Prevention of recurrent hepatitis B infection after liver transplantation

Hong Kong, China

Prevention of recurrent hepatitis B infection after liver transplantation

Tiffany CL Wong, James YY Fung and Chung Mau Lo

Hong Kong, China

BACKGROUND:Recurrence of hepatitis B virus (HBV) infection after liver transplantation can lead to graft loss and a reduction in long-term survival. The purpose of this review is to summarize the current therapeutic options for preventing HBV recurrence in liver transplant recipients.

DATA SOURCES:Up to January 2013, studies that were published in MEDLINE and EMBASE on prevention of HBV recurrence after liver transplantation were reviewed.

RESULTS:There have been remarkable advancements in the past two decades on the prevention of HBV recurrence after liver transplantation, from the discovery of hepatitis B immune globulin (HBIG) and lamivudine monotherapy to the combination therapy using HBIG and lamivudine. With the development of newer and stronger antiviral agents, the need for life-long HBIG is doubtful. With their low resistance prof i le, oral antiviral prophylaxis using these new agents alone is suff i cient and is associated with excellent outcome.

CONCLUSIONS:Restoration of host HBV immunity with adoptive immunity transfer and vaccination may represent the ultimate strategy to withdraw prophylactic treatment and to achieve a drug free regimen against HBV recurrence after liver transplantation.

(Hepatobiliary Pancreat Dis Int 2013;12:465-472)

hepatitis B;liver transplantation; hepatitis B immune globulin; antiviral therapy; adoptive immunity transfer; HBV vaccination

Introduction

It is estimated that more than 2 billion people worldwide have been infected with the hepatitis B virus (HBV) and approximately 240 million people are chronic carriers.[1]Among those with chronic hepatitis B (CHB) infection, approximately 15%-40% will develop cirrhosis or its complications including decompensation and hepatocellular carcinoma.[2,3]Liver transplantation offers the ultimate cure for these patients. However, in the absence of effective prophylaxis, the recurrence of hepatitis B after transplantation was as high as 75%[4]leading to early graft loss and a reduction in long-term survival.[5]In the past two decades, there have been remarkable progresses in the treatment of CHB[6]as more potent antiviral agents became available. The use of hepatitis B immune globulin (HBIG)[4]and lamivudine[7]after liver transplantation has revolutionized the management of CHB in liver transplant recipients. An ideal regimen would be one that can effectively prevent CHB recurrence and yet with minimal side-effects and of reasonable cost. Different agents either alone e.g. HBIG, lamivudine etc. or combined have been studied to prevent CHB recurrence after liver transplantation. The combination of HBIG and lamivudine has been commonly used in many centers, with a recurrence rate of <5% in 5 years.[8]With the availability of newer nucleoside and nucleotide analogues, use of these agents with or without HBIG has recently been explored.[9,10]Debates on whether HBIG is indispensible in preventing CHB recurrence after liver transplantation are enormous. The purpose of this review is to summarize the current therapeutic options for preventing CHB in liver transplant recipients.

Prevention of recurrent hepatitis B infection

Monotherapy with HBIG

The discovery of HBIG was a major milestone in hepatitis B prophylaxis after liver transplantation.Prior to the availability of HBIG, liver transplantation for CHB patients was controversial especially in the presence of active HBV replication, i.e. those who were hepatitis B e-antigen (HBeAg) or HBV DNA positive.[11]The mechanism in which HBIG prevents hepatitis B recurrence remains unknown. It is possible that HBIG confers protection for na?ve hepatocytes against HBV released from extrahepatic sites by blocking putative HBV receptors.[12]Another potential mechanism includes neutralization of circulating virions by immune complex formation.[13]Initial trials had shown promising results by reducing the recurrence rate of hepatitis B in liver transplant recipients to 29% in 2 years using passive immunoprophylaxis with HBIG.[14,15]The benef i t of HBIG to prevent HBV recurrence after liver transplant was conf i rmed in a European multicenter trial in 1993.[4]In this landmark trial, there was a signif i cant reduction in the rate of hepatitis B recurrence in patients who received HBIG after liver transplant compared with those who did not receive HBIG (36% vs 75%,P<0.001).

HBIG is given either at irregular intervals with administration of HBIG to maintain a desired anti-HBs level, e.g. >100 IU/L, or at regular interval to "overshoot" a certain anti-HBs level.[16]Although HBIG alone reduced the recurrence of hepatitis B signif i cantly, the risk of recurrence could be as high as 70%-96% in 2 years among patients with active viral replication.[15,17,18]Recurrence of CHB was associated with either inadequate dosage of HBIG or emergence of mutations that altered the HBIG surface binding.[17]Besides the high recurrence rate, HBIG is costly, and requires repeated parenteral administration and regular monitoring. Also, HBIG is produced from pooled human blood and so there is a potential infection risk.

