Evolution of Hepatitis B Virus Polymerase Gene Mutations in Hepatitis B E Antigen-Negative Patients Receiving Lamivudine Therapy

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Abstract
Lamivudine has been shown to be effective in patients with hepatitis B e antigen (HBeAg)–positive chronic hepatitis B, but its long–term efficacy and the rate of resistant mutations in patients with HBeAg–negative chronic hepatitis B is less clear. Twenty–nine patients with HBeAg–negative chronic hepatitis B, who have received lamivudine for at least 1 year were studied to determine the antiviral response, the rate and pattern of lamivudine–resistant mutations, and the effect of lamivudine–resistant mutations on HBeAg status. 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 detected by solution hybridization assay in 62%, 4%, and 24% and by polymerase chain reaction (PCR) assay in 100%, 31%, and 40% at months 0, 6, and 24, respectively. The cumulative rates of detection of lamivudine–resistant mutations after 1 and 2 years of treatment were 10% and 56%, respectively. In addition to the duration of treatment, core promoter mutation was associated with the selection of lamivudine–resistant mutants. Three patients with lamivudine–resistant mutations had reversion of the precore stop codon mutation; in 2 patients this was accompanied by the reappearance of HBeAg. We found that lamivudine–resistant mutants were detected at similar rates in patients with HBeAg–negative as in patients with HBeAg–positive chronic hepatitis B. Additional changes in other parts of the HBV genome may restore the replication fitness of lamivudine–resistant mutants.

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