Selection of multiresistant hepatitis B virus during sequential nucleoside-analogue therapy

Hepatitis B virus (HBV) drug resistance to lamivudine is always accompanied by mutations in the viral polymerase gene at position 550, termed group 1 (M550V with L526M) or group 2 (M550I) mutations, The latter mutation has no t been associated with famciclovir resistance. Thus, the addition of famcic lovir to lamivudine therapy in persons with group 2 lamivudine resistance m ay lead to virus suppression, The effect of lamivudine/famciclovir combinat ion therapy on HBV infection was monitored in 5 lamivudine-resistant patien ts by quantitative polymerase chain reaction and polymerase gene sequencing of serum virus, No patients treated with combination therapy had a decline in HBV load >1 log(10). Continual evolution of the viral polymerase was de tected in association with virologic resistance to both drugs. Cloning expe riments identified the preexistence of these multidrug-resistant virus vari ants as minority species prior to addition of famciclovir therapy. HBV resi stance to lamivudine monotherapy is associated with a complex mixture of va riants that limit the efficacy of second-line nucleoside-analogue therapy, First-line potent combination therapy may reduce the emergence of HBV drug resistance.