Tsubota Akihito, Arase Yasuji, Suzuki Fumitaka, Kobayashi Mariko, Matsuda Marie, Sato Junko, Suzuki Yoshiyuki, Akuta Norio, Sezaki Hitomi, Hosaka Tetsuya, Someya Takashi, Kobayashi Masahiro, Saitoh Satoshi, Ikeda Kenji, Kumada Hiromitsu
Department of Gastroenterology, Toranomon Hospital, Minato-ku, Tokyo, Japan.
J Med Virol. 2004 May;73(1):7-12. doi: 10.1002/jmv.20055.
The pretherapy factors that could influence the emergence of resistant hepatitis B virus (HBV) tyrosine-methionine-aspartate-aspartate (YMDD) motif mutants against lamivudine are not fully known in prolonged lamivudine therapy for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. We analyzed prospectively 116 consecutive lamivudine-naïve patients who received long-term lamivudine therapy (>1 year) by using multivariate regression analyses. The cumulative HBeAg loss rates were 29, 44, and 47% at 1, 2, and 3 years of treatment, respectively. Stepwise Cox's regression analyses indicated that pretherapy viral load was a significant factor associated with HBeAg loss (P = 0.0068). The cumulative emergence rates of YMDD mutants were 23% at 1 year, 45% at 2 year, and 47% at 3 year of treatment. Stepwise Cox's regression analyses indicated that patient age and presence or absence of severe acute exacerbation of liver disease were independent significant factors associated with emergence of YMDD mutants (P = 0.018 and 0.048, respectively). For the development of virological breakthrough, patient age, the presence or absence of severe acute exacerbation, and pretherapy viral load were independent significant factors (P = 0.028, 0.043, and 0.044, respectively). Severe acute exacerbation tended to reduce or delay development of biochemical breakthrough. The present study provides important information for the development of more effective and rational long-term lamivudine therapy for HBeAg-positive chronic hepatitis B patients infected exclusively with genotype
在对乙肝e抗原（HBeAg）阳性慢性乙型肝炎患者进行长期拉米夫定治疗时，对于可能影响抗拉米夫定的耐药乙型肝炎病毒（HBV）酪氨酸-甲硫氨酸-天冬氨酸-天冬氨酸（YMDD）基序突变体出现的治疗前因素，目前尚不完全清楚。我们采用多因素回归分析方法，对116例连续的初治患者进行了前瞻性分析，这些患者均接受了长期（>1年）拉米夫定治疗。治疗1、2和3年时，HBeAg累计转阴率分别为29%、44%和47%。逐步Cox回归分析表明，治疗前病毒载量是与HBeAg转阴相关的一个显著因素（P = 0.0068）。治疗1、2和3年时，YMDD突变体的累计出现率分别为23%、45%和47%。逐步Cox回归分析表明，患者年龄以及是否存在严重的肝病急性加重是与YMDD突变体出现相关的独立显著因素（分别为P = 0.018和0.048）。对于病毒学突破的发生，患者年龄、是否存在严重急性加重以及治疗前病毒载量是独立的显著因素（分别为P = 0.028、0.043和0.044）。严重急性加重往往会减少或延迟生化突破的发生。本研究为制定更有效、合理的针对仅感染基因型的HBeAg阳性慢性乙型肝炎患者的长期拉米夫定治疗方案提供了重要信息
