HEPATITIS-B-VIRUS RESISTANCE TO LAMIVUDINE GIVEN FOR RECURRENT INFECTION AFTER ORTHOTOPIC LIVER-TRANSPLANTATION

Background Orthotopic liver transplantation for end-stage hepatitis-B- virus (HBV) infection is commonly complicated by recurrence of HBV, La mivudine, a cytosine nucleoside analogue, has been shown to suppress H BV infection. We report the development of resistance to lamivudine in three patients who underwent transplantation for end-stage liver dise ase secondary to hepatitis B. Methods Two of the patients received lam ivudine for recurrent HBV infection after transplantation, whereas the third patient began treatment 1 month before transplantation in an at tempt to prevent HBV recurrence after transplantation. The three patie nts initially responded well to treatment, but viral recurrence occurr ed after 9-10 months of treatment in all patients. HBV DNA was amplifi ed from serum and sequenced through a conserved polymerase domain-the tyrosine, methionine, aspartate, aspartate (YMDD) locus. We assessed t he susceptibility of HBV to lamivudine by infecting primary human hepa tocytes with serum taken before the start of treatment and after recur rence in varying concentrations of lamivudine. Findings DNA sequencing showed a common mutation within the YMDD locus of the HBV polymerase gene in all during lamivudine treatment. In hepatocyte infected with p retreatment serum, HBV DNA concentrations were reduced to less than 6% of those in control cultures by addition of lamivudine in concentrati ons as low as 0.03 mu mol/L. By contrast, in cultures treated with ser um taken after recurrence, HBV DNA concentrations did not fall below 2 0% of control values, even with lamivudine at 30 mu mol/L. Interpretat ion Resistance to lamivudine has been reported in HIV patients with mu tations in the YMDD locus of the polymerase gene. Our findings indicat e a common mechanism of lamivudine resistance for HIV and HBV that inv olves similar point mutations in homologous domains of the viral polym erases.