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Michael Peter Manns, Heiner Wedemeyer, Hans Ludger Tillmann
Departent of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Germany
The treatment of hepatitis B virus infection is particular in certain patient groups such as patients prior to and after kidney transplantation and heart transplanted patients. For all these patient group interferon alpha is either of limited efficacy or even contraindicated. However, lamivudine is highly effective in these patients. If resistance emerges a newer nucleoside analogue, adefovir, has become available.
Furthermore the approach to treat and prevent HBV reactivation in immunosuppressed patients is crucial. Here, the prevention of reactivation is better than treating the reactivation. As the prevention of reactivation usually is only required for a limited time frame the risk of resistance development will be rare.
Finally, fulminant hepatitis is a severe course of acute hepatitis frequently progressing to fulminant hepatic failure. Once liver failure has developed a conservative approach is unlikely to prevent the need of liver transplantation. However, in the early phase of fulminant hepatitis, when severe impairment of liver function is already evident but encephalopathy still absent treatment with nucleosides, especially lamivudine, may be effective.
An estimated 350 million worldwide are infected with the hepatitis B virus (HBV). More than 90% of immunocompetent adult patients clear the HBV after acute infection. In contrast, chronicity develops more frequently in immunocompromised patients, e.g. up to 60% in dialysis patients. After organ transplantation, HBsAg clearance occurs only occasionally. Additionally, as the hepatitis B virus frequently persists even after clearance of HBsAg from the circulation, patients undergoing organ transplantation may suffer HBV reactivation. This is of special importance in patients receiving bone-marrow-transplantation (BMT). In addition organs from donors who are anti-HBc (+) but HBsAg (-) still can transmit HBV infection. While this has frequently been observed after liver transplantation it may also occur with other organ transplantations.
The purpose of this review is to summarise the data on the relevance and treatment of HBV infection in hemodialysis patients and patients after kidney or heart transplantation. Additionally we discuss reactivation of hepatitis B and its treatment in organ transplant recipients and patients undergoing chemotherapy. Finally, we review the data on severe acute and fulminant hepatitis B and the available evidence for preventing liver failure in these patients by early treatment with antiviral agents.
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Due to the high infectivity of HBV and its infection route, many patients requiring dialysis have been infected with HBV in the past associated with blood transfusion and the dialysis procedure itself., ,  However, the introduction of vaccination against HBV has decreased the overall prevalence of HBV infection in this patient group from above 10% in the early 90-ties to below 5% at the turn of the century in most European countries.,  Active HBV vaccination is recommended for all patients with end stage renal disease (ESRD). However, non-response or incomplete response to standard HBV vaccines are more frequent in these patients. Thus general precautions for the prevention of viral transmission are still mandatory.
A number of studies have shown that hepatitis C virus infection can be successfully eliminated with interferon-a in dialysis patients, but side effects are usually higher than in “normal patients”.,  If HCV has been eliminated during dialysis, reactivation after transplantation is rare. In contrast to HCV, neither interferon-a nor nucleoside analogues induce complete HBV elimination. Thus reactivation after transplantation can not be excluded in the case of HBV infection.
No controlled trials for the treatment of HBV with either lamivudine or interferon in dialysis patients are currently available. A single case series describes an HBeAg seroconversion in 3 of 9 dialysis patients treated with interferon-a, thus being not significantly different from immunocompetent patients.
Indications for treatment intervention should thus be similar to immunocompetent patients. We would recommend to perform a liver biopsy if transaminases are elevated. Because of side effects, nucleosides appear to be superior to interferon in this patient population. The potential development of viral resistance to lamivudine should not result in withholding this treatment, as newer options with efficacy against lamivudine resistant HBV will be approved in the near future, and are available through an expanded access program..
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Since many patients have acquired HBV during the time on dialysis, chronic HBV infection can be found in a significant number of kidney recipients. While short term studies with a mean follow-up below 10 years after transplantation often failed to detect a negative effect of HBV infection in this patient population studies including more than 10 year of follow-up usually show impaired survival of HBsAg positive kidney recipients., , ,  Liver failure becomes the leading cause of death in HBsAg positive patients 10 years post kidney transplantation.13 It is also important to note that the natural course of chronic hepatitis B is worse than that of hepatitis C after renal transplantation..
Thus, treatment approaches against HBV are needed in this population. Interferon can lead to rejection precluding its use,, . In some cases a remarkable response to interferon has been observed in single cases,, , . However, a larger case series from Poland did showed disappointing results. Fortunately, alternative options became available in the recent years, which are not associated with the induction of rejection. While famciclovir had been of limited efficacy similar to its use in liver transplant recipients, lamivudine leads to biochemical remission and reduction of viral load in up to 100% of treated patients. Still resistance can emerge, and newer options are needed.
