Combination prophylaxis with Hepatitis B immunoglobulin and lamivudine after liver transplantation minimizes HBV recurrence rates unless evolution of pretransplant lamivudine resistance.
BACKGROUND
Survival rates of hepatitis B patients after liver transplantation improved significantly by introduction of passive immunoprophylaxis. Due to viral escape mutations recurrence still occurs, but recently a combination prophylaxis with hepatitis B immunoglobuline plus lamivudine is evaluated in transplant centers in terms of a further reduction of recurrence rates.


METHODS
Between 1996 and 2000 a postoperative combination prophylaxis with HBIg and lamivudine was initiated in 44 HBsAg positive liver transplant recipients. In total 14 patients were HBV-DNA negative and 30 were HBV-DNA positive at the time of evaluation. In 22 HBV-DNA positive patients a pre-operative lamivudine treatment (150 mg/die) was started. Five of them developed pre-transplant lamivudine resistance with high viral replication (mean HBV-DNA prior to transplantation 728 +/- 219 pg/ml). In all patients passive immunoprophylaxis was started in the anhepatic phase with application of 10.000 units hepatitis B immunoglobuline. It was continued after seroconversion to HBsAg negativity with an aimed titer of more than 100 U/l and only stopped in case of HBV recurrence. Lamivudine was also continued indefinitely after liver transplantation.


RESULTS
Overall recurrence rate in the 44 patients, including retransplantations and patients with pretransplant lamivudine resistance, was 11.5 % under combination prophylaxis. Recurrence was seen only in one of 39 patients (2.6 %) without preoperative lamivudine resistance, in contrast 4 out of 5 patients (80 %) with pre-existing lamivudine resistance suffered from early hepatitis B recurrence. The single patient without preoperative lamivudine resistance, who developed recurrence was pre-transplant HBV-DNA negative without lamivudine treatment, but a postoperative seroconversion to negative HBsAg could not be achieved. The overall 3 year patient survival rate was 91 % in the study population. One patient, who was retransplanted with preoperative lamivudine resistance, died 4.5 months after retransplantation due to hepatitis B recurrence and sepsis, three other patients died for reasons not related to hepatitis B recurrence. Combination prophylaxis was well tolerated in all patients and no severe side effects were observed.


CONCLUSIONS
Combination prophylaxis with hepatitis B immunoglobulin and lamivudine is safe and highly effective in prevention of HBV recurrence after liver transplantation, even in case of positive viral replication. In accordance with the results of other centers it should therefore be the standard regimen. However it fails in the majority of patients with preoperative evolution of YMDD mutations, in which the optimal management has to be determined yet. To minimize preoperative resistance formation universal preoperative antiviral treatment of HBV-DNA positive patients should be replaced by individualized indication for preoperative treatment.
Seehofer
D
D
Department of General-, Visceral- and Transplant-Surgery, Charité Campus Virchow, Humboldt University of Berlin, Germany. daniel.seehofer@charite.de
Rayes
N
N
Steinmüller
T
T
Müller
A R
AR
Jonas
S
S
Settmacher
U
U
Neuhaus
R
R
Berg
T
T
Neuhaus
P
P
D000328:Adult; D004279:DNA, Viral / Q000097:blood; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005500:Follow-Up Studies; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000517:prevention & control / Q000601:surgery; D006801:Humans; D007136:Immunoglobulins / Q000008:administration & dosage* / Q000009:adverse effects; D019259:Lamivudine / Q000008:administration & dosage* / Q000009:adverse effects; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000517:prevention & control; D012008:Recurrence; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D014779:Virus Replication / Q000187:drug effects
D004279:DNA, Viral; D007136:Immunoglobulins; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; C045213:hepatitis B hyperimmune globulin