OBJECTIVE: To evaluate the long-term efficacy and safety of 3-year lamivudine treatment for chronic hepatitis B and the impact of emergence of YMDD mutation of hepatitis B virus (HBV). METHODS: This multi-center, randomized, double-blind, placebo-controlled trial began in 1996. A total of 429 patients with serum HBsAg, HBeAg and HBV DNA positive were randomized to receive either lamivudine 100 mg daily (n = 322) or placebo (n = 107) in a 3:1 ratio for the first 12 weeks. Thereafter, all patients were offered open label lamivudine 100 mg/d for a total of 156 weeks. RESULTS: After 12 weeks of lamivudine treatment, serum HBV DNA levels decreased rapidly; at week 12 the negativity of HBV DNA (< 1.6 pg/ml) was 92.2%, whereas it was only 14.1% (P < 0.01) in the placebo group. After 1 year of lamivudine treatment, in 72.7% of the patients serum HBV DNA was undetectable (< 1.6 pg/ml). At the end of 3 years, serum HBV DNA continued to be substantially suppressed; the median level was below detectable level in non-YMDD variant patients and was increased to 10 pg/ml in YMDD variant patients. At the end of 1, 2 and 3 years, the HBeAg loss rates were 9.5%, 16.8% and 20.0% respectively; and the HBeAg/anti-HBe sero-conversion rates were 8.3%, 11.5% and 17.3% respectively. The rates of HBeAg loss and seroconversion correlated with baseline ALT levels, in patients with baseline ALT > 2ULN and ALT > 5ULN, the loss of HBeAg was 42.2% and 66.7%, sero-conversion rates were 34.4% and 61.1% respectively (P < 0.01) at the end of year 3. ALT levels at year 3 remained normal in 58.8%, and below baseline in 79.1% of the patients whose ALT were abnormal before treatment. YMDD mutations developed in 12.1%, 49.7% and 70.5% of the patients respectively at year 1, 2 and 3. HBV DNA levels were increased slightly or moderately and accompanied with elevation of ALT. HBeAgloss and sero-conversion could be achieved in YMDD variant patients to 20.0% and 15.1% at the end of year 3, but lower than that in non-variant patients (P < 0.01). The adverse drug reactions or events were generally mild to moderate, 2 patients were reported to have serious events related to the study medication. ALT flares (ALT > 5ULN) occurred in 17 patients, 10 with YMDD variants and 7 with non-variants, but all resolved. No deaths were reported in the 3 year treatment period. CONCLUSION: Sustained HBV replication and clinical improvement could be obtained by 3-year long-term Lamivudine therapy with good tolerance.
RCT Entities:
OBJECTIVE: To evaluate the long-term efficacy and safety of 3-year lamivudine treatment for chronic hepatitis B and the impact of emergence of YMDD mutation of hepatitis B virus (HBV). METHODS: This multi-center, randomized, double-blind, placebo-controlled trial began in 1996. A total of 429 patients with serum HBsAg, HBeAg and HBV DNA positive were randomized to receive either lamivudine 100 mg daily (n = 322) or placebo (n = 107) in a 3:1 ratio for the first 12 weeks. Thereafter, all patients were offered open label lamivudine 100 mg/d for a total of 156 weeks. RESULTS: After 12 weeks of lamivudine treatment, serum HBV DNA levels decreased rapidly; at week 12 the negativity of HBV DNA (< 1.6 pg/ml) was 92.2%, whereas it was only 14.1% (P < 0.01) in the placebo group. After 1 year of lamivudine treatment, in 72.7% of the patients serum HBV DNA was undetectable (< 1.6 pg/ml). At the end of 3 years, serum HBV DNA continued to be substantially suppressed; the median level was below detectable level in non-YMDD variant patients and was increased to 10 pg/ml in YMDD variant patients. At the end of 1, 2 and 3 years, the HBeAg loss rates were 9.5%, 16.8% and 20.0% respectively; and the HBeAg/anti-HBe sero-conversion rates were 8.3%, 11.5% and 17.3% respectively. The rates of HBeAg loss and seroconversion correlated with baseline ALT levels, in patients with baseline ALT > 2ULN and ALT > 5ULN, the loss of HBeAg was 42.2% and 66.7%, sero-conversion rates were 34.4% and 61.1% respectively (P < 0.01) at the end of year 3. ALT levels at year 3 remained normal in 58.8%, and below baseline in 79.1% of the patients whose ALT were abnormal before treatment. YMDD mutations developed in 12.1%, 49.7% and 70.5% of the patients respectively at year 1, 2 and 3. HBV DNA levels were increased slightly or moderately and accompanied with elevation of ALT. HBeAg loss and sero-conversion could be achieved in YMDD variant patients to 20.0% and 15.1% at the end of year 3, but lower than that in non-variant patients (P < 0.01). The adverse drug reactions or events were generally mild to moderate, 2 patients were reported to have serious events related to the study medication. ALT flares (ALT > 5ULN) occurred in 17 patients, 10 with YMDD variants and 7 with non-variants, but all resolved. No deaths were reported in the 3 year treatment period. CONCLUSION: Sustained HBV replication and clinical improvement could be obtained by 3-year long-term Lamivudine therapy with good tolerance.