There is a special severe form of hepatitis B occurring in immunosuppressed patients, so called fibrosing cholestatic hepatitis (FCH). This condition was originally described in patients after liver transplantation, but has also been reported in other immunocompromised patients. It is characterized clinically by cholestatic liver disease, and by severe periportal fibrosis, cholestasis, widespread balloon degeneration of hepatocytes, and only mild infiltration of inflammatory cells. Without treatment, FCH is universally fatal within a few months after diagnosis. However, some cases of successful intervention with lamivudine have recently been reported. Interestingly, while the response to lamivudine was only limited for a few weeks in liver transplant recipients a long term response was observed in kidney recipients., , 
In summary, chronic hepatitis B leads to reduced survival in the second decade after renal transplantation and thus requires treatment. Due to the risk of rejection interferon-a is not recommended. Lamivudine is effective, in case of resistance adefovir should be considered.
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Heart transplant recipients
In the 1980-ties it has been recognized that HBV infection can be a cause for impaired liver function in heart transplanted patients. This led to the recommendation that patients awaiting heart transplantation should be vaccinated against HBV. If immunity against HBV is achieved, either by previous infection or by vaccination, even HBsAg positive organs can be transplanted without the induction of HBV infection. Here, it is important to note that patients undergoing heart transplantation should be vaccinated prior to transplantation due to the low response rates achieved after transplantation.
Chronic hepatitis B after heart transplantation is surprisingly frequent. Outbreaks of HBV infection have been identified in several heart transplant centers. Patients frequently acquired HBV during the procedure of endomyocardial biopsies,, ,  which they had to undergo for control of rejection.
In our centre survival was shown to be similar in HBsAg-positive and -negative patients during the first decade after transplantation in a large study including 74 HBsAg-positive heart transplant recipients. However and similar to the experience in kidney recipients, the survival of HBsAg-positive patients is impaired after more than 10 years after transplantation.,  Up to one third of the patients die from liver failure and hepatocellular carcinoma may develop.40 In accordance with our data, another recent study showed no impaired survival during the first 5 years after transplantation.37 However as outlined above, a five year follow-up is too short, as the impairment becomes evident in the second decade. Similar to the experience in other organ transplantations, the course of HBV infection is more severe than that of HCV infection after heart transplantation.
Thus, treatment is highly warranted for these patients with long term survival. Different nucleosides have been used in heart transplant recipients. In 1996, Amand et al. were able to show a benefit of gancilovir, which led to a remarkable improvement of disease activity in a heart recipient who had developed decompensated liver disease due to HBV infection.. In 1997, we initiated a controlled study for the use of famciclovir in HBsAg-positive heart transplant recipients. While virological and biochemical responses were weak using famciclovir, a remarkable improvement in histological grading and staging was observed after a median of 8 months of therapy (s. Figure 1). Due to incomplete virological response or development of resistance, most patients were switched later on to lamivudine, which is nowadays widely used as a first line therapy in these patients. Similar to patients after kidney transplantation, adefovir, (expected to be approved within the year 2003 in many countries) can be used when lamivudine resistance develops.
In summary, as interferon can induce rejection, which might be fatal in heart transplantats, we regard this option as absolutely contraindicated. With direct antivirals, such as nucleoside analogues, not only a biochemical and virological response but also a reduction of liver inflammation and regression of fibrosis can be achieved leading to improved long-term survival. It should be emphasized that not all HBsAg-positive patients necessarily need therapeutic intervention. Thus, we recommend a liver biopsy prior to the start of an antiviral therapy.
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Hepatitis B Virus Reactivation
Reactivation of hepatitis B infection can frequently be observed during cancer chemotherapy in chronic HbsAg carriers especially, when immunosuppressive treatment is stopped, the return of immune competence can be followed by liver damage of varying degrees of severity, including fulminant hepatitis. Hepatitis B flares, during or shortly after chemotherapy, have been reported for more than 20 years. It is a frequent problem, occurring in 21-53% of chronic HBsAg carriers., ,  Acute hepatitis caused by HBV reactivation may be severe, with jaundice occurring in 10-22% of cases and mortality rates from acute liver failure ranging from 4% to 41% of affected patients.47, , ,  It is not possible to predict the occurrence and the clinical severity of HBV reactivation on an individual basis. The use of corticosteroids among the protocol drugs has to be considered a predisposing factor for treatment-induced HBV reactivation. , 45, , 52a The frequency of reactivation after chemotherapy cycles that did or did not include corticosteroids was 47% and 8%, respectively. Furthermore, it has been reported that the frequency as well as the severity of HBV flares were higher in HBeAg-negative patients.45, 47, 50 Furthermore, it is important to note that reactivation can also emerge in anti-HBc positive but HBsAg negative patients as HBV persists even after clearance of HBsAg.,  Thus PCR based detection of HBV-DNA prior to chemotherapy is recommended., 
Viral hepatitis may cause delays and reductions in the application of cytostatic drugs, and may hinder the continuation of the treatment programme. With the more widespread use of chemotherapy and stem cell transplantation, the possibility of HBV reactivation is becoming a significant problem that may ultimately affect the outcome of cancer treatment.
