抗乙型肝炎病毒新药研究进展__培训课件.ppt

* Points of explanation Viral variants with mutations in the gene encoding the HBV polymerase (YMDD variants) have been identified following lamivudine treatment. These variants are less sensitive to inhibition by lamivudine in vitro. YMDD variants are less replication competent compared with wild type HBV, most likely due to lower affinity of the viral polymerase for its nucleotide substrates. YMDD variants have been detected in few chronic hepatitis B patients during the first 6 months of lamivudine therapy (10/267 (4%) patients in the study by Lai, et al). The percentages represent the total of mixed wild type + YMDD variant and YMDD variant alone i.e. these percentages are not for YMDD only. The incidence of detectable YMDD variant HBV increases with duration of therapy. However, lamivudine therapy continues to benefit most patients even if YMDD variants emerge. Additional information Mutations associated with YMDD variants were introduced into the HBV genome by molecular cloning techniques. This altered DNA was then introduced into tissue culture cells, and the rate of virus production was measured. Mutations associated with YMDD variants were sufficient to confer resistance to lamivudine in vitro. However, this analysis also showed that YMDD variants do not replicate as effectively as wild type HBV in vitro (Melegari, et al). References Melegari M, Scaglioni PP, Wands JR. Hepatitis B mutants associated with 3TC and famciclovir administration are replication defective. Hepatology 1998;27:628-633. Allen MI, Deslauriers M, Andrews CW, et al. Identificationand characterisation of mutations in hepatitis B virus resistant to lamivudine. Hepatology 1998; 27;1670-1677. Lai CL, Liaw YF, Leung NWY, et al. Genotypic resistance to lamivudine in a prospective, placebo-controlled multicentre study in Asia of lamivudine therapy for chronic hepatitis B infection: incidence, kinetics of emergence, and correlation with disease parameters. Hepatology 1997;26(4 part 2);430A