Liaw Yun-Fan, Chien Rong-Non, Yeh Chau-Ting
Liver Research Unit, Chang Gung Memorial Hospital and University, Taipei, Taiwan.
Antivir Ther. 2004 Apr;9(2):257-62.
Mutations in the sequence of the conserved tyrosine-methionine-aspartate-aspartate (YMDD) locus of the HBV RNA-dependent DNA polymerase (rt M 204 I/V) may develop after 6-9 months of lamivudine therapy. The current practice of continuing lamivudine therapy has been associated with hepatitis flares or even hepatic decompensation. In addition, experiments have shown that the defective replication competency of rt M 204 I/V restores upon addition of lamivudine.
To evaluate whether continuing lamivudine therapy after emergence of rt M 204 I/V is appropriate.
The clinical courses of 66 patients with continuing lamivudine therapy (continued group) and 68 patients who discontinued lamivudine therapy (discontinued group) were monitored monthly or more frequently if condition required. Hepatitis flare, jaundice, hepatic decompensation and hepatitis B e antigen (HBeAg) seroconversion in HBeAg-positive patients were documented as events.
In a 12-month period, hepatitis flares and decompensations occurred in 67 and 11%, respectively, in patients who continued lamivudine therapy, as compared with 54 and 7%, respectively (P>0.05), in those who stopped therapy. HBeAg seroconversion rate was 19% in continued group and 35% in discontinued group (P=0.08). Serum HBV DNA increased in 48 (73%) of the continued group, and the median level increased from 46 pg/ml upon first detection of mutation to 330 pg/ml (P<0.001) at the end of 12 months continuing therapy. In contrast, serum HBV DNA level in the discontinued group increased in 22 (33%) patients but decreased in 39 patients, and median level decreased from 172 to 55 pg/ml at the end of 12 months after stopping lamivudine.
These results suggest that there is no benefit to continued lamivudine therapy after emergence of rt M 204 I/V.
乙型肝炎病毒（HBV）RNA依赖性DNA聚合酶保守的酪氨酸-甲硫氨酸-天冬氨酸-天冬氨酸（YMDD）位点（rtM204I/V）序列中的突变可能在拉米夫定治疗6 - 9个月后出现。继续使用拉米夫定治疗的现行做法与肝炎发作甚至肝失代偿有关。此外，实验表明，添加拉米夫定后rtM204I/V的缺陷复制能力得以恢复。
评估rtM204I/V出现后继续使用拉米夫定治疗是否合适。
对66例继续使用拉米夫定治疗的患者（继续治疗组）和68例停用拉米夫定治疗的患者（停药组）的临床病程进行每月或根据病情需要更频繁的监测。记录肝炎发作、黄疸、肝失代偿以及HBeAg阳性患者的乙肝e抗原（HBeAg）血清学转换作为事件。
在12个月期间，继续使用拉米夫定治疗的患者中，肝炎发作和失代偿的发生率分别为67%和11%，而停药患者中分别为54%和7%（P>0.05）。继续治疗组的HBeAg血清学转换率为19%，停药组为35%（P = 0.08）。继续治疗组48例（73%）患者的血清HBV DNA升高，继续治疗12个月结束时，中位水平从首次检测到突变时的46 pg/ml升至330 pg/ml（P<0.001）。相比之下，停药组22例（33%）患者的血清HBV DNA水平升高，39例患者降低，停用拉米夫定12个月结束时，中位水平从172 pg/ml降至55 pg/ml。
这些结果表明，rtM204I/V出现后继续使用拉米夫定治疗没有益处。
