慢性乙型肝炎患者持续应用恩替卡韦治疗3年的疗效

Results of 3 years of continuous entecavir treatment in nucleos（t）ide-naive chronic hepatits B patients

目的研究恩替卡韦（ETV）治疗慢性乙型肝炎初治患者3年的病毒学、血清学和生物化学的应答情况，以评价其疗效。方法本研究分两个阶段：第一阶段为ETV和拉米夫定（LAM）的双肓随机对照试验，各有258例和261例人选，分别用ETV0．5mg／d或LAM100mg／d口服，共96周。第一阶段：经96同治疗，患者如未达到综合应答（bDNA〈0．7mEq／ml，HBeAg阴转持续24周以上，ALT〈1．25×正常值上限）者，或出现病毒学突破或停药后复发者，继续服用ETV1．0mg／d48周。共有160例患者完成了连续3年的ETV治疗。持续变量的比较采用了基于线性回归模型的t检验。结果第一阶段结束时（96周），ETV和LAM治疗组患者的HBV DNA阴转率（HBV DNA〈300拷贝／ml）、ALT复常率和HBeAg血清转换率分别为：79％对比46％（P〈0．01），96％对比91％（P=0．06）和21％对比23％。第一阶段：160例持续ETV治疗3年，第144周时，HBV DNA阴性（〈300拷贝／ml）的比例为89％，ALT复常率86％，3年的累计HBeAg血清转换率为27％。耐药性：3例在96周时出现了基因型耐药，另有2例在第96～144周时出现了基因型耐药。ETV的耐受性良好，不良反应与LAM相似，但ETV组较少出现ALT反弹。结论3年的临床试验表明ETV是强效的抗HBV药物，其抑制HBV复制和低耐药性明显优于LAM。

Objective To evaluate the virological, serological and biochemical outcomes of 3 years of entecavir （ETV） treatment in nucleoside-naive chronic hepatitis B patients. Methods This study was divided into two stages： Patients receiving either ETV 0.5 mg/d （n = 258） or lamivudine （LAM） 100 mg/d （n = 261 ） entered the initial 96-week randomized, double blind, controlled efficacy study. Patients not achieving a consolidated response （HBV DNA 〈 0.7 MEq/ml, ALT 〈 1.25 times × ULN, and if HBeAg-positive at baseline, loss of HBeAg for ≥ 24weeks）, or those experienced viral breakthrough or relapse, entered a 48- week entecavir rollover study. Results 96 weeks after the treatment, 79% of ETV treated and 46% of LAM treated patients had HBV DNA 〈 300 copies/ml （P 〈 0.0001）, 96% of ETV treated and 92% of LAM treated patients had normalized ALT （P = 0.06）. 21% of ETV treated and 23% of LAM treated patients achieved HBeAg seroconversion. Among the 160 patients received continuous ETV for 144 weeks, 89% had undetectable serum HBV DNA, 86% showed ALT normalization, and 27% achieved HBeAg seroconversion. ETV resistance was rare： only 3 patients showed ETV resistance 96 weeks after the treatment, and additional 2 patients developed ETV resistance during the following 48 weeks, genotyping indicated the ETV resistance was caused by gene mutation. Adverse event rates in ETV-treated patients were similar to those in LAM- treated patients, but fewer ALT flares were observed in ETV-treated patients. Conclusions This study demonstrates that ETV treatment results in long-term HBV suppression and ALT normalization in Chinese CHB patients, and is associated with low rate of drug resistance.