阿德福韦治疗乙型肝炎e抗原阳性慢性乙型肝炎3年的临床研究

目的评价阿德福韦酯（ADV）10 mg／d治疗HBeAg阳性的慢性乙型肝炎患者52、104、156周末的临床疗效和安全性。方法第一阶段：为随机、双盲、安慰剂对照研究,患者按3：1的比例随机接受ADV 10 mg（36例）或安慰剂（12例）治疗,每日1次,持续12周。第二阶段：患者均接受开放的ADV 10mg治疗,每日1次,持续28周。第三阶段：完成40周的治疗后,最初接受ADV治疗的患者重新按2：1的比例随机分入ADV组（24例）或安慰剂组（12例）接受相应的治疗,持续12周。即分为A、B、C 3组,A组：12例,前12周为安慰剂治疗,后40周为ADV治疗;B组：24例,52周均为ADV治疗;C组：12例,前40周为ADV治疗,后12周为安慰剂治疗。第四阶段：所有仍在研究中的患者继续接受开放的ADV 10 mg治疗共208周（4年）。结果（1）治疗12周后,HBV DNA水平降低,安慰剂组为-0．2 log10拷贝／ml,ADV组为-3．7 log10拷贝／ml,差异有统计学意义（t=8．0,P〈0．01）。（2）治疗12周后,ALT复常率,安慰剂组为0（0／11）,ADV组为10／36（27．8％）,差异有统计学意义（χ^2=3．9,P〈0．05）。（3）治疗40周后,3个治疗组ALT复常率相似。在B组,ALT复常率呈累积性增加。而在C组,ALT复常率显著降低。（4）治疗40周后,3个治疗组HBV DNA水平对数值降低中位数相似。40周后继续12周ADV治疗可以保持HBV DNA水平持续降低至52周。而在C组,HBV DNA水平降低被显著逆转。（5）治疗40周后,3个治疗组HBV DNA转阴率相似。在C组,52周时HBV DNA转阴率显著降低。（6）对于B组,HBeAg消失患者在52周时为12．5％（3／24）。两因素（血清HBeAg转阴,血清抗-HBe转阳）和三因素（血清HBeAg转阴,血清抗-HBe转阳且HBV DNA水平下降到≤10^5拷贝／ml）血清转换比率均为8．3％（2／24）。（7）治疗104周末及156周末,HBV DNA被持续抑制,104周HBV DNA水平对数值降低中位数为-4．2 log10拷贝／ml,156周为-4．3 log10拷贝／ml。HBV DNA阴转率均为31．0％,ALT复常率分别为46．3％、85．4％,HBeAg阴转率分别为23．8％、31．0％,HBeAg血清转换率均为23．8％。（8）研究期间各治疗组肌酐及血磷值平均水平与基线相比无变化,无数据表明肾脏安全性问题。结论ADV 10 mg／d治疗HBeAg阳性慢性乙型肝炎,可明显抑制HBV DNA的复制,使ALT复常,促进HBeAg的血清学转换,使用安全且耐受性良好。

Three year adefovir dipivoxil treatment for hepatitis B e antigen-positive chronic hepatitis B patients

OBJECTIVES: To evaluate the efficacy and safety of adefovir dipivoxil (ADV) treatment in patients with hepatitis B e antigen (HBeAg) positive chronic hepatitis B (CHB). METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study. It was performed in four steps. First step: subjects were randomly assigned to receive either ADV 10 mg once daily (QD) or matching placebo tablets in a 3:1 ratio for 12 weeks. Second step: at week 12, all subjects started to have open-label ADV 10 mg QD for 28 weeks. Third step: subjects who received ADV in the first 12 weeks were rerandomized to receive either ADV or a placebo in a 2:1 ratio for 12 weeks and subjects who initially received a placebo continued to receive open-label ADV, but they were further assigned into 3 groups: A, B and C. In group A (12 patients), they received a placebo for the first 12 weeks and then ADV for the following 40 weeks. In group B (24 patients), they received ADV for the entire 52 weeks. In group C (12 patients), they received ADV in the first 40 weeks and a placebo in the last 12 weeks. Fourth step: all subjects restarted open-label ADV 10 mg QD for 208 weeks. RESULTS: (1) At week 12, the median decrease in serum HBV DNA levels was 3.7 log10 copies/ml in the ADV group and 0.2 log10 copies/ml in the placebo group (P < 0.01). (2) At week 12, serum ALT normalization was observed in 10 of the 36 subjects (27.8%) in the ADV group and 0 of the 11 subjects (0%) in the placebo group (P < 0.05). (3) In group B the proportion of subjects with serum ALT normalization increased to 66.7% at week 52. As for virological parameters in those subjects rerandomized to a placebo for weeks 40-52 (group C), biochemical benefit was rapidly lost (ALT normalization dropped from 50.0% to 25.0%). (4) At week 40, the median reduction in serum HBV DNA was similar across all treatment groups. In subjects rerandomized to ADV (group A and B), there were further reductions in serum HBV DNA from -3.2 to -3.6 and from -4.4 to -4.6 log10 copies/ml, respectively at week 52. In contrast in subjects rerandomized to a placebo during weeks 40-52 (group C), the median reduction in serum HBV DNA decreased from -3.7 to -0.7 log10 copies/ml at week 52. (5) In week 40, the proportion with undetectable HBV DNA (< 300 copies/ml) was similar in these three groups, while at week 52, the proportion with undetectable HBV DNA (< 300 copies/ml) in group C was 0%. (6) At week 52, the proportion with HBeAg loss in group B was 12.5% (3/24). The ratios of HBeAg seroconversion and HBeAg seroconversion with HBV DNA < or = 10(5) copies/ml were both 8.3%. (7) At week 104, the median reduction in serum HBV DNA was -4.2 log10 copies/ml, which was -4.3 log10 copies/ml at week 156. The proportion with undetectable HBV DNA (< 300 copies/ml) was both 31.0% at week 104 and week 156. The proportion of subjects with serum ALT normalization was 46.3% at week 104, which was 86.4% at week 156. The proportion with HBeAg loss was 23.8% at week 104, which was 31.0% at week 156. The proportion with HBeAg seroconversion was 23.8%. (8) No renal toxic effects were observed. CONCLUSION: The treatment with 10 mg ADV QD over 156 weeks was safe and effective in patients with HBeAg-positive CHB.