Monotherapy with lamivudine

The approval of lamivudine for the treatment of HBV was the second major milestone in the management of CHB patients after liver transplantation. Lamivudine is an oral nucleoside analogue that suppresses HBV replication by acting as an inhibitor of viral reverse transcriptase. The eff i cacy of lamivudine in suppressing viral replication in CHB patients has been well documented in various studies.[19-21]Five trials have looked into the role of lamivudine monotherapy in preventing HBV recurrence after liver transplantation.[7,22-25]In the study by Grellier et al,[7]the recurrence rate of CHB was 10% in 1 year after liver transplant. In the trial by Malkan et al, the risk of HBV recurrence was 18.8% (6/32) with a median followup of 24 months.[22]A study by Lo et al reported 3.8% (1/26) HBV recurrence, as def i ned by reappearance of HBV DNA in serum with a median follow-up of 16 months after liver transplant.[23]Five patients in this study remained HBsAg positive, making an overall HBV reinfection rate of 23.1% (6/26). Similar results were shown by two multicenter trials in the United Kingdom and North America.[24]In the study by Mutimer et al,[24]the risk of HBV recurrence was 23.5% (4/17) and the overall survival rate was 64.7% (11/17) with a median follow-up of 36 months. Two out of 6 deaths during the study period was due to HBV recurrence. In Perrillo's multicenter study, the HBV recurrence rate was higher among patients who were HBV DNA positive before commencing lamivudine therapy. The 1- and 3-year post transplant HBV recurrence rates were 40% and 60% among HBV positive recipient, 18% and 0 among patients who were HBV DNA negative before starting lamivudine monotherapy.[25]

The major disadvantage of lamivudine is the emergence of mutation in the YMDD motif of the polymerase gene,[24]with subsequent virological rebound and biochemical fl are leading to graft loss and increase of mortality.[26]The disparity in recurrence rate of different studies is likely contributed by the difference in def i nition of hepatitis B recurrence and also the difference of viral load at the time of transplantation in various studies.

Combination therapy

By combining HBIG with lamivudine, the recurrence rate of hepatitis B after liver transplantation can be further reduced. The synergistic effect of these two agents may be explained by the fact that lamivudine and HBIG have different mechanisms of action and resistance prof i les.[8]In the setting of high viral load, the HBIG binding capacity would more likely be saturated and render HBIG ineffective. The addition of lamivudine suppresses viral replication and so HBIG would not be overwhelmed. On the other hand, passive immunization with HBIG can limit the virus to extrahepatic site where viral replication is less effective and induce antibody dependent destruction of virus. Therefore, combination therapy is theoretically sound and numerous trials have looked into the eff i cacy of combination therapy with lamivudine and HBIG.

Lamivudine and HBIG

High dose

Markowitz et al[8]fi rst reported the outcomes of using high dose HBIG and lamivudine to prevent HBV recurrence after liver transplant. The 1-year graft survival rate was 92.9% (13/14) and all surviving patients had no HBV recurrence in a follow-up period of13 months. Han et al[27]also showed promising outcomes with the use of high dose HBIG and lamivudine. All 59 patients remained seronegative for HBsAg, and combination therapy was in fact signif i cantly more costeffective than HBIG monotherapy. The risk of hepatitis B recurrence was higher in those patients who were HBV DNA positive at the time of transplantation.[15,28]By using combination therapy, the risk of HBV recurrence could be signif i cantly reduced to 11% while this risk was 48% in those with HBIG monotherapy and 67% in those with lamivudine alone. Multivariate analysis showed that combination therapy conferred better overall patient and graft survival.[29]

Several studies adopted a strategy based on the anti-HBs titer levels.[30-32]However, there was no consensus on the optimal target anti-HBs titers level, and therefore most were set arbitrarily. Different approaches include a target anti-HBs level of >100 IU/L[30,32]or a decremented approach (>500 IU/L until day 14, then >200 IU/L) was used.[31]All these trials demonstrated a low HBV recurrence using combination therapy, ranging from 8% to 18% in a 24-month follow-up.

