拉米夫定耐药慢性乙型肝炎患者改用阿德福韦酯单药治疗后发生耐药及处理

Antiviral drug resistance and management after switching-to adefovir dipivoxil therapy in lamivudine- resistant chronic hepatitis B patients

目的探讨拉米夫定耐药慢性乙型肝炎患者改用阿德福韦酯治疗后发生耐药的临床过程及挽救治疗疗效。方法回顾性分析15例慢性乙型肝炎患者拉米夫定耐药后，在阿德福韦酯单药治疗期间出现的病毒学突破，采用基因测序法检测到HBV聚合酶基因阿德福韦酯相关突变位点，接受挽救治疗措施。结果15例拉米夫定耐药患者经中位时间为16个月的阿德福韦酯单药治疗，14例出现与阿德福韦酯耐药相关的rtAl81T／V和（或）rtN236T突变，1例出现rtM204I±rtLl80M±rtAl81T联合突变。耐药后15例患者均给予挽救性治疗措施，其中7例接受拉米夫定联合阿德福韦酯治疗的患者，3个月时HBVDNA平均下降（2．2±0．6）tg拷贝／mL，6个月时，5例HBVDNA低于检测限；另3例接受恩替卡韦治疗患者，6个月时HBVDNA水平下降2．8～3．5lg拷贝／mL。结论拉米夫定联合阿德福韦酯是拉米夫定耐药慢性乙型肝炎患者改用阿德福韦酯单药治疗发生阿德福韦酯耐药后的有效挽救治疗措施。

Objective To analyze clinical courses and rescue therapies of adefovir-resistant chronic hepatitis B patients who had lamivudine resistance before and then changed to take adefovir dipivoxil. Methods 15 patients resistant to lamivudine were retrospectively analyzed, who had virological breakthrough after adefovir dipivoxil monotherapy and were treated with rescue therapy. Adefovir-resistant mutations were detected by direct sequencing of the HBV polymerase gene. Results 15 patients with former lamivudine resistance were treated with adefovir dipivoxil monotherapy for a median of 16 months, and 14 patients were found adefovir-resistant mutations at rtA181T/V and（or） rtN236T, only 1 patient was found multi-mutations at rtM204I ＋ rtL180M ＋ rtA181T. Rescue therapies were given to all the 15 patients after drug resistance. Among the 7 patients treated with lamivudine in combination with adefovir for 3 months,whose HBV DNA levels decreased （2.2±0.6） lg copy/mL on average, 5 patients achieved HBV DNA undetectable after 6 months combinative therapy. The HBV DNA levels of the 3 patients treated with entecavir decreased 2.8-3.5 lg copy/mL within 6 months treatment. Conclusion These preliminary data suggest the combination of lamivudine and adeforvir dipivoxil may be an effective rescue therapy for adefovir-resistant patients who have former lamivudine resistance.