Evolution of hepatitis B virus polymerase gene sequence during famciclovirtherapy for chronic hepatitis B

Prolonged administration of nucleoside analogues for chronic hepatitis B ma y result in the emergence of hepatitis B viral polymerase mutants. To gain insight into the mechanism involved in the virus's resistance to famciclovi r, the amino acid sequences of the terminal protein and reverse-transcripta se (RT) domains of the viral polymerase were determined during therapy amon g 28 patients. The antiviral response was independent of viral genotypes, a nd 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 w ell as 14 novel mutations in 7 patients. Clone sequence analysis of the RT domains of patients undergoing retreatment with famciclovir and/or lamivudi ne showed the selection of a preexisting drug-resistant mutant in one case and indicated that sequential antiviral therapy may allow the rapid selecti on of resistant strains.