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Controversies Regarding the Hepatitis B Immune Globulin Prophylaxis (HBIG) for Liver Transplantation Recipients

Seyed Mohammad Jazayeri, Mario Rizzetto, Seyed Moayed Alavian

Seyed Mohammad Jazayeri, Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
Mario Rizzetto, Department of Gastroenterology, Molinette, University of Torino, Torino, Italy
Seyed Moayed Alavian, Middle East Liver Diseases Center (MELD Centers), Tehran, Iran

Correspondence to: Seyed Moayed Alavian, MD, Middle East Liver Diseases Center (MELD Centers), No 178, Sepahboud Gharanee St. Tehran, Iran.
Email: chariman@meldcenter.com
Telephone:+98-21-88945186-7
Fax:+98-21-88945188
Received: April 27, 2014
Revised: June 30, 2014
Accepted: July 6, 2014
Published online: November 21, 2014

ABSTRACT

Despite the impressive progress that has been made in developing highly effective prophylaxis regimen against HBV recurrence after liver transplantation which reduces the risk of recurrence to 30% in patients with chronic hepatitis B and to less than 10% in patients with fulminant liver failure, however, the effectiveness of such prophylactic options in preventing recurrence of hepatitis B virus (HBV) depends upon the dosage, route of administration, duration of treatment, type of anti-virals and the viremic status at the time of transplantation. This review will discuss the current status of the topic and consider the developments that made for liver pre- and post-transplantation. The ultimate efficacy of hepatitis B immunoglobulin (HBIg) for the prophylaxis against HBV recurrence after LT in relation to variable factors has been discussed in this review. Moreover, different regimen options based on using either concomitant nucleos (t) ide analogues (NA) and HBIg or drug monotherapy etc discussed.

Key words: HBIg; Liver transplantation; Nucleos (t) ide analogues; HBV recurrence

© 2014 The Authors. Published by ACT Publishing Group Ltd.

Jazayeri SM, Rizzetto M, Alavian SM. Controversies Regarding the Hepatitis B Immune Globulin Prophylaxis (HBIG) for Liver Transplantation Recipients. Journal of Gastroenterology and Hepatology Research 2014; 3(11): 1313-3125 Available from: URL: http://www.ghrnet.org/index.php/joghr/article/view/917

Introduction

Hepatitis B virus (HBV) infection is among the top ten causes of death worldwide due to chronic liver disease[1] and accounts for an estimated 370 million chronic infections[2]. Approximately 10-15% of infected patients progress to chronic liver disease[3], and 3% will develop hepatocellular carcinoma (HCC)[4]. The ultimate interventional option for the end stage liver disease for chronic carriers is liver transplantation, however, this has been challenged by a recurrence rate of 80-100% of HBV infection[5], leading to rapid progression to cirrhosis and death. With the utilization of hepatitis B immunoglobulin (HBIg), this frequency has been reduced dramatically depends on the dose, route and the presence of antiviral prophylaxis. In this paper we reviewed the current knowledge about the role of HBIg alone or in combination with antivirals and how they influence the outcome of liver transplantation.

Method

We performed a literature of review by search of National Library of Medicines PubMed and (NCBI) bibliographies of papers and journals from 2000 to April 2014 on the describing the efficacy of HBIg for the prophylaxis against HBV recurrence after LT in association with several factors using the MeSH terms: HBIg dose, HBIg route, HBIg monotherapy, HBIg combination therapy and finally HBIg and new nucleos (t) ide analogous (NA). We classified the selected papers which contained enough data alphabetically.

We included all cross sectional and prospective or retrospective cohort studies comparing the use of HBIg, antivirals, or both for prevention of recurrent HBV infection in liver transplanted patients. Due to the huge amounts of the data, results from some aspects of above criteria were published elsewhere[6] mainly focused on the route of injection and dosage of HBIg liver in transplant settings. Herein, we focused mainly on the different types of HBIG therapy in the era of new NA drugs.

