Entecavir-Resistant.docVIP

Clinical Emergence of Entecavir-Resistant Hepatitis B Virus Requires Additional Substitutions in Virus Already Resistant to Lamivudine D. J. Tenney1,*S. M. Levine1, R. E. Rose1, A. W. Walsh1, S. P. Weinheimer1, L. Discotto1, M. Plym1, K. Pokornowski1, C. F. Yu1, P. Angus2, A. Ayres3, A. Bartholomeusz3, W. Sievert4, G. Thompson3, N. Warner3, S. Locarnini3 and R. J. Colonno1 + Author Affiliations 1Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 2ARMC, Heidelberg 4 Department of Medicine, Monash University, Monash Medical Centre, Melbourne 3Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia ? ABSTRACT Entecavir (ETV) exhibits potent antiviral activity in patients chronically infected with wild-type or lamivudine (3TC)-resistant (3TCr) hepatitis B virus (HBV). Among the patients treated in phase II ETV clinical trials, two patients for whom previous therapies had failed exhibited virologic breakthrough while on ETV. Isolates from these patients (arbitrarily designated patients A and B) were analyzed genotypically for emergent substitutions in HBV reverse transcriptase (RT) and phenotypically for reduced susceptibility in cultures and in HBV polymerase assays. After 54 weeks of 3TC therapy, patient A (AI463901-A) received 0.5 mg of ETV for 52 weeks followed by a combination of ETV and 100 mg of 3TC for 89 weeks. Viral rebound occurred at 133 weeks after ETV was started. The 3TCr RT substitutions rtV173L, rtL180M, and rtM204V were present at study entry, and the additional substitutions rtI169T and rtM250V emerged during ETV-3TC combination treatment. Reduced ETV susceptibility in vitro required the rtM250V substitution in addition to the 3TCr substitutions. For liver transplant patient B (AI463015-B), previous famciclovir, ganciclovir, foscarnet, and 3TC therapies had failed, and RT changes rtS78S/T, rtV173L, rtL180M, rtT184S, and rtM204V were present at study entry. Viral rebound occurred after