Liver Transplantation and Hepatitis B

What Are the Results of Liver Transplantation for Patients with Chronic Hepatitis B?

Because the liver is probably the largest reservoir of HBV, it was hoped that removal of the liver-combined with the blood loss and subsequent transfusion that occur with liver transplantation-would clear the virus from most patients. However, persistent HBV infection is found in 85% to 90% of patients who are positive for hepatitis B surface antigen (HBsAg) and have transplantation; this suggests that extrahepatic sources of HBV are responsible for reinfecting the graft [1, 5]. Although many of these infections may cause mild chronic hepatitis that does not significantly alter the patient's clinical course, some patients may have disease recurrence that leads to a rapidly progressive course [6]. The more aggressive disease syndrome is called fibrosing cholestatic hepatitis, and it often leads to death within days or weeks of onset. In addition, recurrent hepatitis B may evolve rapidly into cirrhosis, which can be further complicated by hepatocellular carcinoma [7].

Not only does HBV persist after transplantation, but survival is also diminished after the procedure. Patients in whom chronic hepatitis B is the primary liver disease necessitating transplantation have 1-and 5-year survival rates of 73% and 44%, respectively. Data from the United Network for Organ Sharing show that a diagnosis of hepatitis B is an independent predictor of increased risk for death [4]. In summary, liver transplantation for patients with chronic hepatitis B who do not receive specific post-operative therapy results in high recurrence rates and worse outcomes compared with transplantation for patients who have other chronic liver diseases.

Do Specific Subgroups of Patients with Hepatitis B Have a Better Outcome after Liver Transplantation?

Patients who have either HBV DNA (detected on standard hybridization assays) or HBe antigen (HBeAg) in serum are more likely to have recurrence of disease after transplantation than are patients who are negative for these traditional markers of active viral replication. Patients having transplantation for HBV who are also infected with the hepatitis D virus (HDV) seem to have a better outcome than do those without coexistent HDV infection; however, this may also reflect the absence of HBV DNA and HBeAg [8]. Patients who undergo transplantation for fulminant hepatitis B also have lower recurrence rates than do those who undergo transplantation for chronic disease [9]. Although these subgroups of patients with hepatitis B have lower recurrence rates and may have improved survival after transplantation, results are still suboptimal; therapy to prevent recurrence is therefore recommended in all HBsAg-positive patients who undergo liver transplantation.

Are Pre- or Post-Transplantation Therapies Available That Might Prevent Recurrence of Hepatitis B?

To prevent the recurrence of hepatitis B, one strategy would be to decrease HBV DNA levels or clear HBeAg before transplantation. Interferon-α has the potential to do this, but it has not been shown to be beneficial and may be dangerous in patients with end-stage hepatitis B because it may induce hepatic decompensation [10]. The nucleoside analogue and antiretroviral agent lamivudine reduces HBV DNA levels [11] and may decrease recurrence rates if given before transplantation, but more information is required. Clinical trials of this approach are under way.

In the early 1990s, European centers began reporting the results of high doses of hepatitis B immune globulin (HBIg) administered intravenously after transplantation. Early therapy (when viral load is lowest) is needed, and most centers use a dose of 10 000 IU at the time of surgery and daily for the first week after surgery. Monthly intravenous HBIg therapy is then continued indefinitely to maintain levels of antibody against HBsAg (anti-HBs) greater than 100 IU/L. A European multicenter study [9] showed that the rate of HBsAg recurrence was 75% in patients receiving no prophylaxis or very short-term HBIg treatment and only 33% in patients receiving long-term HBIg therapy. The benefit was due largely to the effect of HBIg on patients with HBV-related cirrhosis who did not have active viral replication (that is, who were negative for HBV DNA and HBeAg). Prevention of HBV recurrence also resulted in a survival benefit [9]. One report, although from a trial considerably smaller than the European multicenter study, suggests that the use of HBIg to keep anti-HBs titers greater than 250 IU/L may help to prevent HBV reinfection even in patients with active viral replication [12].

