Fukai K, Zhang K Y, Imazeki F, Kurihara T, Mikata R, Yokosuka O
Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Inohana, Chuo-ku, Chiba, Japan.
J Viral Hepat. 2007 Sep;14(9):661-6. doi: 10.1111/j.1365-2893.2007.00852.x.
This study aimed to identify the viral factors responsible for poor sensitivity to lamivudine (LAM). We analyzed 49 LAM-treated chronic hepatitis B patients infected with hepatitis B virus (HBV) genotype C. Serum HBV DNA reached a level below the detection limit of the sensitive PCR assay in 31 (63.3%) within the first 24 weeks of LAM therapy (good responder group). Of the patients who did not achieve undetectable levels of HBV DNA within 24 weeks (poor responder group), 15 (83.3%) experienced virological breakthrough, whilst only four patients in the good responder group (12.9%) experienced virological breakthrough. Multivariate analysis revealed that failure to achieve a reduction in viral load to undetectable levels within 24 weeks was independently associated with the occurrence of virological breakthrough. Sequence analysis of the HBV genome revealed that point mutations in the precore region (G1896A) and enhancer I (A1287G/C) were observed more frequently in the good responder group than in the poor responder group (P = 0.002 and 0.019 respectively), and the number of substitutions in the reverse transcriptase domain of the polymerase was significantly higher in the good responders than in the poor responders (P = 0.026). In conclusion, determining the sequence of preexisting HBV, especially for enhancer I, the precore region, and the RT domain of the polymerase region, may be useful in predicting sensitivity to LAM therapy.
本研究旨在确定导致对拉米夫定（LAM）敏感性差的病毒因素。我们分析了49例接受LAM治疗的感染B型肝炎病毒（HBV）C基因型的慢性乙型肝炎患者。在LAM治疗的前24周内，31例（63.3%）患者的血清HBV DNA水平降至灵敏PCR检测法的检测限以下（良好应答组）。在24周内未达到HBV DNA不可检测水平的患者（不良应答组）中，15例（83.3%）出现病毒学突破，而良好应答组中只有4例患者（12.9%）出现病毒学突破。多变量分析显示，24周内未能将病毒载量降至不可检测水平与病毒学突破的发生独立相关。HBV基因组序列分析显示，前核心区（G1896A）和增强子I（A1287G/C）的点突变在良好应答组中比在不良应答组中更频繁地观察到（分别为P = 0.002和0.019），并且良好应答者中聚合酶逆转录酶结构域的替换数显著高于不良应答者（P = 0.026）。总之，确定预先存在的HBV序列，特别是增强子I、前核心区和聚合酶区的RT结构域，可能有助于预测对LAM治疗的敏感性。
