| Abstract|| |
Hepatitis B virus (HBV) infection is an important indication for liver transplantation worldwide. The most important concern is the prevention of viral recurrence in the post transplant period. With the introduction of Hepatitis B immunoglobulin, there has been a significance reduction in the rate of HBV recurrence with improved patient & graft survival rates. The combination of oral nucleosides along with Hepatitis B immunoglobulin has further reduced the rate of HBV recurrence, and currently the outcome of liver transplantation for HBV infection is comparable to other indications for liver transplantation.
Keywords: Hepatitis B, Liver transplantation, Viral recurrence
|How to cite this article:|
Saigal S, Basnotra A, Soin A S. Management of Hepatitis B in the peri-transplant period. Hep B Annual 2009;6:29-40
| Introduction|| |
Hepatitis B virus (HBV) infection continues to be the leading cause of chronic liver disease in India, although its impact in the western world is gradually decreasing. Acute infection with hepatitis B virus (HBV) can result in fulminant hepatic failure, whereas, chronic HBV infection leads to cirrhosis, hepatocellular carcinoma, and end-stage liver disease. The World Health Organization (WHO) estimates for the year 2000 were that more than 600 000 deaths could be attributed to HBV infection, including nearly 400 000 deaths from primary hepatocellular cancer (HCC). The prevalence of HBV infection remains fairly low in affluent countries, where HBV is not a leading indication for liver transplantation (LT). In contrast, HBV infection is one of the most important indications for LT in the Indian subcontinent.
Results of LT for HBV have improved significantly during the past two decades.  In the 1980s, HBV recurrence was highly prevalent post LT, leading to poor patient and graft survival.  Mechanisms of HBV recurrence in the graft included: 1) immediate reinfection of the graft due to the circulating HBV particles, or 2) reinfection of the graft due to HBV particles coming from the extra-hepatic sites. Large, single-center data in the early 1990s demonstrated increased mortality and graft dysfunction in hepatitis B surface antigen (HBsAg)-positive patients as compared to the HBsAg-negative patients undergoing LT.  It was seen that HBV recurrence in the graft was of a very severe nature, including an aggressive variant of HBV-associated liver injury known as fibrosing cholestatic hepatitis (FCH). 
However, with the introduction of hepatitis B immunoglobulin (HBIg) in the peri transplant period, there was a significant reduction in the rate of HBV recurrence post LT, with improved patient and graft survival rates, and HBV-induced fulminant or end-stage hepatic failure became an accepted indication for LT.
Refinements made in the antiviral prophylaxis and treatment of HBV infection, in particular, the recent introduction of nucleoside analogs, alone or in combination, for the treatment of established graft infection have remarkably transformed the outcome of LT for HBV. In the present day scenario, few if any grafts should succumb to HBV-inflicted damage. HBV infection, perceived as a marginal indication for LT not long ago, is now considered an excellent indication for LT for hepatitis B virus-infected patients who have acute or chronic liver failure and / or primary liver cancer.
Several host / viral factors have been identified that increase the risk of post transplant HBV recurrence.  These include:
- High HBV DNA (>10 5 ) or HBeAg positive status pre-transplant
- Pre-transplant Indication for LT: cirrhosis / HCC
- High Immunosuppression use (e.g., Steroids)
- Drug-resistant mutants: 'a determinant', tyrosine-methionine-aspartate-aspartate (YMDD)
Conversely, the risk of recurrence is lower in persons undergoing transplant for fulminant hepatic failure, due to HBV infection, and in those with hepatitis D virus (HDV) coinfection. 
Emphasis is placed on pre- and post-transplant strategies to prevent disease recurrence. The current impressive graft- and patient-survival figures for HBV transplanted patients are principally a reflection of the improvements in antiviral prophylaxis. Without prophylaxis, the clinically significant HBV recurrence occurred in the transplanted liver. The expression of the disease ranged from subacute graft failure (sometimes with characteristic histological features known as 'fibrosing cholestatic hepatitis') to a more conventional chronic hepatitis, with progressive fibrosis, leading to graft cirrhosis.
The serologic hallmark of HBV recurrence is detection of HBsAg post LT. Those individuals with nonreplicative disease (HBeAg-negative, HBV-DNA generally < 10 4 copies/mL) are at a lower risk of disease recurrence. Post LT, HBV-DNA has been detected in multiple extrahepatic sites, including the spleen, gonads, thyroid gland, kidneys, pancreas, and adrenal glands.  Even in the absence of measurable viremia, HBV has been detected in the peripheral blood mononuclear cells  and bone marrow  of LT recipients. These sites serve as potential viral reservoirs in the transplant recipient.