Thus the prevention of such reactivation is highly desired. As chemotherapy usually only lasts for a few months, a suppression of HBV is only required for about half a year. Within this short time period the development of viral resistance to currently applied nucleosides is unlikely to occur.
Recombinant a-interferon has been widely administered, but its haemopoietic toxicity precludes its use as a prophylactic agent in association with aggressive chemotherapy. In addition, interferon-a is anticipated to be of low efficacy in immunocompromised patients. Nucleoside analogues, such as famciclovir and lamivudine, are active against HBV by interfering with viral DNA replication. Lamivudine has been used extensively and has been proven effective both in the treatment and as a prevention of chemotherapy-related HBV reactivation.46, ,  However, treatment of HBV reactivation does not completely avoid the significant risk of fulminant hepatitis, particularly in HBeAg-negative patients. Thus, primary prevention of HBV reactivation appears to be a more appropriate strategy. Famciclovir was effective in reducing the incidence of HBV reactivation after allogeneic bone marrow transplantation. As shown previously, only about one third of the patients show a good response to famciclovir, while non response to lamivudine is rare. The toxicity profile of lamivudine is particularly favourable because it does not overlap with that of cytostatic agents, making lamivudine particularly suitable for the simultaneous use with chemotherapies. Indeed, recent pilot studies confirmed the feasibility to prevent hepatitis B reactivation with lamivudine., 
In summary, a prophylactic antiviral treatment with lamivudine appears to be indicated for HBsAg positive patients undergoing highly immunosuppressive therapy. A close monitoring of anti-HBc positive / HBsAg negative patients is recommended, and antiviral treatment should be started only if HBsAg turns positive or HBV-DNA levels increase.
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Fulminant hepatitis B
Fulminant hepatitic failure may develop in about 1% of patients suffering from acute hepatitis B. In addition, as outlined above fulminant hepatitis can emerge in immunosuppressed patients. Without liver transplantation, death occurs in the majority of patients with acute fulminant hepatitic failure., , ,  However, in patients with underlying malignancies liver transplantation is contraindicated. No therapy is currently established for fulminant hepatitis B. Foscarnet has been reported useful in a patient with fulminant hepatitis B. The success to prevent death or transplantation has been related to the influence of therapy on the immune function rather than on the level of HBV replication..
For the therapy of chronic hepatitis B, two approved treatment options are currently available: interferon-alpha or lamivudine. Interferon is immune-stimulating and thus may be dangerous in fulminant hepatitis B, where overwhelming immune reaction is believed to be involved in the pathogenesis.,  In contrast, the oral nucleoside analogue lamivudine inhibits hepatitis B viral replication with an immediate decline of serum HBV-DNA. Furthermore, lamivudine’s adverse event profile has been shown to be similar to placebo., 
In the absence of alternatives lamivudine has been used in a few patients with fulminant hepatitis B due to reactivation following organ transplants or anticancer therapy, , , .
However, no published data are available for fulminant hepatitis B. Thus, it is a matter of debate whether lamivudine therapy should be initiated in patients with fulminant hepatitis B, as there has been concerns that lamivudine treatment might be dangerous in fulminant hepatitis B or useless, since HBV-DNA is usually low in these patients. Based on the excellent safety profile of lamivudine, we started treating patients with fulminant hepatitis B with lamivudine immediately after the diagnosis of a fulminant course. Patients were treated with lamivudine 150mg daily (s. Figure 2). All except one of eight patients treated with lamivudine recovered quickly without adverse events. The only patients requiring transplantation despite lamivudine therapy had also ingested paracetamol, (Tillmann et al, unpublished data).
In Summary, lamivudine is safe in patients with fulminant hepatitis B, and might have the potential to prevent fatal liver failure or liver transplantation when administered early. Prospective controlled trails are necessary in order to establish a medical treatment for fulminant hepatitis B.
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