MUTATION IN HBV RNA-DEPENDENT DNA-POLYMERASE CONFERS RESISTANCE TO LAMIVUDINE IN-VIVO

The (-) enantiomer of 3'-thiacytidine (lamivudine) has been found to b e a potent inhibitor of hepatitis B virus (HBV) and human immunodefici ency virus (HIV) replication, Mutation of methionine to valine or isol eucine at the YMDD (tyrosine, methionine, aspartate, aspartate) motif of the HIV reverse transcriptase has been shown to be responsible for lamivudine resistance in HIV, The hepadnaviruses also have the YMDD mo tif in their DNA polymerase, Therefore, it is possible that hepadnavir uses could develop lamivudine resistance by a similar mutation at this motif. We analyzed the HBV from a liver transplantation patient who d eveloped recurrent HBV viremia during lamivudine treatment, The polyme rase gene was amplified by polymerase chain reaction (PCR), and the re gion coding for the YMDD motif was sequenced, The pretreatment HBV seq uence coded for YMDD, while the lamivudine-resistant mutant HBV coded for YIDD (tyrosine, isoleucine, aspartate, aspartate). With the docume nted changes in the YMDD motif of lamivudine-resistant HIV, it is like ly that the methionine-to-isoleucine mutation in the YMDD motif of the HBV polymerase contributes significantly to the lamivudine-resistance of HBV isolated from this patient.