One limitation on the use of HBIg is the lack of U.S. Food and Drug Administration (FDA) approval for an intravenous HBIg preparation. Although some researchers have shown that reasonable levels can be obtained with intramuscular administration, the largest trials have used intravenous HBIg. An additional concern is the expense of the high doses of HBIg that are required. The estimated costs for the first year of intravenous HBIg therapy range from $15 000 to $38 000. Costs in subsequent years are between $4500 and $15 000 per year [13]. Nevertheless, most centers that perform transplantations for patients with HBV-related liver disease use HBIg despite the cost and the lack of U.S. Food and Drug Administration approval.

Hepatic xenografting is even more experimental. Although transplantation with a baboon hepatic xenograft has not led to long-term survival, the transplanted liver has not become infected with HBV. Unfortunately, extrahepatic HBV DNA persists, and the effect of this potential for re-infection on long-term outcome is currently unknown [14]. Hepatic xenografting has an uncertain future, but it may be applicable to some patients with hepatitis B.

Does Effective Therapy Exist for the Patient with Recurrent Hepatitis B after Transplantation?

Preliminary trials have shown that ganciclovir decreases HBV DNA levels. One group evaluated long-term ganciclovir treatment for recurrent hepatitis B in a small group of liver transplant recipients [15]. Serum HBV DNA levels decreased by 90%, and HBV DNA became undetectable in 44% of patients. This was often accompanied by a decrease in both alanine aminotransferase levels and the histologic expression of HBV antigens. Ganciclovir therapy is safe but expensive and will probably need to be continued indefinitely. Currently, intravenous ganciclovir for recurrent hepatitis B should be considered experimental. Famciclovir has been investigated in the post-transplantation setting, but its effects seem to be modest [16]. Lamivudine also has the potential to benefit patients who have recurrent hepatitis B after transplantation, although drug resistance has been reported [17].

Interferon-α is effective for the treatment of chronic hepatitis B in immunocompetent patients. Treatment with interferon-α 2b in 14 patients who had recurrent hepatitis B after transplantation resulted in a loss of HBeAg in 2 patients, 1 of whom also lost HBsAg [18]. Chronic rejection may occur with interferon; the agent should therefore be used cautiously in liver transplant recipients [19].

Final recommendations for liver transplantation in patients with hepatitis B should be made with the knowledge that an estimated 6000 patients are currently awaiting a liver donor. Approximately 600 patients on the waiting list die each year. Waiting list deaths and increasing waiting times mandate the optimal use of donor organs. On the basis of the above data, we suggest the following guidelines.

All patients with fulminant hepatitis B should be considered candidates for liver transplantation. For patients with chronic hepatitis B and cirrhosis who do not have the traditional markers of viral replication, the long-term survival with HBIg after liver transplantation is similar to that after liver transplantation for other diseases. Therefore, these persons should be considered acceptable candidates for transplantation. Most patients with HDV infection complicating hepatitis B also have good survival and should be included as transplantation candidates. All patients should receive HBIg therapy indefinitely after liver transplantation. Transplantation for these HBV-infected patients would be facilitated by FDA approval of an intravenous HBIg preparation, less expensive HBIg, and recognition by third-party payers that this group of patients has an acceptable outcome after transplantation.

Finally, the most controversial recommendation concerns patients with hepatitis B and cirrhosis who are positive for HBV DNA or HBeAg at the time of liver transplantation. Because the largest series suggests that these patients have high recurrence rates even with the administration of HBIg [19], we recommend liver transplantation at this time only in the context of a clinical trial. Perhaps the attainment of higher levels of anti-HBs with HBIg therapy with or without lamivudine will improve outcomes in this group, albeit at a substantial increase in cost. In addition, the results of current trials investigating preoperative lamivudine in such patients are eagerly awaited.

Liver transplantation should remain a viable option for many patients with hepatitis B-related chronic liver disease. Further work with antiviral agents and immunoprophylaxis is needed in the effort to improve outcomes and lessen the chance for recurrence. In addition, new antiviral agents should be considered for testing in patients who have recurrent hepatitis B after liver transplantation. Measured outcomes should include not only graft and patient survival but also quality of life and resource utilization.

John J. Poterucha, MD

Russell H. Wiesner, MD

Mayo Clinic; Rochester, MN 55905