Is hepatitis B immune globulin still needed after liver transplantation for chronic hepatitis B?
Authors: Edward J. Gane
Journal: Hepatology (2017)

Potential conflict of interest: Prof. Gane advises for and is on the speakers' bureau for Gilead Sciences, AbbVie, and Merck. He advises for Alios, Janssen, and Roche. See Article on Page 1036 Before the development of perioperative antiviral prophylaxis, hepatitis B virus (HBV) infection was considered a contraindication to liver transplantation (LT) because of a high rate of recurrent HBV infection resulting in an aggressive cholestatic hepatitis, with rapid progression to graft loss and death.1 A large multicenter European study demonstrated that high‐dose intravenous hepatitis B immune globulin (HBIG) reduced overall recurrence rate by 60% with dramatic improvement in patient and graft outcomes.2 Patients with high HBV‐DNA levels at the time of transplant remained at risk for both early recurrence because of insufficient neutralizing antibody in the immediate perioperative period. This risk could be mitigated by aggressive intravenous HBIG dosing targeting very high trough (hepatitis B surface [HBs] antibody) titers (above 500 IU/mL).3 But in order to achieve and maintain such “protective” levels, weekly then monthly intravenous infusions of 5‐10,000 IU are required, costing US$100,000 for the first year and US$50,000 each year thereafter. This very high cost has driven the development of HBIG‐sparing and HBIG‐avoidance strategies. Pretransplant and posttransplant suppression with potent oral nucleos(t)ide analogues (NUCs) should improve the neutralizing effect of perioperative HBIG. This combination has reduced the rate of recurrent HBV below 5% and has facilitated HBIG withdrawal in some “low‐risk” patients.5 However, complete HBIG avoidance remains the ultimate goal, especially in countries with endemic HBV where intravenous HBIG is either unavailable or unaffordable. The first HBIG‐free regimen with lamivudine monotherapy was associated with high late rates of HBV recurrence attributed to emergence of lamivudine resistance.8 Entecavir and tenofovir would seem better candidates for HBIG avoidance strategies because of their higher barrier to antiviral resistance. In this issue of Hepatology, Fung et al. report long‐term outcomes of HBIG‐free prophylaxis with entecavir monotherapy post‐LT for HBV‐related liver disease.11 In this large, single‐center cohort, 256 LT candidates received entecavir monotherapy for a median of 8 years. The cumulative rates of serum hepatitis B surface antigen (HBsAg) loss and undetectable HBV DNA were 86% and 99% at 12 months and 92% and 100% after 8 years. These excellent results were achieved in an Asian population with a high prevalence of hepatitis B e antigen positivity and HBV genotype C, both factors associated with increased risk of HBV recurrence.12 Although all patients had undetectable HBV DNA posttransplant, most remained HBsAg positive for several weeks and those with high pretransplant serum HBV‐DNA levels (>4 log IU/mL) remained HBsAg positive for up to 3 years. The transient detection of HBsAg would suggest that entecavir monotherapy does not prevent initial allograft infection and is consistent with previous observations that low‐level HBV replication may persist in the allograft despite absence of detectable serum HBsAg.13 If the allograft provides a permanent reservoir of latent HBV infection, then HBsAg loss following transplantation would not indicate a functional cure and cessation of entecavir may result in HBV reactivation. The mean interval between transplantation and HBsAg loss in patients who received entecavir prophylaxis was shorter than reported at the same center in a previous cohort who received lamivudine prophylaxis.14 This difference may reflect the higher proportion who received NUC therapy before transplant in the entecavir cohort. The clinical outcomes of entecavir monotherapy in this series were excellent—no patient developed active chronic hepatitis B (CHB) in the allograft. As a result, graft and patient survival was excellent and superior to all other indications for LT. Certainly, the long‐term outcomes following elective LT for CHB are now superior to all other elective indications.15 No patient developed entecavir resistance. Previous lamivudine resistance is the major risk factor for developing entecavir resistance.18 In such patients with documented lamivudine resistance before transplant, tenofovir monotherapy should be the preferred antiviral prophylaxis.19 Thanks to the ability of NUCs to rescue most patients with hepatic decompensation, hepatocellular carcinoma (HCC) has become the chief indication for listing in patients with CHB and HCC recurrence has replaced HBV recurrence as the major cause of posttransplant mortality.20 In this current study, 13 of 97 patients transplanted for HBV‐related HCC developed recurrent HCC and 6 of these also became HBsAg positive and 4 remained HBsAg+ until death. In previous reports, reappearance of HBsAg was associated with a higher rate of HCC recurrence, suggesting a causal association between HBV infection and HCC recurrence.22 However, two recent studies have demonstrated that reappearance of HBsAg in serum is isolated with no other HBV protein secretion or HBV‐DNA replication, consistent with transcription of integrated HBs gene within tumour tissue rather than recurrent HBV infection.24 To conclude, this study by Fung et al. demonstrates that pretransplant and posttransplant entecavir monotherapy prevents recurrent HBV infection post‐LT. This regimen is better tolerated, more convenient, and more cost‐effective than current HBIG‐containing regimens. The results from this large, single‐center study in an Asian population at high risk of HBV recurrence should support the adoption of HBIG‐free antiviral prophylaxis in all other regions.