Evolution of hepatitis B virus polymerase gene mutations in hepatitis B e antigen-negative patients receiving lamivudine therapy

Lamivudine has been shown to be effective in patients with hepatitis B e an tigen (HBeAg)-positive chronic hepatitis B, but its long-term efficacy and the rate of resistant mutations in patients with HBeAg-negative chronic hep atitis B is less clear. Twenty-nine patients with HBeAg-negative chronic he patitis B, who have received lamivudine for at least 1 year were studied to determine the antiviral response, the rate and pattern of lamivudine-resis tant mutations, and the effect of lamivudine-resistant mutations on HBeAg s tatus. The mean duration of treatment was 21 +/- 7 months. Before treatment , core promoter Variant was detected in 16 (55%) patients and precore stop codon variant in 18 (62%) patients. Serum hepatitis B virus (HBV) DNA was d etected by solution hybridization assay in 62%, 4%, and 24% and by polymera se chain reaction (PCR) assay in 100%, 31%, and 40% at months 0, 6, and 24, respectively. The cumulative rates of detection of lamivudine-resistant mu tations after 1 and 2 years of treatment were 10% and 56%, respectively. In addition to the duration of treatment, core promoter mutation was associat ed with the selection of lamivudine-resistant mutants. Three patients with lamivudine-resistant mutations had reversion of the precore stop codon muta tion; in 2 patients this was accompanied by the reappearance of HBeAg. We f ound that lamivudine-resistant mutants were detected at similar rates in pa tients with HBeAg-negative as in patients with HBeAg-positive chronic hepat itis B. Additional changes in other parts of the HBV genome may restore the replication fitness of lamivudine-resistant mutants.