Short-term lamivudine therapy in patients with chronic hepatitis B

Lamivudine is a nucleoside analogue with potent inhibitory effects on hepatitis B virus (HBV) polymerase/reverse transcriptase activity. The rate of hepatitis B e antigen (HBeAg) seroconversion in a large series of Asian patients treated with lamivudine 100 mg daily for 1 year was only 16% and the incidence of YMDD mutants was 14%. Further analysis of this Asian trial has shown that patients with a pretreatment alanine aminotransferase (ALT) level higher than 5-fold the upper limit of normal (ULN) have a much higher HBeAg seroconversion rate as compared with patients with a pretreatment ALT level <2 x upper limit of normal (64 vs. 5%; p < 0.001). In order to avoid the development of YMDD mutants, we selected 186 patients with acute exacerbation for treatment with lamivudine during 9 months, if possible, and not more than 15 months. They were all seropositive for both hepatitis B surface antigen and HBeAg for more than 6 months and also had serum HBV DNA; 138 (74%) of them were male. HBV genotypes were A in 2 (1%), B in 115 (62%), C in 65 (35%), D in 2 (1%) and F in the remaining 2 (1%). Four patients (2%) had liver cirrhosis. They had mean pretreatment levels of ALT at 608 IU/l (range: 184-2,400 IU/l), total bilirubin at 1.5 mg/dl (0.3-14.8 mg/dl), and HBV DNA at 2,246 pg/ml (0.5-25,903 pg/ml). After a median of 8.2 months (3-15 months) on lamivudine, 96 patients (51%) achieved HBeAg seroconversion, while the other 90 (48%) patients did not. Genotype B was detected comparably frequently in seroconverters and nonconverters (63 vs. 61%). During 1-year follow-up after withdrawal of lamivudine, 56 (58%) of the 96 seroconverters experienced flare-ups with ALT levels elevated higher than 5 x ULN in 50 (89%). Of 90 patients who remained HBeAg-positive, in contrast, 80 (86%) experienced ALT flares (with ALT >5 x ULN in 84%) within 1 year. YMDD mutants did not develop in any of these 186 patients during the course of lamivudine therapy. In conclusion, short-term lamivudine therapy in patients with chronic active hepatitis B can reduce the incidence of YMDD mutants and achieve an acceptable HBeAg seroconversion rate. However, the relapse rate was high (60% during 1-year follow-up). Further study is needed to establish how to improve a sustained HBeAg response.