Role of HBIG in the Prophylaxis

Over the past two decades, prophylactic treatment for the prevention of HBV re-infection following liver transplantation involves passive immunity offered by low- to high-dose HBIG alone or in combination with an antiviral NA has been suggested as a gold standard regimen[7], which reduces the risk of recurrence to 30% in patients with chronic hepatitis B and to less than 10% in patients with fulminant liver failure[7-10]. This strategy has led to the concomitant improvement in graft and overall survival rates. Despite being effective as an immunomodulator for HBV infection prophylaxis, however, the effectiveness of HBIg in preventing recurrence of HBV depends upon multiple factors: dosage, route, type of therapy, duration of HBIg, HBV DNA levels pre-LT etc. Also, there is currently no consensus over those factors for prevention and/or suppression recurrence of HBV post-LT and yet have not been standardized and tend to vary widely from one transplant center to another[11-15]. Some of those important controversial factors include:

1. Route of HBIG administration.

As a standard procedure, high dosage of HBIg requires intravenous (IV) administration. As an accepted alternative for intravenous route, intramuscular injection (IM) of HBIg has been studied in many reports worldwide. Regarding the limited volumes that can be given per IM injection, only patients with low HBIG requirements are suited for intramuscular HBIG administration[16,17]. Currently, switching from intravenous HBIg during anehepatic and a few days post-LT (which usually involved the application of high-dosage) to IM route for either short term or indefinitely has been using widely in different centers (Table 1). Subcutaneous (SC) HBIg either alone or in combination with NA to prevent recurrent HBV infection before LT has been reported only in few studies (Tables 1 and 2). Low recurrence rate, lower dosage of HBIg (500 to 1,000 IU), self-administration by the patients, low drug adverse effects, stability of anti-HBs levels were the advantages[18-23].

In a cost-effectiveness analysis by Dan et al the overall cost for intravenous HBIg for the first and subsequent years were 108,300 and 51,300 US Dollar, respectively. However, the same calculation for intramuscular HBIg for the first and subsequent years were 80,000 and 90,00-10,000 US Dollars, respectively[24].

2. HBIG doses (low dose versus high dose).

During 1990s, numerous reports from US and European centers have shown the benefit of continuous use of high-dose HBIg post liver transplantation that dramatically reduced the incidence of recurrent HBV infection[25-27], prior to the availability of effective antiviral therapy[10]. However, selection of surface protein mutants, high costs and patients incompliance have limited the efficacy of this application[7,16,28-31]. Therefore, HBIG at lower doses (300-800 IU) and conversion of intravenous to intramuscular route have been used instead[32-50] (Table 1). Combination of low-dose HBIg with NA resulted in lower costs as well as similar recurrence and survival rates with high dosage regimen[34,51].

3. Duration of therapy

Many centers worldwide have employed lifelong prophylaxis by the administration of either low or high HBIg dose in combination with NAs[7,52-54] despite no significant differences for HBV recurrence 5 years after LT for different HBIG regimens[52]. However, the cost of such treatment is very high and, in recent years, several centers have used short-term HBIg in combination with indefinite nucleos(t)ide analogue therapy[30,38,50]. Discontinuation of HBIG after some defined interval and continuing treatment with new antivirals alone have been applied by some centers with a promising results indicating no rate of recurrence[55-57] (Table 1).

4. Type of HBIG Therapy (mono vs combination with NA).

Although some studies showed that high-dose HBIG monotherapy to be equivalent to the combination regimen for prevention of HBV post-LT[21,58], combination therapy have become a common strategy to reduce HBV recurrence rate post-LT and the efficacy has been investigated extensively[30,32,37,40,45,48,49,51] (Table 1). Development of new antiviral agents and the use of HBIG plus antiviral NA have decreased the risk of recurrent hepatitis and death in transplant recipients by decreasing the amount of circulating virus at the time of transplant and by prolonging the half-life of HBIG[10,59]. Generally, HBIg plus antiviral NA combination prophylaxis consists of antiviral agents administered pre-transplantation (especially in HBV-DNA-positive patients) to reduce the viral load, followed by high (IV) or low (IM) dose (2,000 to 10,000 IU) during the anhepatic phase and a combination of long term antiviral NA and high (IV) or low (IM) dose (400 to 10,000 IU HBIg) with different intervals following transplantation (Table 1)[21,60].

5. Pre-LT HBV DNA levels.

a: Early recurrence: Typically, early recurrence graft infection (80% to 100%) in the absence of prophylaxis occurs between 6 and 12 months after LT[5]. Several reports have noted that serum HBV DNA level at the time of transplant would be an important predictor of the half-life of HBIG[10,17,61] and different high levels of pre-operative viral load (>104 copy/mL) have been suggested to be a risk factor for graft HBV re-infection[32,52,62-64]. Lenci et al showed that patients without detectable HBV DNA in the liver before transplantation have a low risk of HBV recurrence[7,65] and long-term follow-up studies confirmed that recurrence rates differed with HBV DNA titers prior to antiviral therapy[34,45]. Neff et al[13] found that none of the 51 patients with undetectable HBV DNA pre-LT experienced evidence of HBV viral recurrence post-LT regardless of the different prophylactic strategy[30,50]. However, following studies showed that suppression of HBV-DNA in serum does not indicate clearance of the virus from hepatocytes[46,66] and the long half-life of cccDNA in reinfected hepatocytes is responsible for viral recurrence following OLT[67-71]. Therefore, the authors suggested the complete withdrawal of prophylaxis with caution.