Low dose

The main disadvantages on the use of HBIG include its limited availability, high cost, and the risk of infection and mercury toxicity. As similar outcomes were achieved by using an anti-HBs titer approach when compared to the conventional high dose approach, a lower dose of HBIG may be effective. Angus et al[33]used lamivudine plus intramuscular injection of low dose HBIG, in doses of 400 IU or 800 IU daily for the fi rst week and then monthly thereafter. Thirty-one out of 32 patients remained HBsAg negative and all patients were HBV DNA negative in a mean follow-up of 18.4 months. The eff i cacy of low dose HBIG was also demonstrated in subsequent trials.[34,35]The risk of HBV recurrence in those who received combination therapy when compared to lamivudine monotherapy was 13.5% versus 27.4% in 1 year and 15.2% versus 39.4% in 2 years respectively.[34]In the study by Gane et al,[35]the risk of HBV recurrence was 1% in 1 year and 4% in 5 years, with a cost of less than 10% of the conventional high dose regimen.

The superiority of combination therapy when compared to HBIG or lamivudine alone was conf i rmed in two meta-analyses. In the meta-analysis by Loomba et al,[36]the odd ratio for HBV recurrence with HBIG and lamivudine versus HBIG alone was 0.08 (95% conf i dence interval [CI], 0.03-0.21) and HBV-related death and all cause mortality were 0.08 (95% CI, 0.02-0.33) and 0.02 (95% CI, 0.06-0.82), respectively. In another meta-analysis involving 551 patients, Rao et al[37]compared HBIG and lamivudine with lamivudine alone and showed that the relative risk for HBV recurrence was 0.38 (95% CI, 0.25-0.58;P<0.0001), and for emergence of YMDD mutant was 0.40 (95% CI, 0.23-0.72;P=0.002). There was, however, no difference in overall survival (RR, 1.02; 95% CI, 0.95-1.09;P=0.59) and graft survival (RR, 1.02; 95% CI, 0.95-1.09;P=0.56).

Based on the results from these trials, combination of HBIG and lamivudine was used in many centers as the standard therapy for preventing CHB recurrence after liver transplantation. However, unanswered questions remained as to the optimal HBIG dosage, route of administration, and target anti-HBs levels due to heterogeneous nature of the HBIG regimen adopted in the different trials. In addition, even with lower doses of HBIG, the disadvantages of HBIG use remain, including the need for frequent monitoring, parental administration, and high cost.

HBIG-free strategy

In the last decade, four other nucleoside/nucleotide analogues have been approved for the treatment of HBV. Newer nucleoside analogues include telbivudine and entecavir, both of which have higher antiviral potency than lamivudine. Telbivudine is limited by the development of resistant mutations, whereas entecavir has a high barrier to resistance and is an ideal agent. Nucleotide analogues, including adefovir and tenofovir, are both effective against lamivudine-resistant HBV, and are used commonly as rescue therapy. Adefovir, however, is limited by its weak antiviral potency, and its use is mostly in combination with a nucleoside analogue. Tenofovir is highly potent with a high barrier to resistance, and can be used as a fi rst line agent or as rescue therapy in the setting of lamivudine resistance. These newer and more powerful antiviral agents such as entecavir, tenofovir and telbivudine have replaced lamivudine as the fi rst line therapy to treat CHB. It is likely that, with their low resistance prof i le, these agents would be the preferred treatment for preventing HBV recurrence after liver transplantation. Currently, there are 2 strategies for implementing an HBIG-free regimen. The fi rst is HBIG withdrawal after initial combination therapy with or without an additional oral antiviral agent after stopping HBIG. The second is a completely HBIG-free regimen using one or two oral antiviral agents.

HBIG withdrawal

Lamivudine alone

Several studies have reported on the outcomes of HBIG withdrawal to lamivudine alone.[38-40]However, thelong-term eff i cacy of lamivudine monotherapy remained a concern due to the development of resistant mutants. In a prospective study, 29 patients received combination of HBIG and lamivudine for the fi rst month after liver transplant and were then randomized to continue the combined therapy or to switch to lamivudine alone.[38]None of the patients had HBV recurrence at a 18-month follow-up. However, subsequent follow-up trial showed that 15% of these patients developed HBV recurrence. The risk of HBV recurrence is similar among the two prophylactic strategies.[39]

Lamivudine and adefovir

In a prospective randomized trial, low dose HBIG was substituted by adefovir in patients without HBV recurrence for at least 12 months after liver transplant.[41]Sixteen patients received adefovir combined with lamivudine while 18 continued low dose intramuscular HBIG combined with lamivudine. No patient had evidence of HBV recurrence in a median follow-up of 21 months. Similar outcomes were also seen in a recent trial where all HBsAg positive patients were given lamivudine and HBIG after liver transplant.[42]HBIG was discontinued after 12 months and it was substituted with adefovir (n=23, 82%) or tenofovir (n=5, 18%), whereas another 10 (21%) and 9 (19%) patients received tenofovir and entecavir monotherapy respectively. Despite the heterogeneous protocol for CHB prophylaxis, all remained HBV DNA negative with a median followup of 24 months.[42]

