摘要
OBJECTIVE: To evaluate the long-term efficacy and safety of lamivudine therapy for the treatment of chronic hepatitis B and the clinical influence of emergence of tyrosine methionine aspartic acid (YMDD) motif mutation of hepatitis B virus (HBV). METHODS: This multicenter, double-blind, randomized, placebo controlled trial began in 1996. A total of 429 patients with HBsAg, HBeAg and HBV CNA positives were enrolled. They were randomized to receive either lamivudine 100 mg daily (n = 322) or placebo (n = 107) on 3 : 1 ratio for the first 12 weeks. Thereafter all patients were offered open label lamivudine treatment and assessed every 4 weeks for a total of 104 weeks. RESULTS: After 1 year treatment 72.7% patients (285/392) had a sustained serum HBV DNA response. HBV DNA continued to be substantially suppressed at the second year, except in patients with the emergence of YMDD mutation whose mean HBV DNA levels increased to 86 Meq/ml (bDNA assay) but were much more lower than that of pre-treatment baseline level. lamivudine therapy resulted in increased HBeAg loss and HBeAg/anti-HBe seroconversion, which were correlated with both baseline alanine transaminase (ALT) levels and also with duration of lamivudine treatment. HBeAg loss was achieved in 26.8% of patients with ALT > 1-fold upper limit of normal at 2 yeas and in 35.6% and 55.6% of patients with ALT > 2-fold upper limit of normal and ALT > 5-fold upper limit of normal, respectively. For HBeAg seroconversion, these figures were 17.4%, 22.2%, and 33.3% respectively. By the end of 2 years, ALT levels were remained in normal ranges in 50.3% whose ALT were abnormal before treatment, and in 83% whose ALT were mormal before treatment. YMDD mutation were developed in 49.7% of the patients. Their serum HBV DNA levels were slightly increased to bDNA median level 86 Meq/ml and 15% of the patients they were ALT exceeded baseline levels. Four patients clinically flared-up and recovered after stop treatment. The adverse drug reactions (ADRs) of lamivudine were mild to moderate, only two patients were reported as drug related severe ADR. CONCLUSION: Sustained HBV replication and clinical improvement could be obtained by the long-term lamivudine therapy with good tolerance and safety.
目的 评价拉米夫定治疗慢性乙型肝炎的长期疗效和安全性以及YMDD变异对临床的影响。方法 这是一项多中心、随机双盲、安慰剂对照临床试验 ,始于 1996年。 4 2 9例HBsAg、HBeAg和HBVDNA阳性病人进入本研究。病人以 3∶1的比例随机接受拉米夫定 (10 0毫克 /日 ,n =32 2 )或安慰剂 (n =10 7)治疗 12周。随后所有病人接受拉米夫定开放治疗 ,每 4周随访一次 ,共 10 4周。结果 治疗一年后 72 7%病人 (2 85 / 392 )持续HBVDNA阴转。除外YMDD变异病人 ,病毒DNA在第二年持续受到抑制。YMDD变异病人血清HBVDNA的平均水平上升至 86Meq/ml (bDNA分析 ) ,但远低于治疗前水平。拉米夫定治疗可促进HBeAg消失和HBeAg/抗 HBe血清转换 ,二者均与治疗前ALT水平和治疗时间有关。第二年HBeAg消失率在治疗前ALT水平高于正常一倍的病人中为 2 6 8% ,在治疗前ALT水平高于正常二倍、五倍的病人中分别为 35 6%和 5 5 6%。HBeAg血清转换率分别为 17 4 % ,2 2 2 % ,33 3%。二年后 ,5 0 3%治疗前ALT异常的病人ALT保持正常。 83%治疗前ALT正常的病人仍保持正常。YMDD变异发生率为 4 9 7%。其血清HBVDNA中位数水平轻度升高至 86Meq/ml,其中 15 %病人ALT高于治疗前水平。 4例病人临床症状出现反复停药后恢复。拉米夫定的不良反?