b: Late recurrence: Late recurrences are usually caused by the emergence of mutations caused by the selection pressure of HBIg on the surface protein[28,29,72,73]. Moreover, the emergence of YMDD variants following NA resulted in HBV reinfection following LT as a result of selection pressure of the drugs on the polymerase protein. However, in contrast to HBIg, this emergence being variable according to the type of drug regimen, in a range being highest (16%) to lowest (0%) following lamivudine and entecavir combination therapy. On the other hand, higher occurrence of resistance have been reported following monotherapy with either HBIg (0% to 71%) or NA (lamivudine) (0% to 39.7%)[74,75] (Table 1). Further, multiple drug/HBIg variants have been reported in patients receiving both interventions (especially in combination with lamivudine)[72,73,76, 77]. Obviously with current new NA agents like adefovir, entecavir, tenofovir, etc, the recurrence rate decreased to 0% to 12.9% (Tables 1-3). However, there are only limited data available for these new antiviral NAs and further studies needed to test their effectiveness as part of combination therapy with HBIG and/or montherapy strategies[78-80].

6. Anti-HBs target levels

Despite there is no consensus regarding sustained levels of anti-HBs following HBIg administration before and after LT, it is widely accepted that anti-HBs plasma titers should not fall below 100 IU/L during HBIg therapy. Protection against HBV recurrence seems to obtain better with higher anti-HBs levels (300-500 IU/ L)[81,82]. The proposed levels ranges from >70 to >500 IU/mL among centers. Furthermore, serum HBsAb levels monitoring after HBIg injections is also controversy among centers and the need for an intensive care of the level of anti-HBs (and subsequent frequent reinjection) to prevent HBV recurrence are still unclear[13,30,50]. The ideal method for establishment of anti-HBs variability in response to HBIg administration would be through individualized dosing proportional to anti-HBs levels obtained in a timely fashion interpatiently[59].

Prophylaxis with NA

1. NA monotherapy

Among the NAs, lamivudine was the first that introduced as a monotherapy before and after LT for prophylaxis against HBV recurrence post-LT especially in certain patients such as those who were HBV-DNA-negative and at low risk of re-infection[36,75,83]. Subsequently, there was a dramatic decrease of the HBV recurrence rate in patients receiving lamivudine (LAM) monotherapy (3 years post-LT recurrence rate of 40%)[75,84].

Unfortunately a recurrence rate of 3.8 to 40% at 2 years post-LT have been reported by multiple centers as a consequence of drug-resistance phenomenon caused by the emergence of mutants in the highly conserved motif YMDD within the polymerase[30,72,73,77,85]. Lu et al investigated two groups of LT recipients receiving lamivudine (in combination with HBIG) at long and short term periods. The longer period-group (mean 698.5 days) showed 9% HBV recurrence compared to 0% for shorter period group (mean 36.9 days)[39]. Moreover, others showed that in patients on lamivudine monotherapy, high viral load pretransplantation could be a predictor for the development of posttransplantation lamivudine resistance[51,74]. Therefore, long term LT prophylaxis using lamivudine monotherpy has been not recommended, particularly in replicative patients[30,35,84,86].

The data on using new NA monotherapy for prophylaxis in the absence of HBIg are few. Adefovir (ADV) monotherpay has been used by few studies with encouraging results (Tables 1-3)[87]. The rate of recurrence after LT was 0%. Similarly, entecavir, Telbivudine monotherapy[78,88-91] pre-and post LT resulted in 0% to 8% HBV recurrence rate (Table 2). Only one study found a relatively high rate of recurrent HBV infection (22.5%) using ENT[91] (Table 3). Based on experience in non-transplant patients, telbivudine can be substituted for lamivudine. Similar to lamivudine, telbivudine should not be used as monotherapy, and if used it should be combined with adefovir or tenofovir to minimize the risk of drug resistance[10].