Several strategies have evolved over the last two decades to prevent post LT HBV recurrence. These include use of HBIg and oral nucleosides either alone or in combination.
| Hepatitis B Immune Globulin|| |
The mechanism of action of HBIg is unclear, but it probably involves the binding of HBV receptors on uninfected hepatocytes, thereby occupying the potential viral entry sites. These hepatocytes are subsequently protected from infection by the HBV particles released from the extrahepatic reservoirs.  Samuel and colleagues published the experience of European LT centers (EUROHEP) with regard to HBIg use and outcome data in the HBsAg positive transplant recipients.  Of more than 300 HBsAg positive LT recipients, survival was 75% at one year and 63% at three years, post LT. Among those undergoing LT for HBV-related cirrhosis, the risk of HBV recurrence (as defined by detectable HBsAg) at three years post LT was 67%. This risk was further sub-stratified to 83% among patients with detectable HBV DNA at the time of transplant, 66% among those with undetectable HBV DNA, but detectable HBeAg at the time of transplant, and 58% in those with both undetectable HBV DNA and HBeAg. Superinfection with HDV and fulminant onset of liver disease was an additional factor predictive of a lower risk of HBV recurrence.  This European Concerted Action on Viral Hepatitis (EUROHEP) study, provided the first large scale data supporting the efficacy of HBIg in preventing disease recurrence. The patients were classified into three groups: no immunoprophylaxis, short-term HBIg (< 6 months), and long-term HBIg (> 6 months). Among all the patients with HBV infection, the rate of HBV recurrence was 75% when no prophylaxis or short-term prophylaxis was used. In comparison, with the use of long-term HBIg prophylaxis, the recurrence rate was reduced to 33% (P < 0.001).
Typical protocols commenced HBIg during the anhepatic phase of the transplant operation, gave repeated doses during the early postoperative period, and maintained serum anti-HBs titres above a predefined threshold by subsequent, titrated, intermittent administration. HBIg appeared to provide successful prophylaxis when transplantation was undertaken for patients with low pretransplant serum HBV titres (fulminant HBV, HBV/delta virus coinfection, and HBeAg negative chronic hepatitis). Inferior results were observed for patients who were HBeAg positive at the time of transplantation. Typically, serum HBsAg became and remained positive during the first six months after transplantation.
The current HBIg treatment protocols typically consist of an initial dose of 10,000 U by intravenous administration during the anhepatic phase of transplant, followed by daily administration of 10,000 U during the first week post LT. Multiple subsequent studies have addressed the optimal dosing and duration of HBIg administration for the remainder of the post-LT course. The downside of long-term HBIg administration includes its expense and the inconvenience of administration. HBIg pharmacokinetics vary on both an inter- and intrapatient basis. In particular, patients who are HBeAg-positive at the time of LT may require higher amounts of HBIg, to maintain a given anti-HBs titer in the early post-LT period, as compared to HBeAg-negative persons. Intramuscular HBIg eliminates the requirement for long-term intravenous infusion. Protocols, including intramuscular HBIg, either alone or in addition to a second antiviral agent, have been shown to be efficacious. 
The potential side effects of HBIg infusion include back pain, skin rash, and myalgia. These symptoms are typically preventable or tolerable with premedication. HBV recurrence post LT despite HBIg administration may occur as a result of viral resistance. Mutations occurring in the "a" determinant, a product of the S gene and a putative immune binding site, have been identified post LT. ,, A practical approach for HBIG administration based on Asia-Pacific consensus statement on management of HBV infection has been outlined in [Table 1].
|Table 1: Practical Guidelines for HBIg use in Indian scenario using a low dose protocol*|
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| Lamivudine as Single-Agent Prophylaxis|| |
HBIg failure is principally experienced by patients who have high serum HBV titres at the time of transplantation. Lamivudine has been the most extensively studied oral nucleoside analog with activity against HBV DNA polymerase. It has been shown to reduce serum titres by at least two logs and has been extensively used before and after LT.  The aim of lamivudine use is to lower the serum titres of HBV DNA before transplantation, and to continue lamivudine, to maintain viral inhibition post LT. Failure of prophylaxis is invariably associated with the emergence of lamivudine-resistant HBV during the first two years post LT. For those who do not experience HBsAg relapse during the early post-LT period, a subsequent relapse is unlikely during the prolonged follow-up. Lamivudine monoprophylaxis, given before and indefinitely following transplantation can provide safe and effective protection against significant graft HBV reinfection in a large proportion of patients. However, in patients with high pre-LT serum titres of HBV, neither lamivudine nor HBIg as single agents can prevent graft reinfection. Prolonged use of lamivudine selects HBV variants harboring mutations in the YMDD active site motif of the HBV DNA polymerase, which leads to resistance to lamivudine.
| HBIG and Lamivudine Combination Therapy|| |
Although both HBIg and Lamivudine when used as monotherapy improved survival and decreased the likelihood of disease recurrence in HBV-infected LT recipients, there still existed a significant proportion of patients who had disease relapse in the graft. The next major step in this aspect was the use of a combination therapy, using both HBIg and Lamivudine in HBV-related LT recipients.  The efficacy of lamivudine/HBIg combination therapy in the prevention of HBV recurrence has been confirmed in many subsequent series, including several protocols with low-dose HBIg.  Combination HBIg and lamivudine therapy has also been shown to be cost-effective. Initiation of lamivudine pre LT, particularly in patients with detectable HBV-DNA, while offering the benefit of viral suppression, carries the attendant risk of selecting for resistance. The emergence of mutants pre LT has been implicated as a cause for disease recurrence post LT, despite combination therapy. 
