Entecavir is an epoxy hydroxycarbon deoxyguanosine, the triphosphate structural form of entecavir mainly through inhibition of viral polymerase guidance, reverse transcription from the pre-genome to the negative strand, and positive DNA strand synthesis. Entecavir inhibits the replication of lamivudine-resistant strains, but its antiviral activity is reduced. In vitro experiments showed that lamivudine-resistant strains were less susceptible to entecavir than wild strains, and the hepatitis B virus variants were rt184, rt202, and rt250, possibly by limiting the binding of entecavir to hepatitis B virus polymorphic enzymes, leading to the development of drug resistance. The antiviral activity of entecavir against different mutant strains was reduced to different degrees, and the M204I mutant required higher entecavir concentration (about 30-fold). The results of the phase III clinical study showed that increasing the entecavir dose to lmg daily was effective in inhibiting hepatitis B virus DNA replication in patients with the YMDD variant. The incidence of resistance to entecavir was 0 at 1 year of treatment in primary patients, but 5.8% at 1 year of treatment in patients with established YMDD variants, and the entecavir-resistant phenotype was observed only in patients infected with lamivudine-resistant variants.