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

Rescued antiviral therapy of patients with hepatitis B virus rtM204/ rtA181 mutants resistant to lamivudine or adefovir

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。

Objective To 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. Methods 142 nucleos（t）idenaive 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.Results Among CHB patients with lamivudine resistance,mutation patterns were mainly M204 V and IL180 M,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,A181 V and N236 T mutation rates were63.9%（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. Conclusions Addition 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.