国产阿德福韦酯片治疗HBeAg阳性慢性乙型肝炎的双盲、随机、多中心临床研究

A randomized,double-blind,multicenter study of adefovir dipivoxii in treating patients with HBeAg-positive chronic hepatitis B

目的评价国产阿德福韦酯片(ADV,孚玮)治疗慢性乙型病毒性肝炎(慢乙肝)48周的疗效和安全性。方法采用随机、双盲(24周)、安慰剂对照、多中心临床研究。筛选合格的HBeAg阳性的慢乙肝患者210例,2:1比例,按计算机随机化表随机分为试验组(ADV 10 mg/d,治疗48周,共142例)和对照组(安慰剂10 mg/d,24周,后改用ADV 10mg/d,治疗24周,共68例)。1～24周为双盲、安慰剂对照研究期,24周后为开放研究期。主要疗效评价指标为双盲治疗结束和48周时的病毒学应答。次要疗效评价指标为HBV血清学和生化学应答。结果24周双盲期治疗结束时,试验组患者血清中HBV DNA与基线值相比平均下降量、HBV DNA阴转率(<3 log_(10)拷贝/mL)、HBV DNA抑制率(<5 log_(10)拷贝/mL )、与基线值相比下降≥2 log_(10)拷贝/mL的患者比分别为3.1 2 log_(10)拷贝/mL、26.1%、90.8%、85.9%,明显高于对照组的0.95log_(10)拷贝/mL、1.5%、29.4%、19.1 (P值均为0.000);ALT复常率也明显较高(54.2%比5.9%,P=0.000);但试验组患者的HBeAg阴转率、HBeAg血清转换率(12.9%,7.0%)仅稍高于对照组(5.9%,4.4%),差异无统计学意义(P=0.1 25、0.459)。双盲期(24周)结束后,两组均用ADV治疗至48周,两组患者的病毒学、HBV血清学和生化学应答均有进一步提高。48周研究过程中用测序方法未发现rtN236T和(或)rtAl81V突变。两组患者总的不良事件发生率、与药物相关的不良事件发生率和不良事件种类方面差异均无统计学意义。结论国产ADV 10 mg/d具有明显的随治疗时间延长而增强的抗HBV复制和改善肝功能的作用,可有效治疗HBeAg阳性慢乙肝,其安全性与安慰剂相似。

Objective To evaluate the efficacy and safety of adefovir dipivoxil （ADV） in treating patients with hepatitis B e antigen （HBeAg） positive chronic hepatitis B. Methods In this randomized, double-blind, placebo-controlled, multicenter trial, 210 eligible patients with HBeAg positive chronic hepatitis B were recruited and randomized （randomization ratio was 2 ： 1） receiving ADV 10 mg/d for 48 weeks（ADV＋ABV group, n = 142） or placebo for 24 weeks followed by ADV 10 mg/d for 24 weeks （PLB＋ADV group, n = 68）. The primary endpoint was virological response. The secondary endpoint was serologic response （HBeAg loss rate and HBeAg seroconversion rate） and alanine aminotransferase normalization rate. Results After 24 weeks therapy, mean reduction of hepatitis B virus （HBV） DNA level comparing with that of baseline was 3.12 log10 copy/mL in ADV ＋ADV group while it was 0.95 log10 copy/mL in PLB＋ ADV group. The percentages of patients with HBV DNA clearance （HBV DNA level 〈3 log10 copy/mL）, HBV DNA inhibition （HBV DNA level 〈5 log10 copy/mL） and HBV DNA decrease （the reduction ≥ 2 log10 copy/mL comparing with the baseline） in ADV ＋ADV group were significantly higher than those in PLB ＋ADV group （26.1%, 90.8%, 85.9%vs 1.5%, 29.4%, 19.1%, respectively, P= 0.000）. Thealanine amin otransferase normalization rate in ADV ＋ ADV group was significantly greater than that in PLB ＋ ADV group （54.2% vs 5. 9%, P = 0. 000）. HBeAg loss rate and HBeAg seroconversion rate in ADV＋ADV group were slightly higher than those in PLB＋ADV group （12.9% and 7.0% vs 5.9% and 4.4 %, respectively）, but the differences were not statistically significant. In both groups, more patients achieved virological response, serologic response and alanine aminotransferase normalization after continuous 24 weeks therapy. The overall safety profile of ADV was similar to that of placebo. rtN236T and （or） rtA181V mutations were not detected during 48 weeks therapy. Conclusions ADV is an effective and well-tolerated treatment for patients with HBeAg positive chronic hepatitis B.