Liver transplantation is often the best option for hepatocellular carcinoma when this complicates cirrhosis because it treats not only the malignancy but also the underlying disease. Currently, the scarcity of donors is the main limitation in the treatment of this disorder, and increased time on the waiting list compromises survival even with the use of adjuvant therapies such as chemoembolization and ethanol injection.1 The use of living donors or marginal grafts has been successful in dealing with this situation. However, living donor programs are found in a small minority of transplant centers, and more institutions have been forced to resort to the use of anti-HBc–positive and other marginal organ donors. While organs from anti-HBc–positive donors have been associated with de novo hepatitis in seronegative recipients, this possibility can almost always be prevented with HBIg, antiviral therapy, or both.2, 3 Also, the risk for HBsAg-positive recipients should be minimal due to the need for immunoprophylaxis and/or antiviral therapy. Less than 10% of the general population, however, is HBsAg negative but anti-HBc–positive in low-risk areas for hepatitis B virus (HBV) infection such as the United States.4 Thus, other ways of expanding access to donors remain a high priority in patients with potentially transplantable hepatocellular carcinoma.
Chronic infection with HBV is the most common cause of hepatocellular cancer in the world today.5 One means of dealing with donor organ shortages that may be particularly well suited for HBV-infected patients with hepatocellular carcinoma involves the use of HBsAg-positive donors. Surprisingly, thus far there has been extremely limited experience with the use of organs from HBV-infected donors.6 Theoretically, this procedure could be accomplished successfully if the donor liver is free of significant disease and the donor has low serum HBV DNA levels (for example,102-103 copies/mL) as seen in an inactive HBV carrier. The latter can be difficult to ensure because the donor's HBV DNA status is seldom available at the time of transplantation, and some HBV carriers who lack liver disease are in the immunotolerant phase of infection and have high levels of viral replication.7 Another concern is that the HBsAg-positive donor should ideally be free of other hepatitis viruses, such as the hepatitis delta virus (HDV), because recurrent HDV infection could cause added liver injury after transplantation should immunoprophylaxis fail.8
In this issue of Liver Transplantation Franchello et al. describe their preliminary experience with the use of HBsAg positive donors for a group of patients with hepatocellular carcinoma.9 Three patients with rapidly evolving hepatocellular carcinoma received transplants by the Italian investigators. All three donors had low levels of serum HBV DNA and were free of HDV infection. The authors were able to do this as part of a protocol that the Italian Ministry of Health had approved for patients likely to die while awaiting an organ. Importantly, two of the three recipients in this study were coinfected with HDV. Despite both HBIg and lamivudine (the latter started several months before transplant in two of the recipients), all three recipients remained persistently positive for HBsAg after transplantation. Equally disturbing, both delta antibody–positive recipients developed clinically obvious delta hepatitis, which is one case was severe and greatly complicated the management of the patient. As the authors indicate, the use of HDV-infected recipients was problematic from a selection standpoint because in the setting of failed immunoprophylaxis, the inhibitory effects of lamivudine on HBV replication probably allowed HDV an opportunity to replicate and provide additional injury to the graft. The best outcome in their case series occurred in the single delta antibody–negative patient who did so well that, despite recurrent HBV infection, liver biopsy was not deemed necessary.
The report by Franchello et al. reminds us that patients with HDV coinfection can have serious damage to the liver graft when immunoprophylaxis fails.10 Accordingly, it is important to consider the means of treating HDV infection before and after transplantation. Nucleoside analogues have excellent safety profiles and can be easily given to patients with decompensated hepatitis B, but these drugs have not been successful in the treatment of delta infection.11 This is probably due to the fact that these agents work by suppressing HBV polymerase and do not result in clearance of HBsAg, which is an obligate protein if HDV is to survive. Interferon is the only antiviral that has been successfully used in the treatment of HDV and has the capacity to lead to HBsAg reduction or elimination, but the majority of patients would not be able to tolerate the side effects. It has been well documented that serious infections and life-threatening flares of hepatitis often occur when this drug is used in patients with moderate to severe hepatic decompensation.12 Thus, the treatment of HDV infection remains problematic in the pre-transplant setting and prevention of recurrent HBV infection (and associated HDV infection) after transplantation remains key.
What do the cases in the report by Franchello et al. teach us about the mechanism of action of HBIg? Traditionally, high doses of HBIg (10,000 IU) have been utilized in the anhepatic phase, then daily for the first week, weekly, monthly, and ultimately less frequently with the decision to reduce the frequency of administration based on the titer of antibody to HBsAg (anti-HBs).13 The mode of action of this material is not entirely clear, but it is generally thought to bind to free viral particles and thereby prevent attachment to receptors on noninfected cells. Recently, in vitro experiments in hepatocyte-derived cell lines have shown that HBIg also enters hepatocytes by endocytosis, then binds HBsAg and inhibits the secretion of HBV virions.14 If the primary mode of action of HBIg is through neutralization of circulating virus, as has been generally thought, failure to “prevent” infection in the cases described by the authors could have been anticipated, due to the fact that there was an established repository of virus within hepatocytes. The results of their study strongly suggest that intracellular inhibition of HBV secretion has little to do with the efficacy of HBIg.
While this study raises interesting questions, the data are by no means definitive in allowing one to judge why clinically severe HDV hepatitis became apparent after transplantation. The authors attributed this to the use of lamivudine therapy, which upset the balance between HBV and HDV replication. While this effect seems plausible, several questions also can be raised about the protocol the authors followed. For example, the protocol of HBIg administration used a nonconventional dose and the measurement of HBsAg by a qualitative assay does not permit an assessment of whether or not the HBsAg concentration in these patients was low. In the absence of this information, it can not be ascertained whether higher doses of HBIg might have further reduced HBsAg levels and diminished the chances for clinically apparent HDV reactivation.
The use of HBsAg-positive donors is unlikely to have significant impact on critical donor shortages in geographic regions with a low rate of HBV infection such as North America and Western Europe, where the carrier frequency is less than 1-2%. It can be argued that greater impact would be found in intermediate- to high-risk areas such as the Mediterranean region and Asia, where 5-15% of the population are chronically infected with HBV and where a considerable number of potential donors are inactive HBV carriers without liver disease or high serum HBV DNA levels.15 It is these same areas, however, where one also encounters more donors who are anti-HBc positive (20-60% of the general population), and the considerably lower level of transmissible virus in their livers should lead to preferential use of these organs instead.16
In conclusion, until more definitive evidence is forthcoming, it is probably best to avoid the use of HBsAg-positive donors in patients with HBV infection, particularly in recipients who are co-infected with HDV. The small study by Franchello et al. with only one positive outcome does not provide enough data to draw definitive conclusions. The recipient of an HBsAg-positive donor organ will remain HBsAg-positive, despite attempts at immunoprophylaxis, and the best that can be done is to control liver injury with antiviral therapy. While prolonged antiviral drug therapy may appear to be a reasonable trade-off in situations where HBsAg-positive patients are in dire need of transplantation, this situation is also likely to be a rare occurrence in low-prevalence areas for HBV infection and safer alternatives probably exist in the use of the anti-HBc–positive donor.