The combination of nucleos(t)ide analogues (NAs) and hepatitis B immune globulin has been established as safe and effective prophylaxis against hepatitis B virus (HBV) reactivation after liver transplantation (LT). However, the essential weak point of this regimen is its high cost. The hepatitis B (HB) vaccine is an attractive alternative that costs less, and it enables some patients to have sufficiently high hepatitis B surface antibody (HBsAb) titers. Almost no data exist on whether NAs can be stopped safely in such successfully vaccinated patients. We investigated the incidence of HB vaccine escape mutants in liver recipients who had sufficient HBsAb titers after LT and stopped NAs. Among 18 HBV carriers and 7 non-HBV patients who received grafts from hepatitis B core antibody-positive donors, 2 HBV carriers and 6 non-HBV patients who achieved HBsAb titers >100 IU/L for >3 months after posttransplant vaccination were weaned from NAs. For the patients who showed viremia, we analyzed amino acid sequences of the HB envelope protein, and we performed a statistical analysis for the factors associated with viremia. In 4 of the 8 patients who achieved sufficient HBsAb levels after vaccination and stopped NAs, HBV DNA appeared after a median of 12 months. A sequence analysis showed various amino acid mutations, including the a-determinant, in the HB envelope region. Frequent vaccination was shown to be a statistically significant risk factor for inducing viremia. In conclusion, although the HB vaccine is an effective substitute for prophylaxis against HBV reactivation in some patients after LT, frequent vaccination could be a risk factor for producing escape mutants. Our data demonstrate not only that caution must be exercised in stopping NAs in effectively vaccinated patients (especially in patients vaccinated frequently) but also that it is important to set stopping rules for vaccination in transplant patients.
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