Previous trial has shown that the use of adefovir resulted in signif i cant improvement in clinical, virological and biochemical parameters in pre- and post-transplant patients with wildtype and lamivudine resistant YMDD mutant.[43]In a study of 16 HBsAg positive patients, Lo et al[44]reported the addition of adefovir to lamivudine in transplant recipients with lamivudine resistance. Eight of these patients were given HBIG and subsequently withdrew the regimen, but the remaining 8 were transplanted without HBIG. At a median follow-up of 21 months, all patients remained HBV DNA negative.

Tenofovir/emtricitabine (TDF/FTC)

Only one trial investigated the use of TDF/FTC to replace HBIG in 21 patients after transplantation.[45]HBIG was given to these patients for at least 6 months after transplant and it was discontinued and replaced with TDF/FTC. After a mean follow-up of 31 months, all 21 patients had no detectable HBV DNA and 20/21 patients were HBsAg negative. Three out of 21 patients had acute renal failure, two were due to tacrolimus nephrotoxicity and renal allograft rejection respectively and the remaining one had acute tubular necrosis as a result of TDF toxicity. Although this is a small case series consisting of only 21 patients, it provided important insight into the safety and effectiveness of TDF/FTC in suppressing HBV replication, and showed that concept of replacing HBIG with a stronger antiviral agent is feasible.

Complete HBIG-free regimen

A regimen with oral antiviral therapy alone for prophylaxis of hepatitis B after liver transplantation can avoid the inconvenience, side effects and cost of longterm administration of HBIG. With its high barrier to resistance, both entecavir[46]and tenofovir have now become the fi rst line agents for CHB treatment, and the ideal agents for the prevention of hepatitis B recurrence after transplantation.

By far the strongest evidence to support the use of oral antiviral agent as monotherapy to suppress HBV recurrence after liver transplantation was reported by Fung et al.[47]Eighty consecutive HBsAg positive patients received entecavir monotherapy without HBIG as prophylaxis. With a median follow-up of 26 months, the cumulative rate of HBsAg loss was 86% and 91% in 1 and 2 years respectively, and 98.8% patients have undetectable HBV DNA. The safety prof i le for entecavir was excellent as well, with no patient encountering side effect related to entecavir. The superiority of entecavir was demonstrated in a long-term study of 142 patients taking entecavir versus 176 patients using lamivudine.[48]Although the rate of HBsAg seroclearance and HBV DNA suppression was similar between the two agents, there was a signif i cantly higher rate of virological rebound in those taking lamivudine when compared with entecavir (17% vs 0 in 3 years,P<0.001). More importantly, the long-term outcomes in 362 patients on oral nucleoside/ nucleotide analogue therapy without HBIG demonstrated that the rate of HBV DNA suppression was sustainable and associated with excellent long-term survival. The rate of HBsAg seronegativity and HBV DNA suppression to undetectable level was 88% and 98% at 8 years, respectively. The overall survival rate was 83% in 8 years after transplantation and none of the mortality was due to HBV recurrence.[48]

Objective of HBV prophylaxis

With better understanding on HBV recurrence, the objective of HBV prophylaxis after transplantation becomes clearer since graft HBV reinfection occurs universally despite prophylaxis therapy and HBsAg seroclearance. The def i nition of HBV recurrenceneeds reconsideration. In the past, most trials used reappearance of HBsAg as the marker. The use of HBIG in fact leads to a lower detection rate of HBsAg but may not confer additional advantage if HBV replication is already completely suppressed by antiviral agents. On the other hand, in the setting of complete HBV DNA suppression using a potent oral antiviral agent, the importance of HBsAg status remains to be determined given that seronegativity does not equate to cure. In future studies, HBV recurrence should be based on more clinically relevant markers such as virological relapse.

It is likely that despite HBsAg seroclearance with effective prophylaxis using antiviral agent and/or HBIG, graft reinfection occurs universally and complete eradication of HBV does not occur because of the existence of covalently closed circular DNA (cccDNA) in the nuclei of hepatocytes acting as templates for HBV replication.[49-51]A recent study attempted to withdraw prophylaxis in patients with undetectable HBV DNA and no evidence of intrahepatic total and cccDNA.[52]Twenty-f i ve out of 30 patients remained HBsAg negative at a median follow-up of more than 2 years but 5 patients became HBsAg positive.[52]More studies with a long follow-up are needed to determine if withdrawal of prophylaxis is possible but at present, life-long HBV prophylaxis is the standard.

