国产阿德福韦酯片治疗拉米夫定失效HBeAg阳性慢性乙型肝炎患者的临床研究

目的评价国产阿德福韦酯片（ADV）10mg／d治疗拉米夫定（LAM）失效的HBeAg阳性慢性乙型肝炎患者的疗效和安全性。方法随机、有限的（12周）双盲、安慰剂对照、多中心临床研究。筛选合格的慢性乙型肝炎患者按照2：1的随机比例,分为ADV＋LAM→ADV组：ADV10mg／d联合LAM100mg／d,治疗12周后改为单用ADV10mg／d治疗36周,共41例;安慰剂＋LAM→ADV组：安慰剂10mg／d联合LAM100mg／d,治疗12周后,改为单用ADV10mg／d,治疗36周,共18例。结果12周双盲治疗结束时,ADV＋LAM→ADV组患者血清中HBV DNA水平与基线相比的平均下降量（2．69lg拷贝／ml）、HBV DNA〈5lg拷贝／ml的患者比例（92．7％）、与基线相比下降≥2lg拷贝／ml的患者比例（78．1％）明显高于安慰剂＋LAM→ADV组（1．06lg拷贝／ml、33．3％、27．8％）,P=0．00。两组患者继续治疗,病毒学、血清学和生化学应答均有进一步改善。两组的不良事件发生率及其种类差异无统计学意义。治疗48周内未发现rtN236T和rtA181V突变。结论ADV10mg／d具有明显抗LAM失效的HBV株复制作用,且随着治疗时间延长作用增强,其安全性与安慰剂相似。

A clinical study of adefovir dipivoxil in treating lamivudine refractory HBeAg-positive chronic hepatitis B

OBJECTIVE: To evaluate the efficacy and safety of adefovir dipivoxil (ADV) in treating patients with lamivudine (LAM) refractory HBeAg-positive chronic hepatitis B. METHODS: It is a randomized, double-blind, placebo-controlled, multicenter study. 226 eligible patients with HBeAg-positive chronic hepatitis B were randomized (randomization ratio was 2:1) into two groups. One group received ADV 10 mg/d and LAM 100 mg/d for 12 weeks and followed by ADV 10 mg/d for 36 weeks (ADV + LAM-->ADV group); the other received placebo and LAM 100 mg/d for 12 weeks and followed by ADV 10 mg/d for 36 weeks (placebo + LAM-->ADV group). The primary efficacy measure was virological response. The secondary efficacy measure was serological response (HBeAg loss rate and HBeAg seroconversion rate) and ALT normalization rate. RESULTS: After 12 weeks of therapy, mean reduction of HBV DNA level, the percentage of patients with HBV DNA lower than 5 l g copies/ml and the percentage of patients with HBV DNA level decrease of more than 2 l g copies/ml in patients of ADV + LAM-->ADV group were significantly higher than those in patients of placebo + LAM-->ADV group (2.69 lg copies/ml vs. 1.06 lg copies/ml, 92.7% vs. 33.3%, 78.1% vs. 27.8%), all the P values were 0.00. HBV DNA undetectable (<3l g copies/ml) rate and serological response (HBeAg loss rate and HBeAg seroconversion rate) in patients of ADV + LAM-->ADV group was slightly higher than those in patients of placebo + LAM-->ADV group (12.2% vs 5.6%, 5.1% vs 0, 4.9% vs 0), but did not reach statistical significance. Much more patients in both treatment arms achieved virological response, serological response and ALT normalization after another 36 weeks of therapy. The overall safety profile of ADV was similar to that of placebo. rtN236T and rtA181V mutation was not found in this 48-week study. CONCLUSION: ADV is an effective and well-tolerated treatment option for patients with LAM refractory HBeAg-positive chronic hepatitis B.