Yang Jing-Xian, Liu Bao-Ming, Li Xiao-Guang, Yan Chun-Hui, Xu Jie, Sun Xie-Wen, Wang Yu-Hua, Jiao Xiu-Juan, Yan Ling, Dong Jian-Ping, Hou Chun-Sheng, Abuduheilili Xiernayi, Li Tong, Zhuang Hui
Department of Microbiology, Peking University Health Science Center, Beijing, China.
Antivir Ther. 2010;15(8):1171-8. doi: 10.3851/IMP1677.
Antiviral drug-resistant HBV mutants under a variety of treatment protocols are complex and only partly understood. Here, a population-based cross-sectional study was performed to analyse the profile of resistance mutations in distinct evolutionary pathways refractory to different nucleoside/nucleotide analogues (NAs).
Serum samples of 199 chronic hepatitis B patients undergoing NA treatment from five hospitals in four northern cities of China were obtained between January 2007 and July 2009. The genotypic resistance of HBV in these samples was characterized. The full-length HBV reverse transcriptase region was amplified, sequenced and analysed with particular focus on the following NA-resistant changes: rtL80, rtI169, rtV173, rtL180, rtA181, rtT184, rtA194, rtS202, rtM204, rtN236 and rtM250.
Among 199 HBV isolates, 30 (15.08%) and 169 (84.92%) were genotypes B and C, respectively, and 65 (32.66%) harboured NA-resistant mutations. The prevalence of mutations at rtM204 was 34.33% in 134 patients who had received or who had been exposed to lamivudine-based therapy. Five cases of rtN236 mutations were detected exclusively among 75 patients receiving adefovir-dipivoxil-based therapies. A total of 19 cases of multidrug resistance rtA181 mutations were observed in those with lamivudine-, adefovir-dipivoxil- or telbivudine-based treatment (186 cases), but not in those undergoing entecavir treatment (13 cases). Mutations were not found at rtI169, rtT184, rtA194 or rtS202. rtM204 mutations (27 rtM204I, 15 rtM204V and 5 rtM204I/V cases) were detected at the highest frequency among 65 mutants (72.30% [47/65]) and found to display 16 combination mutation patterns, in which rtM204I and rtM204V were significantly associated with rtL80I/V and rtL180M, respectively (P<0.01).
One-third of the studied population harboured NA-resistant HBV with complicated mutation patterns. Monitoring HBV genotypic resistance mutation markers and patterns is therefore shown to be beneficial for optimizing antiviral therapies and for avoiding clinical deterioration.
在各种治疗方案下，抗病毒药物耐药的乙肝病毒（HBV）突变体情况复杂，目前仅部分被了解。在此，我们开展了一项基于人群的横断面研究，以分析不同进化途径中对不同核苷/核苷酸类似物（NA）耐药的突变情况。
2007年1月至2009年7月期间，收集了来自中国北方四个城市五家医院正在接受NA治疗的199例慢性乙型肝炎患者的血清样本。对这些样本中HBV的基因型耐药情况进行了鉴定。扩增、测序并分析了全长HBV逆转录酶区域，特别关注以下与NA耐药相关的变化：rtL80、rtI169、rtV173、rtL180、rtA181、rtT184、rtA194、rtS202、rtM204、rtN236和rtM250。
在199株HBV分离株中，分别有30株（15.08%）和169株（84.92%）为B型和C型基因型，65株（32.66%）存在NA耐药突变。在134例接受过基于拉米夫定治疗或曾接触过基于拉米夫定治疗的患者中，rtM204位点的突变发生率为34.33%。仅在75例接受阿德福韦酯治疗的患者中检测到5例rtN236突变。在接受基于拉米夫定、阿德福韦酯或替比夫定治疗的患者（186例）中，共观察到19例多重耐药rtA181突变，但在接受恩替卡韦治疗的患者（13例）中未发现。在rtI169、rtT184、rtA194或rtS202位点未发现突变。在65个突变体中，rtM204突变（27例rtM204I、15例rtM204V和5例rtM204I/V）的检出频率最高（72.30% [47/65]），并发现呈现16种组合突变模式，其中rtM204I和rtM204V分别与rtL80I/V和rtL180M显著相关（P<0.01）。
三分之一的研究人群携带具有复杂突变模式的NA耐药HBV。因此，监测HBV基因型耐药突变标志物和模式有助于优化抗病毒治疗并避免临床病情恶化。
