JH：替诺福韦单药或与恩曲他滨联用对HBV准种演化的影响相当

对于乙肝治疗来说，很多抗病毒药物并不能完全清除HBV病毒。在长期的治疗过程中，可能会出现耐药毒株，从而导致治疗失败。因此，乙肝治疗药物的耐药屏障和交叉耐药谱是决定乙肝治疗策略的重要因素。在体外实验中，已证明阿德福伟（ADV）耐药突变只会引起低水平的替诺福韦交叉耐药。

基于上述情况，来自法国里昂的Fabien Zoulim等人展开一项研究，他们使用富马酸替诺福韦酯（TDF）单药或恩曲他滨+TDF（FTC/TDF）联合用药治疗经选择的乙肝患者（对ADV应答不完全的患者），旨在比较这两种治疗方案对HBV病毒动力学、核苷酸类似物耐药突变以及病毒准种（QS）演化的影响。该研究结果在线发表于2013年6月4日的《肝脏病学杂志》（Journal of Hepatology）杂志上。作者发现，TDF单药治疗以及FTC/TDF联合治疗对HBV病毒QS演化的影响相当。

研究人员将对ADV应答不完全的慢性乙型肝炎患者随机双盲分组——TDF组和FTC/TDF组。在48周的治疗中，利用17例患者的数据来对QS的演化情况进行广泛的分析。

研究结果如下：在第24周时，48%的患者（9/17）无法检测到HBV DNA（<69 IU/mL），两个治疗组间没有差别。在基线水平时，所有的17例患者均可检测到ADV和/或LAM（拉米夫定）耐药突变，而在第48周时，在6例可分析的患者中，有5例可检测到耐药突变。研究人员一共分析了1224个逆转录酶克隆。克隆分析表明，两个治疗组基线水平的QS复杂性和多样性不存在显著差异。在第12周时，两个治疗组的QS复杂性均表现出增加的趋势，而至第48周时，其复杂性和多样性均有所下降。对病人个体进行分析发现，治疗期间并未出现特定病毒耐药模式的积累，但第48周时，有4例患者在rtA181处存在突变。

研究发现，TDF或FTC/TDF治疗对ADV应答不完全的患者具有强效的病毒抑制作用，并对已有的ADV或LAM突变毒株没有明显的选择压力。TDF单药治疗以及FTC/TDF联合治疗对QS演化的影响相当。

Similar evolution of Hepatitis B virus quasispecies in patients with incomplete adefovir response receiving tenofovir/emtricitabine combination or tenofovir monotherapy.
Objective
Adefovir (ADV) resistance mutations induce low-level cross-resistance to tenofovir in vitro. Our aim was to compare viral kinetics, nucleos(t)ide analog resistance mutations, and quasispecies (QS) evolution during therapy with tenofovir disoproxil fumarate (TDF) or emtricitabine + TDF (FTC/TDF) in selected patients with incomplete ADV responses.
Design
Patients with chronic hepatitis B and incomplete response to ADV were randomized in a double-blind trial of TDF versus FTC/TDF. Extensive analysis of QS evolution was performed in 17 patients through 48 weeks of treatment.
Results
At week 24, 48% of patients (9/17) achieved HBV DNA undetectability (<69 IU/mL) with no difference between treatment groups. ADV and/or LAM resistance mutations were detected in all 17 patients at baseline and in 5/6 analyzable patients at week 48. A total of 1224 reverse transcriptase clones were analyzed. Clonal analysis revealed no significant difference at baseline in QS complexity or diversity between treatment groups. There was a trend in both treatment groups for an increase in QS complexity at week 12, followed by a decrease in complexity and diversity by week 48. Analysis of individual patients showed no consistent selection/accumulation of specific viral resistance patterns during treatment, but at week 48 mutations at rtA181 persisted in 4 patients.
Conclusion
TDF or FTC/TDF demonstrated strong viral suppression in patients with an incomplete response to ADV and no significant selective pressure on pre-existing ADV or LAM resistant strains. TDF monotherapy and FTC/TDF combination therapy had a comparable impact on QS evolution.