Evolution of hepatitis B virus polymerase gene sequence during famciclovir therapy for chronic hepatitis B.

B Seignères, C Pichoud, S S Ahmed, O Hantz, C Trépo, F Zoulim

Journal: The Journal of infectious diseases 2000;181(4):1221-33

PMID: 10762559

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Abstract

Prolonged administration of nucleoside analogues for chronic hepatitis B may result in the emergence of hepatitis B viral polymerase mutants. To gain insight into the mechanism involved in the virus's resistance to famciclovir, the amino acid sequences of the terminal protein and reverse-transcriptase (RT) domains of the viral polymerase were determined during therapy among 28 patients. The antiviral response was independent of viral genotypes, and nonresponse to famciclovir was associated with a complex variability of the RT domain. No mutation in the YMDD motif was observed, whereas an L528M mutation was clearly selected by famciclovir treatment in 2 patients, as well as 14 novel mutations in 7 patients. Clone sequence analysis of the RT domains of patients undergoing retreatment with famciclovir and/or lamivudine showed the selection of a preexisting drug-resistant mutant in one case and indicated that sequential antiviral therapy may allow the rapid selection of resistant strains.

Address: Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 271, Lyon, France.

DOI: 10.1086/315368

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MeSH Terms: 2-Aminopurine, Adult, Amino Acid Sequence, Antiviral Agents, Cloning, Molecular, Drug Resistance, Microbial, Evolution, Molecular, Famciclovir, Female, Gene Products, pol, Hepatitis B e Antigens, Hepatitis B virus, Hepatitis B, Chronic, Humans, Longitudinal Studies, Male, Middle Aged, Molecular Sequence Data, RNA-Directed DNA Polymerase, Sequence Alignment