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Novel patterns of amino acid mutations in the hepatitis B virus polymerase in association with resistance to lamivudine therapy in Japanese patients with chronic hepatitis B
Author(s) -
Ogata Norio,
Fujii Kyuichi,
Takigawa Shingo,
Nomoto Minoru,
Ichida Takafumi,
Asakura Hitoshi
Publication year - 1999
Publication title -
journal of medical virology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.782
H-Index - 121
eISSN - 1096-9071
pISSN - 0146-6615
DOI - 10.1002/(sici)1096-9071(199911)59:3<270::aid-jmv2>3.0.co;2-1
Subject(s) - lamivudine , virology , valine , hepatitis b virus , polymerase , biology , isoleucine , genotype , virus , methionine , leucine , reverse transcriptase , hepadnaviridae , hepatitis b virus dna polymerase , polymerase chain reaction , microbiology and biotechnology , amino acid , gene , genetics
Lamivudine is effective in suppressing replication of hepatitis B virus (HBV). However, the emergence of HBV variants resistant to lamivudine is a concern. Lamivudine resistance has been attributed mainly to a substitution of isoleucine or valine for methionine at residue 550 (M550I or M550V) in the catalytic site of the virus polymerase. A substitution of methionine for leucine at residue 526 (L526M) has also been identified. To examine such virus genotypic mutations in Japanese patients, we studied five patients with chronic hepatitis B, who showed HBV breakthrough while on a 1‐year lamivudine treatment. The entire nucleotide and deduced amino acid sequences of the proposed reverse transcriptase domain of the polymerase gene were determined on HBV DNA amplified by polymerase chain reaction from patient sera collected at the start and at the end of therapy. The HBV sequences from all five patients were of genotype C. In four patients, a substitution of valine or isoleucine for leucine at residue 426, which has not been reported previously, emerged in combination with M550I. One also harbored L526M. In the remaining patient, an alteration of leucine to methionine at residue 428 co‐occurred with M550V. Longitudinal study of the mutations showed that the two or three mutations in each patient emerged almost simultaneously 4 weeks before or at the time of breakthrough and were replaced by wild‐type virus after completing the therapy. Our results indicate that occurrence of HBV polymerase mutations at residue 426 in combination with M550I is frequent in Japanese or genotype C virus‐in‐ fected patients who develop resistance to lamivudine. J. Med. Virol. 59:270–276, 1999. © 1999 Wiley‐Liss, Inc.