Hepatology,2014,60(2):468-476.
[6]KIM J E,LEE S Y,KIM H,et al.Naturally occurring mutations in the reverse transcriptase region of hepatitis B virus polymerase from treatment-naive Korean patients infected with genotype C2[J].World J Gastroenterol,2017,23(23):4222-4232.
[7]陈灿峰,徐传彬,黄雪辉.深圳地区乙型肝炎病毒基因分型和预存耐药变异的研究[J].国际检验医学杂志,2014,35(23):3190-3191.
[8]薛彩花,吴玮,安俊丽,等.987例乙型肝炎患者HBVDNA P区多位点耐药突变分析及临床意义[J].胃肠病学和肝病学杂志,2014,23(10):1187-1190.
[9]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.
[10]孙静怡,贾蓓,黄文祥.乙型肝炎病毒相关性原发性肝癌术后患者对核苷(酸)类似物预存耐药变异的研究[J].牡丹江医学院学报,2017,38(1):35-39.
[11]许正锯,潘兴南,杨环文,等.乙型肝炎病毒RT区原发性耐药变异的研究[J].胃肠病学和肝病学杂志,2012,21(10):927-929.
[12]林菲,姚贝,胥婕,等.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[J].临床肝胆病杂志,2014,30(3):269-273.
[13]罗新月,韩峰,张琳.乙型肝炎病毒逆转录酶区预存耐药研究[J].中国实用内科杂志,2015,35(9):786-789.
[14]SCHINAZI R F,BASSIT L,CLAYTON M M,et al.E-valuation of single and combination therapies with tenofovir disoproxil fumarate and emtricitabine in vitro and in a robust mouse model supporting high levels of hepatitis Bvirus replication[J].Antimicrob Agents Chemother,2012,56(12):6186-6191.
[15]MURRAY K F,SZENBORN L,WYSOCKI J,et al.Randomized,placebo-controlled trial of tenofovir disoproxil fumarate in adolescents with chronic hepatitis B[J].Hepatology,2012,56(6):2018-2026.
[16]CHAN H L,CHAN C K,HUI A J,et al.Effects of tenofovir disoproxil fumarate in hepatitis B e antigen-positive patients with normal levels of alanine aminotransferase and high levels of hepatitis B virus DNA[J].Gastroenterology,2014,146(5):1240-1248.
[17]慢性乙型肝炎核苷(酸)类似物经治患者抗病毒治疗专家委员会.慢性乙型肝炎核苷(酸)类似物经治患者抗病毒治疗专家共识(2016年更新)[J/CD].中华实验和临床感染病杂志(电子版),2016,10(5):527-533.