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.

用拉米夫定治疗乙型肝炎病毒可有效抑制病毒复制并减少炎症活动。然而，已经报道了拉米夫定耐药突变病毒的出现，其DNA聚合酶的YMDD基序中的氨基酸被取代。使用本研究中开发的基于灵敏且特异的聚合酶链式反应的方法，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。我们还在长期拉米夫定治疗期间和之后检测到 YMDD 突变体的出现和接管以及野生型的重新接管。 YMDD 突变体的累积出现量随着时间的推移而增加，但在治疗开始三年后达到稳定水平。 YMDD突变体最终出现率为47.6%。我们的结果表明，YMDD 突变病毒的复制低于野生型，并且在治疗停止后又被野生型复制。重新给予拉米夫定，可能与其他抗病毒治疗联合使用，可能对一些患有拉米夫定耐药变异型肝炎的患者有用。

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。

Kazuaki Chayama: "Emergence and takeover of YMDD Motif Mutant Hepatitis B Virus During Long-Term Lamivudine Therapy and Retakeover by Wild Type After cessation of Therapy"HEPATOLOGY. 27・6. 1711-1716 (1998)

Kazuaki Chayama：“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》27・6（1998）。