Restoration of host HBV immunity

Restoration of host HBV immunity may represent the ultimate strategy to withdraw prophylactic treatment and to achieve a drug free regimen against HBV recurrence after liver transplantation.

Vaccination

Active immunization to restore HBV immunity has been attempted in patients after liver transplantation but the results of the studies are conf l icting. In a cohort of carefully selected low risk patients, seroconversion was achieved in 14 out of 17 (82.4%) patients, after one or three doses of second generation HBV vaccine.[53]None had HBV fl are and all remained HBsAg and HBV DNA negative at a median follow-up of 14 months. However, similar results were not reproducible. A similar trial from Italy using reinforced triple course of the same HBV vaccine showed only a response rate of 17.6%,[54]and a trial conducted in Hong Kong found an overall response rate of 7.7% only.[55]HBV vaccine apparently failed to mount a humoral or cellular immune response in most patients.[56]With the use of a third generation, more immunogenic recombinant pre-S containing vaccine (Sci-B-Vac?) was used in patients who were receiving lamivudine prophylaxis; however, an overall response rate of 50% was achieved in a study from Hong Kong. A signif i cantly higher response rate was noted in young patients of <50 years old (88% vs 25%,P=0.02).[57]It is important to understand why some patients respond whereas others do not and when new vaccine or alternative vaccination regimen with superior results become available, restoration of active immunity by HBV vaccination may provide the ultimate strategy to replace life-long costly prophylaxis such as HBIG or other antiviral agents.

Adoptive immunity transfer

Adoptive immunity transfer of HBV was fi rst detected in bone marrow transplant recipients from HBV immune donors and donor derived antibody might help HBsAg seroconversion in bone marrow transplant recipients.[58,59]In liver transplant recipients, clearance of HBsAg and spontaneous development of anti-HBs were fi rst reported in 21 out of 50 (42%) patients in Hong Kong.[60]Most (19/21) of these patients received liver grafts from anti-HBs positive donors and this raised the possibility of adoptive HBV immunity transfer through a liver graft. A subsequent study by the same group conf i rmed the presence of donor derived HBV specif i c lymphocytes in the liver graft as HBV specif i c T- and B-lymphocytes were found in 59% and 28% of liver grafts respectively.[61]Although the antibody titer exceeded 1000 IU/L in some patients, the antibody disappeared at a median of 7 months after transplantation and the duration and titer of such anti-HBs was inadequate to confer life-long immunity to HBV. Augmentation of the intensity and duration of HBV adoptive immunity transfer may be another potential strategy to restore host HBV immunity and to achieve discontinuation of life-long HBV prophylactic medications.

Discussion

There have been great progresses in the past two decades in the prevention of hepatitis B recurrence after liver transplantation, from the discovery of HBIG and lamivudine monotherapy[4]to combination therapy of HBIG and lamivudine.[8,33]While combined therapy using HBIG (high or low dose) with lamivudine has been the cornerstone for HBV prophylaxis after liver transplantation, the choice of prophylaxis has broadened with the availability of highly potent antiviral agents with a high barrier to resistance.[47]The use of HBIG has originated from an era where lamivudine was the only agent approved. The role of HBIG is doubtful in thepresent therapeutic environment and it is clear that in the long-term, oral antiviral prophylaxis using these new agents alone is suff i cient and is associated with excellent outcome. The clinical role of immunoprophylaxis with active vaccination and adoptive immunity transfer is limited currently, but restoration of host immunity is the ultimate strategy for the prevention of HBV recurrence in future.

In summary, the paradigm for HBV prophylaxis after liver transplantation for CHB has shifted from the use of high dose HBIG to combination therapy using HBIG and lamivudine and then to the use of newer nucleoside/nucleotide analogues. Restoration of host immunity remains an exciting prospect as it will facilitate stopping life-long and expensive prophylaxis, and further studies will be anticipated.

Contributors:WTCL wrote the manuscript. FJYY and LCM critically reviewed the manuscript. LCM is the guarantor.

Funding:None.

Ethical approval:Not needed.

Competing interest:No benef i ts in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received June 10, 2013

Accepted after revision July 22, 2013

AuthorAff i liations:Department of Surgery (Wong TCL and Lo CM); Department of Medicine (Fung JYY), Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China

Prof. Chung Mau Lo, MBBS, MS, FRCS (Edin), FRACS, FACS, FHKAM (Surgery), FCSHK, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China (Tel: 852-2255-4748; Email: chungmlo@hku.hk)

? 2013, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(13)60074-0