Are immunoglobulins against the HBsAg still needed in liver transplantation for hepatitis D?
Authors: Silvia Martini, Lucio Caccamo, Mario Rizzetto
Journal: Hepatology (2018)

Potential conflict of interest: Nothing to report. TO THE EDITOR: In the October issue of the Journal, Dr. Fung and colleagues1 have reported excellent results with entecavir alone in the post–liver transplant prophylaxis of hepatitis B virus (HBV) reinfection, prompting Dr. Gane to conclude in his Editorial2 that entecavir monotherapy should be generally adopted as hepatitis B immunoglobulins (HBIG)‐free antiviral prophylaxis to prevent HBV recurrence. A proportion of the hepatitis B surface antigen (HBsAg)‐positive transplants have disease caused by the hepatitis D virus (HDV), not by the HBV; the latter provides to the former biological support to thrive, but remains a bystander with no pathogenic impact throughout most HDV infections.3 Given that there is no therapy against HDV, the combination of HBIG with HBV antivirals has been adopted by default as prophylaxis against HDV reinfection, with excellent results.4 The paper by Fung raises nevertheless the issue whether monotherapy with HBV antivirals could be equally efficacious after liver transplantation, dispensing with the cost and inconvenience of the administration of the HBIG. In principle, this approach would seem dangerous as the HDV is thought to require only HBsAg to coat its virion.3 Entecavir and other HBV antivirals do not interfere with HBsAg, and in Fung's study the HBsAg antigen persisted in serum of around 15% of the recipients. However, in contrast to this theoretical concern, 81 HDV transplants were given in recent years' long‐term prophylaxis with antivirals only, in monotherapy or in various combinations, right from surgery or after a short course of concomitant HBIG (Table 1). The patients were followed up to 20 years. Table 1 - HDV Liver Transplants on Long‐Term Prophylaxis With Antivirals Only Study HDV pts NA After HBIG Discontinuation NA Duration Median (Range) HBV/HDV Recurrence Manini MA, Dig Liv Dis 2017;49S:e11 8 ETV or TDF 61 mo (31‐78) 0 Caccamo L, Transpl Infect Dis 2017;19:e12641 5 LAM 20 y (18‐20) 0 Cholongitas E, Transplant Infect Dis 2016;18:667‐673 33a LAM or ADF or ETV or TDF or LAM + ADF or LAM + TDF 28 mo (12‐58) 1 ptb Öcal S, Exp Clin Transplant 2015;13(Suppl 1):133‐138 25 LAM or ADF or ETV 59 mo (3‐120 mo) 6 pts HBsAg+ Fernández I, Transpl Infect Dis 2015;17:695‐701 10 ETV or TDF mean 28 ± 5 mo (13‐36) 0 aOne patient who received an HBsAg‐positive liver graft was disregarded.bThe patient was rescued with HBIG for 12 months and LAM/ADF was changed to TDF.Abbreviations: ADF, adefovir; ETV, entecavir; LAM, lamivudine; mo, months; NA, nucleos(t)ide; pt, patient; TDF, tenofovir; y, years. Remarkably, only 1 of the 81 (1.2%) recipients experienced a relapse of HBV/HDV disease; and in the report by Őcal (Table 1), HBs antigenemia became detectable in the blood of 6 patients, none of whom had a disease relapse. These data would suggest that, to recur in the liver graft, the HDV must be rescued by a reactivation of the HBV infection, an event which is of course preventable with HBV antivirals. Interestingly, in a recent case report from Japan, HDV infection recurred in association with an HBV flare5 several years after grafting, at a time when HBV antiviral therapy had been discontinued. This evidence calls for the consideration of monotherapy with HBV antivirals as an equally efficacious, but cheaper, prophylaxis also against HDV reinfection.