Mutational pattern of hepatitis B virus on sequential therapy with famciclovir and lamivudine in patients with hepatitis B virus reinfection occurring under HBIg immunoglobulin after liver transplantation

Famciclovir (FCV) and lamivudine (LAM) reduce viral replication in patients with recurrent hepatitis B virus (HBV) infection after orthotopic liver tr ansplantation (OLT). Eighteen of 20 patients with insufficient response to FCV were treated with 100 mg LAM daily after OLT. These patients had shown nonresponse (n = 5), partial response (n = 7), or breakthrough (n = 6) duri ng FCV therapy. Despite passive immunoprophylaxis with hepatitis B immunogl obulin after liver transplantation, HBV reinfection had occurred in 14 of 1 5 transplanted patients. HBV-DNA levels and the regions A to E of the HBV-D NA polymerase gene were analyzed before and after treatment failure to eith er therapy. Within 4 weeks on LAM, all but 1 patient showed a 95% average r eduction of the HBV-DNA level. As with FCV, we did not observe any severe s ide-effects attributable to LAM, However, 7 patients developed a breakthrou gh within 12, 29 (n = 2), 32, 37, 54, and 145 weeks under treatment with LA M associated with the methionine-to-valine signature mutation (M552V) in th e YMDD motif in all. With FCV, no unique, but a dominant, resistance patter n with the L528M mutation was identified for patients with breakthrough und er FCV. In contrast, nonresponders or patients with partial response to FCV did not exhibit such mutations. Our results indicate that the L528M mutati on is a risk factor for LAM breakthrough, because breakthrough during LAM o ccurred earlier in patients with this mutation (50 +/- 10 weeks vs. 120 +/- 21 weeks). Because breakthrough on either treatment is frequent for this s pecific group of patients, the use of combination therapy should be explore d.