| Adefovir|| |
Adefovir is a nucleotide analog, active against HBV-DNA polymerase. Adefovir has both in vitro and in vivo efficacy against both wild-type and lamivudine-resistant HBV. Use of adefovir therapy in the transplant setting should be considered an important treatment option for patients with lamivudine-resistant HBV.  First-line use of adefovir monotherapy in transplant candidates, in the absence of documented lamivudine resistance, has not yet been extensively studied, but may be reasonable for those patients with decompensated cirrhosis in whom the emergence of lamivudine resistance may be associated with worsening of the disease. Nephrotoxicity is one of the main adverse effects of adefovir and concomitant nephrotoxic medications such as calcineurin inhibitors or a prior renal dysfunction may limit its use in transplant patients.
| Other Antiviral Agents|| |
Several newer oral antiviral agents are now available, which are more potent than lamivudine and have a far lesser rate of emergence of resistance. Significant among them are Entecavir, Tenofovir, and telbivudine. The experience with these agents in the transplant population is increasing, although published data is scarce. Entecavir, a specific HBV DNA polymerase inhibitor, when compared with lamivudine, leads to a superior reduction in HBV DNA levels in patients naοve to nucleoside therapy.  Its dual efficacy against wild-type and lamivudine resistant strains of HBV, and its favorable toxicity profile make it an effective agent for use in post LT patients.
Tenofovir is a nucleotide analog that has potent inhibitory activity against lamividine resistant-, adefovir resistant-, and Entecavir-resistant strains. It has great potential and there are ongoing trials in post LT patients. [Table 2] provides a practical approach to the use of antiviral agents in managing HBV infection in LT.
| De Novo HBV Infection Post Transplant and Donor HBV Serostatus|| |
It is possible that HBV infection is detected following transplantation in patients who were not known to have HBV infection in the pre-transplant period. Such de novo HBV infection can be due to transmission via contaminated blood products or via healthcare personnel in the perioperative period. However, de novo HBV infection is more likely to represent the emergence of occult HBV infection, the source of which may be either the liver donor or the recipient. The clinical course of de novo HBV infection in the transplant recipient is often relatively mild when compared to the recurrent HBV in the transplant population, and may present as an asymptomatic elevation in aminotransferase levels.  Lamivudine is effective in individuals who go on to develop chronic infection. However, as in other circumstances, the prolonged use of this agent has the risk of the emergence of YMDD mutants.
There is a potential risk of de novo HBV infection in recipients of livers from anti-HBc positive donors. With sensitive PCR-based assays, low-level HBV viremia can be detected in the serum of anti-HBc positive liver donors.  The risk of transmission of HBV from core antibody positive donors is the highest in recipients who are anti-HBc negative and anti-HBs negative, and may be as high as 94% in the absence of a prophylaxis. It is recommended that prophylactic therapy should be instituted in instances when the liver donor is anti-HBc positive. Both HBIg and lamivudine, either as monotherapy or in combination, have been used in this setting. Many centers follow the policy of offering anti-HBc positive liver grafts to recipients who are either HBsAg positive or anti-HBs positive. However, de novo HBV infection has been seen even in recipients who are anti-HBs positive, indicating that prophylaxis is required even in the previously vaccinated LT recipients.
| Fibrosing Cholestatic Hepatitis|| |
Fibrosing cholestatic hepatitis (FCH) is a severe form of HBV-associated liver injury following LT.  Fibrosing cholestatic hepatitis is characterized by the histopathological findings of periportal fibrosis, cholestasis, and hepatocyte ballooning. HBsAg is present at very high levels in the cytoplasm of these hepatocytes. The degree of inflammatory infiltrate is generally mild. FCH may occur as a result of either recurrent or de novo HBV infection in the LT recipient. The clinical manifestation is one of rapidly progressive liver dysfunction. FCH is typically seen in the immunocompromised host, and cases have been reported in renal and bone marrow transplant recipients as well as in patients with the acquired immune deficiency syndrome (AIDS). ,
| Adoptive Immune Transfer|| |
In recipients of a live-related liver graft from an HBV-immune donor, adoptive immune transfer may result in de novo anti-HBS production in the recipient.
| Vaccination|| |
All potential LT recipients should be screened for HBsAg and anti-HBs. HBsAg-negative recipients, without evidence of HBV immunity, should undergo HBV vaccination. Unfortunately, the vaccine response rates appear to be poor in patients with advanced liver disease.Double-dose vaccination and newer HBV vaccines might be more successful.
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Room No. 313, Department of Gastroenterology, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi-110 060
[Table 1], [Table 2]