拉米夫定和阿德福韦酯抗乙型肝炎病毒耐药位点检测及临床意义

doi:10.3969/j.issn.1672-5069.2014.05.013

摘要/Abstract

摘要： 目的对应用拉米夫定或阿德福韦酯治疗后耐药的慢性乙型肝炎患者给予联合治疗,观察治疗前后乙型肝炎病毒（HBV）变异模式的变化及对疗效的影响。方法在142例对拉米夫定耐药患者中,给予72例拉米夫定联合阿德福韦酯、70例给予恩替卡韦联合阿德福韦酯冶疗,在72例对阿德福韦酯耐药患者中,给予36例联合拉米夫定、另36例联合恩替卡韦治疗,各组均治疗48 w,测定和比较治疗前后所有患者HBV DNA聚合酶逆转录区相关变异位点变化。结果在拉米夫定初治发生耐药的患者中,发生M204V和IL180M变异率分别为98.6%（140/142）和56.3%（80/142）,接受拉米夫定联合阿德福韦酯治疗患者HBV DNA阴转率为86.1%,与恩替卡韦联合阿德福韦酯治疗患者（97.1%）比,无显著性差异;在阿德福韦酯初治发生耐药的患者中,A181V和N236T变异频率分别为63.9%（46/72）和52.8%（38/72）,接受阿德福韦酯联合拉米夫定治疗患者HBV DNA阴转率为52.8%,显著低于阿德福韦酯联合恩替卡韦组（77.8%,P<0.05）;在阿德福韦酯联合拉米夫定治疗的36例患者中,19例（52.8%）HBV DNA阴转,在阿德福韦酯联合恩替卡韦治疗的36例患者中,28例（77.8%）患者HBV DNA阴转,差异具有显著性（x²=4.963,P<0.05）。结论以rtM204变异为主的拉米夫定耐药在联合阿德福韦酯进行挽救治疗后疗效确定;以rtA181变异为主的阿德福韦酯耐药患者在接受阿德福韦酯联合恩替卡韦治疗后的疗效优于联合拉米夫定。

关键词: 慢性乙型肝炎, 拉米夫定, 阿德福韦酯, 耐药, 挽救治疗

Abstract: ObjectiveTo evaluate hepatitis B virus （HBV） mutations and its impact on antiviral effects in chronic hepatitis B（CHB） patients with mutants resistant to lamivudine or adefovir.Methods142 nucleos（t）ide-naive CHB patients treated with lamivudine were switched to lamivudine plus adefovir（n=72） or entecavir plus adefovir （n=70） because of lamivudine resistance and 72 nucleos（t）ide-naive CHB patients treated with adefovir were switched to adefovir plus lamivudine （n=36） or adefovir plus entecavir （n=36） after resistance occurred. HBV DNA polymerase reverse transcriptase mutations were analyzed before and after 48 weeks of rescue therapy.ResultsAmong CHB patients with lamivudine resistance,mutation patterns were mainly M204V and IL180M, with a frequency of 98.6%（140/142） and 56.3%（80/142）,respectively;Undetectable serum HBV DNA were noted in 86.1% of patients in lamivudine and adefovir treatment group,and 97.1% of patients in entecavir and adefovir treatment group（P>0.05）;Among CHB patients with adefovir resistance,A181V and N236T mutation rates were 63.9%（46/72） and 52.8%（38/72）,respectively;Undetectable serum HBV DNA were found in 52.8%（19/36） of patients in adefovir and lamivudine treatment group,significantly lower than that [77.8% （28/36）,x²=4.963,P<0.05] of patients in adefovir and entecavir treatment group.ConclusionsAddition of adefovir dipivoxil to lamivudine is effective rescue therapy in patients with rtM204 mutation resistance to lamivudine,but in patients with rtA181 mutation resistance to adefovir dipivoxil,the addition of entecavir is superior to lamivudine.

Key words: Hepatitis B, Lamivudine, Adefovir, Drug resistance, Rescue therapy

贾德兴, 冯静, 李萍, 伦秀英, 于贤杰. 拉米夫定和阿德福韦酯抗乙型肝炎病毒耐药位点检测及临床意义[J]. 实用肝脏病杂志, 2014, 17(5): 497-502.

