Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
J Hepatol. 2010 Apr;52(4):478-85. doi: 10.1016/j.jhep.2010.01.006. Epub 2010 Feb 2.
BACKGROUND & AIMS: The aim of this study was to determine the evolution of full-length hepatitis B virus (HBV) sequences in chronic hepatitis B (CHB) patients with sequential lamivudine (LAM) and adefovir (ADV) resistance.
The full-length genomes of HBV were sequenced from 11 CHB patients before LAM treatment and at the emergence of LAM- and ADV-resistant HBV.
Besides the known LAM-resistant polymerase gene mutations, 10 of 11 patients who had LAM-resistant HBV variants had additional amino acid changes in the reverse transcriptase (RT) domain, and ADV therapy reversed these additional changes to pre-LAM therapy status. Furthermore, new amino acid changes in the RT domain, distinct from the known ADV-resistant HBV variants, were selected at the emergence of ADV resistance in six of 11 patients. Seven patients had amino acid changes within the known T-cell or B-cell epitopes of HBV surface and core antigens at the emergence of LAM and/or ADV resistance. The frequency of pre-S deletions between nucleotide 3037-56 was higher at the emergence of ADV resistance compared with that at the emergence of LAM resistance (7/11 vs. 1/11; p=0.024). Combined LAM-ADV resistance was detected in one of 11 patients. This patient had resistant mutations to both drugs on the same viral genome by molecular cloning (5/24 polymerase gene clones).
In addition to the known LAM- and ADV-resistant mutations accompanying the emergence of LAM and ADV resistance, the changes of nucleotide or amino acid sequences occurred commonly in the HBV surface antigen or RT domain and were scattered along the full-length HBV genomes.
本研究旨在确定慢性乙型肝炎（CHB）患者在序贯应用拉米夫定（LAM）和阿德福韦（ADV）耐药后，全长乙型肝炎病毒（HBV）序列的演变情况。
对 11 例 LAM 治疗前和出现 LAM 和 ADV 耐药的 CHB 患者的 HBV 全长基因组进行测序。
除了已知的 LAM 耐药聚合酶基因突变外，11 例出现 LAM 耐药 HBV 变异的患者中有 10 例在逆转录酶（RT）结构域中还有额外的氨基酸变化，ADV 治疗将这些额外的变化逆转至 LAM 治疗前的状态。此外，在 11 例患者中有 6 例在出现 ADV 耐药时，在 RT 结构域中选择了与已知的 ADV 耐药 HBV 变异不同的新的氨基酸变化。7 例患者在出现 LAM 和/或 ADV 耐药时，在 HBV 表面和核心抗原的 T 细胞或 B 细胞表位内有氨基酸变化。与出现 LAM 耐药相比，在出现 ADV 耐药时，前 S 区核苷酸 3037-56 缺失的频率更高（7/11 比 1/11；p=0.024）。在 11 例患者中有 1 例发生了联合 LAM-ADV 耐药。该患者通过分子克隆在同一病毒基因组上发现了对两种药物都有耐药突变（24 个聚合酶基因克隆中有 5 个）。
除了在出现 LAM 和 ADV 耐药时伴随的已知 LAM 和 ADV 耐药突变外，HBV 表面抗原或 RT 结构域中的核苷酸或氨基酸序列变化常见，并散在全长 HBV 基因组中。
