拉米夫定治疗慢性乙型肝炎4年的长期疗效

Long-term efficacy of 4 years trial of lamivudine for chronic hepatitis B

目的 :评估拉米夫定治疗乙型肝炎 4a的长期疗效和安全性 ,以及对病毒变异的发生率的影响。方法 :42 9例HBsAg,HBeAg阳性的慢性乙型肝炎 (慢乙肝 )病人 ,先按 3∶1随机双盲分成拉米夫定组和安慰剂组 ,治疗共 1 2wk ,以后所有病人均服拉米夫定 1 0 0mg·d-1,共 4a。结果 :治疗 1 2wk ,拉米夫定组HBVDNA累计阴转率 (<1 .6ng·L-1)为 92 .2 % ,安慰剂组仅为 1 4.1 % (P <0 .0 1 )。服药 4a后 ,血清HBVDNA仍持续降低。 4a结束时 ,HBeAg阴转率和HBeAg/抗HBe血清转换率为2 7.4%和 2 6.7%。此与治疗前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 ,4a时HBeAg阴转率和血清转换率均为 5 0 %和 67%。治疗前ALT增高的病人 ,4a治疗后 ,ALT的复常率为 67.0 % ,治疗前ALT正常的病人 ,83 .6%仍正常。 1 ,2 ,3和 4a的YMDD变异率分别为 1 2 .1 % ,49.7% ,70 .5 %和67.0 %。发生变异后 ,HBVDNA大多仍抑制 ,在基线以下少部分可回升。在YMDD变异病人 ,继续有HBeAg阴转和血清转换 ,分别为 2 0 %和1 5 .5 % ,低于非变异组病人。疗程中ALT增高 >5×ULN有 2 2例 ,其中变异者 1 5例 ,非变异者 7例 ,经处理后均缓解。在 4a治疗期间 ,不良反应2 4.8%。结论

AIM: To evaluate the long-term efficacy and safety of lamivudine four years tre atment of ch ronic hepatitis B and the impact of emergence of YMDD mutation of hepatitis B vi rus (HBV). METHODS: This multi-center, double-blind, placebo, randomized, controlled tr ial began from 1996. A total 429 patients with serum HBsAg, HBeAg and HBV DNA po sitive were randomized to received either lamivudine 100 mg, qd, (n=322) or placebo (n=107) in a 3∶1 ratio for 12 wk at first. Thereafter, all patients were administrated with lamivudine 100 mg, qd for 4 a. RESULTS: After 12 wk lamivudine therapy, serum HBV DNA levels decreased rapidl y, at wk 12 the negativity of HBV DNA (<1.6 ng·L -1 ) was 92.2 %, whereas H B V DNA negativity was only 14.1 % in the placebo group. There was a statistically significant difference(P<0.01). After 1 a lamivudine treatment 72.7 % of pat i ents serum HBV DNA was undetectable(<1.6 ng·L -1 ). At the end of 4 a, seru m HBV DNA continued to be substantially suppressed; the median level was below d etectable level in patients with non-YMDD mutant HBV and was increased to 172.6 Eq·L -1 (bDNA method, equivalent hybridization method 20 ng·L -1 ), but stil l below baseline level in patients with YMDD mutant. At the end of 4 a, the HBeA g negativity and the HBeAg/anti-HBe sero-conversion rate was 27.4 % and 26.7 % . That was sig nificantly related with ALT level before treatment. In patients with baseline AL T>2×ULN and ALT>5×ULN, the negativity of HBeAg was 50 % and, sero-conversion rate was 67 %, respectively ( P<0.01) at the end of 4 a. ALT levels at a 4 remained norm al in 67.0 % patients whose baseline ALT were elevated, and sustained normal in 83.6 % patients whose ALT were normal before treatment. YMDD mutations developed in 12.1 %,49.7 %, 70.5 % and 67.0 % of patien ts respectively at a 1,2,3, and 4. In YMDD mut ant patients HBV DNA levels were increased slightly and accompanied with mild to moderate elevations of ALT. HBeAg loss and sero-conversion could be achieved i n p atients with YMDD mutant in 20 % and 15.5 % which was lower than that of non-mu tant patients (P<0.01). There were 22 patients with ALT>5×ULN. Among them 15 pa tients were patients with YMDD mutant, 7 patients with mon-YMDD mutant. The adv erse drug reactions or events were generally mild to moderate during the 4 a tre atment. There were 12 patients were reported to have serious adverse drug reacti ons. During four years there were no patients died. CONCLUSION: Long-term lamivudine therapy can constantly inhibit HBV replicca tion and improve sero-conversion with good tolerance and safety.