Jia Dexing, Feng Jing, Li Ping. Rescued antiviral therapy of patients with hepatitis B virus rtM204/rtA181 mutants resistant to lamivudine or adefovir[J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2014, 17(5): 497-502.

参考文献

[1] 乙型肝炎病毒耐药专家委员会. 乙型肝炎病毒耐药专家共识.中华实验和临床感染病杂志（电子版）,2008,2：90-98.
[2] 乙型肝炎病毒耐药专家委员会.乙型肝炎病毒耐药专家共识：2009年更新. 中华实验和临床感染病杂志（电子版）,2009,3：72-79.
[3] 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（2010年版）. 实用肝脏病杂志,2011,14（2）：81-89.
[4] Liaw YF,Kao JH,Piratvisuth T,et al. Asian-Pacific consensus statement on the management of chronic hepatitis B:a 2012 update. Hepatol Int,2012,6:531-561.
[5] European Association For The Study Of The Liver. EASL clinical practice guidelines:management of chronic hepatitis B virus infection. J Hepatol,2012,57:167-185.
[6] 参加乙型肝炎病毒讨论会专家.核苷和核苷酸类药物治疗慢性乙型肝炎的耐药及其管理. 中华肝脏病杂志,2013,21：15-21.
[7] 姚光弼,崔振宇,姚集鲁,等. 国产拉米夫定治疗2200例慢性乙型肝炎的Ⅳ期临床试验. 中华肝脏病杂志,2003,11：103-108.
[8] 姚光弼,王宝恩,崔振宇,等. 拉米夫定治疗慢性乙型肝炎三年疗效观察. 中华内科杂志,2003,42：382-387.
[9] Yao GB,Zhu M,Cui ZY,et al.A 7-year study of lamivudine therapy for hepatitis B virus e antigen-positive chronic hepatitis B patients in China.J Dig Dis,2009,10:131-137.
[10] Delney IV WE,Yang H,Westlane CE,et al.The hepatitis B virus polymerase mutation rtV173L is selected during lamivudine therapy and enhances viral replication in vitro.J Virol,2003,77:11833-11841.
[11] Orlando R,Tosone G,Portella G,et al. Prolonged persistence of lamivudine-resistant mutant and emergence of new lamivudine-resistant mutants two years after lamivudine withdrawal in HBsAg-positive chronic hepatitis patients:a case report.Infection,2008,36:472-474.
[12] Yeh CT,Chien RN,Chu CM,et al.Clearance of the original hepatitis B virus YMDD-motifmutants with emergence of distinct lamivudine-resistant during prolonged lamivudine therapy .Hepatology,2000,31:1318-1326.
[13] Tenney DJ,Levine SM,Rose RE,et al.Clinical emergence of enticavir-resistant hepatitis-B virus requires additional substitutions in virus already resistant to lamivudine.Antimicrob Agents Chemother,2004,48:3498-3507.
[14] Sherman M,Yurdaydin C,Simsek H,et al.Entecavir therapy for lamivudine-refractory chronic hepatitis B improved virologic,biochemical,and serology outcomes through 96 weeks.Hepatology,2008,48:99-108.
[15] 吴珍萍,韩涛,高英堂,等.拉米夫定耐药后阿德福韦酯治疗应答欠佳患者乙型肝炎病毒耐药变异模式.中华肝脏病杂志,2010,18：498-501.
[16] 刘峰,王磊,王丽娜,等.阿德福韦酯治疗慢性乙型肝炎过程中发生病毒学突破患者的（HBV）P基因变异分析. 山东大学学报（医学版）,2008,46：407-410.
[17] Villet S,Pichoud C,Billioud G,et al.Impact of hepatitis B virus rtA181V/T mutants on hepatitis B treatment failure.J Hepatol,2008,48:747-755.
[19] 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.
[20] European Association For the Study of the Liver. EASL clinical practice guidelines:management of chronic hepatitis B. J Hepatol,2009,50:227-242.
[21] Cho HC,Kim YJ,Gwar GY,et al.One -year study of entecavir and adefovir combination therapy for rtA181V/T mutants in prior lamivudine-resistant hepatitis B virus. Hepatology,2011,54（Suppl）:1065A-1066A.