Antiviral Resistance and Hepatitis B Therapy Marc G. Ghany1 and Edward C. Doo2 The management of chronic hepatitis B currently rests with long-term therapy using oral nucleoside analogs. The major limitation of long-term therapy is antiviral resistance. Antiviral resistance is due to the high rate of mutations that can occur during hepatitis B virus (HBV) replication and the selection of these mutants due to a replication advantage in the presence of the antiviral agent. Indeed, high rates of antiviral resistance have been found with long-term use of lamivudine, in up to 76% of patients treated for 5 years or more. Rates of antiviral resistance are lower with adefovir therapy, ⬃30% at 5 years. Newer more potent nucleoside analogs (tenofovir and entecavir) have proven to have much lower rates of antiviral resistance (