Evolution of hepatitis B virus polymerase gene sequence during famciclovir therapy for chronic hepatitis B.
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.
Seignères
B
B
Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 271, Lyon, France.
Pichoud
C
C
Ahmed
S S
SS
Hantz
O
O
Trépo
C
C
Zoulim
F
F
D015075:2-Aminopurine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000328:Adult; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000627:therapeutic use*; D003001:Cloning, Molecular; D004352:Drug Resistance, Microbial / Q000235:genetics; D019143:Evolution, Molecular; D000077595:Famciclovir; D005260:Female; D015684:Gene Products, pol / Q000737:chemistry / Q000235:genetics*; D006513:Hepatitis B e Antigens / Q000032:analysis; D006515:Hepatitis B virus / Q000201:enzymology*; D019694:Hepatitis B, Chronic / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D012194:RNA-Directed DNA Polymerase / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment
D000998:Antiviral Agents; D015684:Gene Products, pol; D006513:Hepatitis B e Antigens; C066027:P protein, Hepatitis B virus; D015075:2-Aminopurine; D012194:RNA-Directed DNA Polymerase; D000077595:Famciclovir