拉米夫定治疗HBeAg阳性慢性乙型肝炎患者7年结果总结

The 5-years long-term efficacy and 2-years follow-up of lamivudine treatment for HBeAg positive chronic hepatitis B

目的评估拉米夫定治疗乙型肝炎5年的长期疗效和安全性,以及对病毒变异发生率的影响。方法429例HBsAg,HBeAg阳性的慢性乙型肝炎患者,先按3∶1随机双盲分成拉米夫定组和安慰剂组,治疗共12周,以后所有患者均服拉米夫定100mg/d,共5年。结果服药治疗5年后,血清HBVDNA仍持续降低,在YMDD变异患者中则增高,中位值为107.5Meq/ml。HBeAg阴转率和HBeAg/抗HBe血清转换率分别为28.6%和27.5%。与治疗前ALT水平有显著关系。治疗前ALT基础值>2×ULN(正常值上限)和>5×ULN者,5年时HBeAg阴转率和血清转换率均为50%和67%。治疗前ALT增高的患者,5年治疗后,ALT的复常率为58%,治疗前ALT正常的患者,67.0%仍正常。1,2,3,4和5年的YMDD变异率分别为12.1%,49.7%,70.5%,67.0%和70.8%。发生变异后,HBVDNA大多仍可有一定程度抑制,在基线以下少部分可回升。在YMDD变异患者,继续有HBeAg阴转和血清转换,分别为18.4%和17.8%,低于非变异组患者。疗程中ALT增高>5×ULN有22例,其中变异者16例,非变异者6例,经处理后均缓解。在5年治疗期间,不良反应24.8%。结论长期应用拉米夫定可持久抑制HBV复制和促进血清转换,耐受性和安全性好,选择适合的患者,可取得最佳疗效。

Objective To evaluate the long-term efficacy and safety of 5-year lamivudine treatment chronic hepatitis B and the impact of emergence of YMDD mutation of hepatitis B virus （HBV）.Methods This multi-center, randomized, double-blind, placebo-controlled trial began from 1996. A total of 429 patients with serum HBsAg, HBeAg and HBV DNA positive were randomized to received either lamivudine 100 mg daily, qd, （ n = 322） or placebo （ n = 107） in a 3 ： 1 ratio for the first 12 wk. Thereafter, all patients were administrated with lamivudine 100 mg/ d for 5a. Results After 12 wk of lamivudine treatment, serum HBV DNA levels decreased rapidly ; at week 12 the negativity of HBV DNA （ 〈 1.6 pg/ml） was 92.2%, whereas it was only 14.1% （ P 〈 0.01 ） in the placebo group. After 1 year of lamivudine treatment, in 72.7 % of the patients serum HBV DNA was undetectable （ 〈 1.6 pg/ml ）. At the end of 5 years, serum HBV DNA continued to be substantially suppressed; the median level was below detectable level in non-YMDD variant patients and was increased to 107.5 Meq/ml in YMDD variant patients. At the end of 5 years, the HBeAg loss and the HBeAg/ anti-HBe seroconversion rates were 28.6 % and 27.5% . That was significantly correlated with baseline ALT levels, in patients with baseline ALT 〉 2xULN and ALT 〉 5xULN, the loss of HBeAg was 50% and seroconversion rate was 67 % , respectively （ P 〈 0.01 ）. At the end of year 5 years, ALT levels remained normal in 58% , patients whose baseline ALT were elevated, and sustained normal in 67% of the patients whose ALT were normal before treatment. YMDD mutations developed in 12.1%, 49.7%, 70.5 %, 67.0% and 70.8 % of the patients respectively at year 1, 2, 3, 4and 5. In YMDD mutant patients, HBV DNA levels were increased slightly or moderately and accompanied with mild to moderate elevations of ALT. HBeAg loss and seroconversion could be achieved in YMDD variant patients to 18.4% and 17.8 % at the end of year 5, but lower than that in non-variant patients （P 〈 0.01 ） . ALT flares （ALT 〉 5ULN） occurred in 22 patients, 16 with YMDD variants and 6 with non-variants, The adverse drug reactions or events were 24.8%, were generally mild to moderate, No deaths were reported in the 5 years treatment period. Conclusion Sustained HBV replication,clinical improvement and improve seroconversion could be obtained by 5-years long-term Lamivudine therapy with good toleranceland safety.