OBJECTIVE 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. CONCLUSIONS The treatment with 10 mg ADV QD over 156 weeks was safe and effective in patients with HBeAg-positive CHB.