Chayama K, Suzuki Y, Kobayashi M, Kobayashi M, Tsubota A, Hashimoto M, Miyano Y, Koike H, Kobayashi M, Koida I, Arase Y, Saitoh S, Murashima N, Ikeda K, Kumada H
Department of Gastroenterology, Toranomon Hospital, Okinaka, Memorial Institute for Medical Research, Tokyo, Japan.
Hepatology. 1998 Jun;27(6):1711-6. doi: 10.1002/hep.510270634.
Treatment of hepatitis B virus (HBV) 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. We report the emergence and takeover of YMDD mutant and re-takeover by wild type during and after long-term lamivudine therapy. YMDD mutants were detected in five patients who showed DNA breakthrough (HBV DNA becoming detectable after a period of DNA negativity), which occurred after 9 to 14 months of lamivudine therapy. Four of five mutants had amino acid sequence YIDD, and the remaining mutant had YVDD. Patients with high HBV-DNA titer and/or hepatitis B e antigen tended to develop breakthrough (P = .038). Using a sensitive and specific polymerase chain reaction (PCR)-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 the pretreatment sera. The mutants were predominant at breakthrough, but were replaced by wild-type virus 3 to 4 months after cessation of therapy in the two patients who discontinued therapy. One of these patients had a relapse of hepatitis. Mutant continued to replicate in the remaining three patients who continued to receive treatment, and relapse occurred in only one of these patients. 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 antiviral 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（HBV）可有效抑制病毒复制并降低炎症活性。然而，已有报道出现了拉米夫定耐药突变病毒，其DNA聚合酶的YMDD基序中有氨基酸替代。我们报告了长期拉米夫定治疗期间及之后YMDD突变体的出现、取代以及野生型的重新取代情况。在5例出现DNA突破（在一段时间的DNA阴性后HBV DNA变得可检测）的患者中检测到了YMDD突变体，DNA突破发生在拉米夫定治疗9至14个月后。5个突变体中有4个的氨基酸序列为YIDD，其余突变体为YVDD。HBV-DNA滴度高和/或乙肝e抗原阳性的患者倾向于发生突破（P = 0.038）。使用本研究开发的一种灵敏且特异的基于聚合酶链反应（PCR）的方法，在DNA突破前1至4个月检测到了YMDD突变体的出现，但在任何预处理血清中均未检测到。突变体在突破时占主导，但在两名停药患者中，停药后3至4个月被野生型病毒取代。其中一名患者肝炎复发。在继续接受治疗的其余三名患者中，突变体继续复制，且只有一名患者复发。我们的结果表明，YMDD突变病毒的复制能力低于野生型，且在停药后会被野生型重新取代。重新给予拉米夫定，可能联合其他抗病毒治疗，对一些出现拉米夫定耐药变异体肝炎的患者可能有用。
