Recurrence of Hepatitis B Infection in Liver Transplant Patients Receiving Long-Term Hepatitis B Immunoglobulin Prophylaxis

Abstract

BACKGROUND Long-term real-world data are relatively sparse regarding recurrence of chronic hepatitis B virus (HBV) infection after liver transplantation using hepatitis B immunoglobulin (HBIg) and nucleos(t)ide analogue (NUC) prophylaxis. MATERIAL AND METHODS Data from 371 adults transplanted for HBV-related disease at 20 European centers and given HBIg for ³12 months ± NUC therapy were analyzed retrospectively. RESULTS HBIg comprised Hepatect® (iv HBIgB; n=299), subcutaneous Zutectra® (sc HBIg, n=236), and other HBIg preparations (n=130); 93.5% received NUC therapy. Mean follow-up was 6.8±3.5 years. The primary efficacy variable, freedom from HBV recurrence, occurred in 95.7% of patients (95% CI [93.1%, 97.5%]). The observed incidence of recurrence was 16/371 (4.3%) (annual rate 0.65%); 5/16 patients with recurrence had discontinued HBIg and 7/16 had anti-HBs <100 IU/l. Excluding these 7 patients, the HBV recurrence rate was 2.4%. The recurrence rate while on HBIg therapy was 1 per 2069 months. In patients who discontinued HBIg, risk of HBV recurrence versus sc HBIg users was increased by 5.2-fold (1 per 1 603 versus 1 per 8379 treatment months). The annual rate of HBV-related hepatocellular carcinoma (HCC) recurrence was 1.7%. CONCLUSIONS These results support the long-term use of HBIg with NUC therapy as an effective management strategy to minimize risk of HBV recurrence and virus-related complications after liver transplantation.

Conflict of interest statement

Disclosures

Susanne Beckebaum has received speakers’ fees, travel reimbursement, and research funding from Biotest and was a member of the Biotest AG medical advisory board. Artur Bauhofer and Gabriele Niemann are employees of Biotest AG. Paolo De Simone has received speakers’ fees and served as advisory board member for Biotest AG. Robert de Man has received research funding from Biotest AG. Beat Müllhaupt has received travel reimbursement from Biotest AG. Kerstin Herzer and Julien Vionnet have received travel grants and research funding from Biotest AG. Patrizia Burra has taken part in advisory boards and meetings sponsored by Biotest AG. Lutz Fischer has received travel reimbursement from Biotest AG. William Gelson, Cornelius Engelmann, Mauro Salizzoni, Riccardo Volpes, Giorgio Ercolani, Luciano De Carlis, Paolo Angeli, Jean-François Dufour, Massimo Rossi, Umberto Cillo, Ulf Neumann, Luca Toti, and Giuseppe Tisone have no conflicts of interest to declare.

Figures

Figure 1

Flow diagram of the 371 patients transplanted for hepatitis B virus (HBV)-related disease who were included in the analysis, of whom 332 (89.5%) were alive at the time of study entry. More than 1 type of hepatitis B immunoglobulin (HBIg) could be given (iv HBIgB, sc HBIg, or other licensed HBIg preparations). By the final documentation, 270/332 patients (81.3%) were receiving HBIg therapy. HCC, hepatocellular carcinoma.

Figure 2

Mean [SD] daily dose of hepatitis B immunoglobulin (HBIg) therapies (A) from time of liver transplantation (LT) to month 3 post-transplant, (B) from month 3 post-transplant therapies to end of documentation (EOD) in patients transplanted for hepatitis B virus (HBV)-related disease. Data are shown for any HBIg therapy and for iv HBIgB, sc HBIg, and other HBIg products. LT was defined as day of LT and up to 7 days after LT.

Figure 3

Time to first hepatitis B virus (HBV) recurrence in the 16 patients who developed HBV recurrence out of 371 patients (4.3%) transplanted for HBV-related disease.

Figure 4

Rate of HBV recurrence according to type and adequacy of hepatitis B immunoglobulin (HBIg) treatment, based on the total population of 371 patients transplanted for HBV-related disease. HBIg included iv HBIgB, sc HBIg, or other licensed HBIg preparations. ‘All treatment’ includes all patients who developed HBV recurrence regardless of the type or duration of HBIg treatment; ‘Patients under HBIg’ includes all patients who developed HBV recurrence while receiving HBIg therapy; ‘Patients under HBIg with adequate treatment’ includes all patients who developed HBV recurrence while receiving any HBIg therapy and who had a serum level of anti-HBs ≥100 IU/l; ‘Patients under sc HBIg with adequate treatment’ includes all patients who developed HBV recurrence while receiving sc HBIg therapy and who had a serum level of anti-HBs ≥100 IU/l. If the serum anti-HBs level was not available, it was assumed conservatively to be ≥100 IU/l for the purposes of analysis.

Figure 5

(A) Time to first recurrence of hepatitis B virus (HBV)-hepatocellular carcinoma (HBV-HCC) in the 14 patients (14/147, 9.5%) transplanted for HCC and who had HBV-HCC recurrence, (B) time to first occurrence of de novo non-HCC cancer in the 26 patients (26/371, 7.0%) transplanted for HBV-related disease who developed a de novo non-HCC cancer.