乙型肝炎病毒YMDD联合前C变异及其临床意义

Emergence of the pre C and YMDD mutations and its clinical significance during lamivudine treatment

目的 研究拉米夫定治疗过程中乙型肝炎病毒 (HBV)前C区、P区YMDD基序变异及其对疗效的影响。方法 对 5例拉米夫定 ( 10 0mg/d)治疗过程中HBeAg血清转换而HBVDNA仍阳性的慢性乙型肝炎患者 ,采用聚合酶链反应 (PCR)产物直接测序方法分析HBV前C、P区的基因序列。结果 5例患者前C区均发现有G1896A变异 ,其中 3例HBeAg血清转换前未发现此变异 ,2例已有此变异 ;同时 5例患者在拉米夫定治疗后检测出YMDD变异 ,变异类型均为M5 5 2I ,其中有 1例在出现M5 5 2I变异 4 0周后变为M5 5 2V变异 ,有 2例M 5 5 2I联合L5 2 8M变异 ;5例患者中有 1例治疗无反应 ,另 4例在治疗过程中HBVDNA突发。结论 拉米夫定治疗过程中YMDD变异的出现可导致HBVDNA突发 ,而前C区G1896A变异可致HBeAg阴转 ,因此在治疗过程中出现HBeAg血清转换后需结合HBVDNA检测 。

Objective To explore pre C and YMDD motif mutant of hepatitis B virus during lamivudine therapy. Methods From five chronic hepatitis B patients with serum HBeAg seroconversion but HBV DNA positive by polymerase chain reaction(PCR) following lamivudine therapy, sequences of the pre C and P genes of hepatitis B virus were analyzed by direct PCR product sequencing methods. Results All the five patients were observed to have G to A variations at nucleotide 1896. However, such mutations were observed only in 2 of the 5 patients before HBeAg seroconversion emerged. Meanwhile YMDD mutations were found in all the five patients during lamivudine therapy three of which were M552I mutants, two were M552I associated with L528M. One of the five patients had no reaction to the therapy, four had HBV DNA breakthrough during therapy. Conclusions The mutants of pre C associated with YMDD mutations may arise in the patients with HBeAg seroconversion and positive HBV DNA during the treatment of lamivudine. HBV DNA should be detected in the patients with HBeAg seroconversion to exclude the pre C mutation.