Emergence of YMDD motif mutants of hepatitis B virus during lamivudine treatment of immunocompetent type B hepatitis patients

Lamivudine is an effective antiviral agent for the treatment of chronic typ e B hepatitis. Recent studies have shown the appearance of lamivudine resis tant viruses with mutations at the tyrosine-methionine-aspartate-aspartate (YMDD) motif of the viral polymerase in hepatitis B virus (HBV) infected pa tients who received orthotopic liver transplantation. In order to confirm t he appearance of such mutant HBV in immunocompetent patients, the HBV seque nces in and around the YMDD motif of HBV DNA polymerase were examined in th e sera from 16 lamivudine treated and 10 untreated control patients. Approx imately 200 bases including the YMDD motif of HBV DNA polymerase were ampli fied by polymerase chain reaction (PCR) and sequenced directly by an automa ted sequencer. Of the 16 patients receiving lamivudine, mutant viruses with mutations in the YMDD motif were found in 3 of 8 patients treated with lam ivudine for 52 weeks. However, this mutation was not found in any of the 8 patients treated for 32 weeks or a shorter period. Mutant viruses appeared after 40 weeks of treatment and were undetectable within 12 weeks after the cessation of the treatment. Such mutant viruses were not detected in any o f the 10 untreated patients. This study confirms the emergence of YMDD muta nt viruses during long-term lamivudine treatment in immunocompetent type B hepatitis patients. The results from this study suggest the need for combin ation therapies to reduce the levels of such mutant viruses in some patient s. J. Med. Virol. 60:8-76, 2000. (C) 2000 Wiley-Liss, Inc.