Detection of drug resistant mutant hepatitis B virus strain and its clinical application.

乙型肝炎病毒耐药突变株检测及其临床应用

• 批准号: 10670524
• 负责人: CHAYAMA Kazuaki
• 金额: $ 2.18万
• 依托单位: Hiroshima University (2000)Okinaka Memorial Institute for Medical Research (1998-1999)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670524/
• 关键词: lamivudine; PCR-RFLP; mutation; resistance; PCR; YMDD; 長期投与; B型肝炎ウイルス; 点突然変異; C型肝炎ウイルス; ラミブジン; YMDDモチーフ; YVDD; YIDD

Treatment of hepatitis B virus with lamivudine is effective in suppressing virus replication and results in reduced inflammatory activity. However, the emergence of lamivudine-resistant mutant virus, with amino acid substitution in the YMDD motif of DNA polymerase, has been reported. Using a sensitive and specific polymerase chain reaction-based method developed in this study, the emergence of YMDD mutants was detected 1 to 4 months before DNA breakthrough but not detected in any of pretreatment sera. We also detected the emergence and takeover of YMDD mutant and re-takeover by wild type during and after long-term lamivudine therapy. Cumulative appearance of YMDD mutants increased by time, but became plateau three years from the beginning of the therapy. The final appearance rate of YMDD mutants was 47.6%. Our results suggest that the replication of YMDD mutant viruses is less than wild type and is re-overtaken by wild type after cessation of therapy. Re administration of lamivudine, possibly combined with other anti viral therapy, might be useful in some patients experiencing hepatitis with lamivudine resistant variants.

用拉米夫定治疗B型肝炎病毒可有效抑制病毒复制，并导致炎症活动减少。然而，已经报道了DNA聚合酶的YMDD基序中的氨基酸取代的拉米夫定抗性突变病毒的出现。使用本研究中开发的一种灵敏和特异的基于聚合酶链反应的方法，在DNA突破前1至4个月检测到YMDD突变体的出现，但在任何预处理血清中均未检测到。我们还检测了在长期拉米夫定治疗期间和治疗后YMDD突变体的出现和接管以及野生型的重新接管。YMDD突变体的累积出现随着时间的推移而增加，但在治疗开始后三年达到平台期。YMDD突变体的最终出现率为47.6%。我们的研究结果表明，YMDD突变病毒的复制比野生型少，并在停止治疗后重新被野生型取代。拉米夫定的再给药，可能与其他抗病毒治疗相结合，可能对一些拉米夫定耐药变异型肝炎患者有用。

项目成果

Chayama K, Suzuki Y, et al.: "Emergence and takeover of YMDD motif mutant hepatitis B virus during long-term lamivudine therapy and re-takeover by wild type after cessation of therapy."Hepatology. 27(6). 1711-1716 (1998)

Chayama K、Suzuki Y 等人：“长期拉米夫定治疗期间 YMDD 基序突变型乙型肝炎病毒的出现和接管，以及治疗停止后野生型的重新接管。”肝病学。

K.Chayama F.Suzuki, et al.: "Association of amino acid sequence in the PKR-eIF2 phosphorylation homology domain and response to interferon therapy"Hepatology. 32. 1138-1144 (2000)

K.Chayama F.Suzuki 等人：“PKR-eIF2 磷酸化同源结构域中的氨基酸序列与干扰素治疗反应的关联”肝病学。

M.Kobayashi K.Chayama, et al.: "Incidence of primary liver cancer-cholangiocellular type in Japanese patients with hepatitis C virus related cirrhosis"Cancer. 88. 2471-2477 (2000)

M.Kobayashi K.Chayama等人：“日本丙型肝炎病毒相关肝硬化患者中原发性肝癌-胆管细胞型的发病率”癌症。

Y.Arase K.Chayama, et al.: "Time course of histological changes in patients with a sustained biochemical and virological response to corticosteroid withdrawal therapy for chronic hepatitis B"Am J Gastroenterol. 94. 3304-3309 (1999)

Y.Arase K.Chayama 等人：“对慢性乙型肝炎的皮质类固醇戒断治疗具有持续生化和病毒学反应的患者的组织学变化的时间进程”Am J Gastroenterol。

Suzuki Y,Chayama K, et al.: "Histological changes in liver biopsies after one year of lamivudine treatment in patients with chronic hepatitis B infection."J Hepatol. 30(5). 743-748 (1999)

Suzuki Y、Chayama K 等人：“慢性乙型肝炎感染患者接受拉米夫定治疗一年后肝活检的组织学变化。”J Hepatol。