Evolution of full-length HBV sequences in chronic hepatitis B patients with sequential lamivudine and adefovir dipivoxil resistance

Background & Aims: The aim of this study was to determine the evolution of full-length hepatitis B virus (HBV) sequences in chronic hepatitis B (CHB) patients with sequential lamivudine (LAM) and adefovir (ADV) resistance. Methods: The full-length genomes of HBV were sequenced from 11 CHB patients before LAM treatment and at the emergence of LAM- and ADV-resistant HBV. Results: Besides the known LAM-resistant polymerase gene mutations, 10 of 11 patients who had LAM-resistant HBV variants had additional amino acid changes in the reverse transcriptase (RT) domain, and ADV therapy reversed these additional changes to pre-LAM therapy status. Furthermore, new amino acid changes in the RT domain, distinct from the known ADV-resistant HBV variants, were selected at the emergence of ADV resistance in six of 11 patients. Seven patients had amino acid changes within the known T-cell or B-cell epitopes of HBV surface and core antigens at the emergence of LAM and/or ADV resistance. The frequency of pre-S deletions between nucleotide 3037-56 was higher at the emergence of ADV resistance compared with that at the emergence of LAM resistance (7/11 vs. 1/11; p = 0.024). Combined LAM-ADV resistance was detected in one of 11 patients. This patient had resistant mutations to both drugs on the same viral genome by molecular cloning (5/24 polymerase gene clones). Conclusions: In addition to the known LAM- and ADV-resistant mutations accompanying the emergence of LAM and ADV resistance, the changes of nucleotide or amino acid sequences occurred commonly in the HBV surface antigen or RT domain and were scattered along the full-length HBV genomes.