2. Rescue therapy

During the new NA era for the prophylaxis against HBV recurrence following LT, many centers have been using these drugs only in the case of drug resistance following lamivudine administration as either add-on or switching approaches in combination with HBIg as rescue therapy[13,37,45,49,92-97] (Table 4). ADV has been at the top of this list for only cases who acquired HBV reinfection due to LAM-resistance. Schiff et al[94] reported a survival of one-year 84% for pre-LT and 93% for post-LT patients with no cases of ADV-resistance in patients who experienced HBV recurrence after LT. HBV DNA was undetectable at week 144 in 78% of cases. Longer follow up study showed a 3 year sustained survival of 87% in these patients group[87]. Also, entecavir showed promising results for these patients with no cases of recurrence[38,88,93,98]. However, despite entecavir is an ideal antiviral agent in nucleoside-naïve patients for its potent antiviral effects, low rate of drug resistance, and lack of nephrotoxicity, as entecavir-resistant mutations are more likely to be selected in the presence of lamivudine-resistant mutations, some authors have not recommended this drug in patients with lamivudine-resistant HBV[10]. Other new NA agents like Emtricitabine (FTC), Tenofovir (TDF); Famciclovir (FAM)[13,28,38,93] (Table 4) showed to be effective for lamivudine-resistant variants following liver transplantation. However, the sample sizes in these studies on the effectiveness of new NA agents were too small to make a definite conclusion.

3. NA combination therapy

New NAs including adefovir, entecavir, tenofovir, and telbivudine are antiviral agents of choice for the treatment of HBV. However, due to lack of data and despite some few studies that showed their effectiveness when they included in the prophylactic regimen[38,93,96] (Table 3), combination of NAs without the concomitant use of HBIg is generally not recommended. Further, comparison of trails that used a combination of antivirals compared with a combination of HBIg plus either NA alone showed that both regimens provides equivalent protection against recurrent HBV infection after LTx with fewer side effects and lower cost[32,88]. Furthermore, treatment with adefovir plus lamivudine before LTx and the addition of HBIg after LTx has shown to prevent graft reinfection[7,87,94,99].

Due to the potential nephrotoxicity, tenofovir is not an ideal drug in the transplant setting in nucleoside naïve patients but tenofovir alone or in combination with a nucleoside, lamivudine, emtricitabine, telbivudine or entecavir, is recommended for patients with lamivudine resistance[10].

4. HBIg+NA prophylaxis

As it shown in the table 1, the incidence of de novo HBV was ranged from zero to 2.7% in patients receiving LAM-only prophylaxis versus zero to 20% in those receiving HBIG plus LAM combination therapy. Thus, both prophylactic treatment strategies were associated with HBV breakthrough post-LT.

Following lamivudine, adefovir has been introduced as more potent NA antiviral for post-LT prophylaxis. Although the sample size of the patients-studied was low in compare with Lam-receiving patients, the reported recurrence after prophylaxis with ADV was 0%[44,87,99]. Among new NAs, entecavir, telbivudine, tenofovir and emtricitabine have been used with 0% recurrence rate (Table 2) [22,46,56,93,95,100-105].

5. NAs cross-regimen

There are some recommendation regarding switching from HBIg monotherapy or combination therapy to NAs monotherapy (Tables 1-2). Patients without virus replication at the time of LTx, with at least 2 years of HBIg treatment and those who are negative for HBV DNA by polymerase chain reaction before stopping HBIg seem to be the best candidates to switch to a monotherapy with NAs[7,13,28,49,74]. In a study by Xie et al, of 17 patients who experienced HBV recurrence after LT, 12 switched from LAM+HBIg to adefovir plus lamivudine. HBV DNA fell below 103 copy/mL in 10 cases after 6 months (one case died due to HCC) and subsequently in one patient who switched to entecavir[95].




Concluding remarks

Despite the absence a consensus on prophylaxis against HBV reinfection following liver transplantation, in an attempt to determine an optimal regimen for HBIG administration that can be more cost-effective, convenient, and widely-accepted alternative approaches have been studied including: lower HBIG doses, the use of intramuscular or subcutaneous HBIG rather than the intravenous route, non-HBIG forms of anti-HBs, and low-dose or short-term HBIG in combination with antivirals and tailoring HBIG administration guided by plasma concentrations rather according to a fixed time schedule. The choice of options depend on the availability of antivirals and cost of HBIG regimen. Regarding new NA monotherapy, due to the lack of adequate data, for a definite conclusion more prospective, cohort studies needed though the available results are optimistic.

CONFLICT OF INTERESTS

There are no conflicts of interest with regard to the present study.

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Peer reviewers: Jinyang Gu, PhD, Department of Hepatobiliary Surgery, Affiliated DrumTower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, China; Nermine A Ehsan, Professor, Department of pathology, National Liver Institute, Menoufiya University, Shebin ElKom, Menoufiya, Egypt.

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