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Hepatitis B remains worldwide one of the most common causes of end-stage liver disease and hepatocellular carcinoma. In much of Asia, it is the most common indication for liver transplantation. In the West, it remains a relatively small but still very important indication for liver transplantation. In the United States, approximately 7% of transplants are due to hepatitis C, whereas in Europe, almost 40% of patients undergoing transplantation for viral hepatitis have hepatitis B.1
The initial enthusiasm for performing liver transplantation in patients with chronic hepatitis B virus (HBV) infection was tempered in the early 1990s by a high rate of recurrent infection with subsequent development of severe recurrent hepatitis, which frequently led to loss of the allograft.2 In the absence of effective therapy, recurrent infection, defined as the appearance of detectable hepatitis B surface antigen (HBsAg) in serum following transplantation, occurred in 70% to 90%2 of patients who were HBsAg(+) preoperatively. The subsequent histologic findings of hepatitis were seen in most patients, including the lesion, which has been termed fibrosing cholestatic hepatitis.3 This lesion is marked by overexpression of HBV proteins in hepatocytes, with cellular swelling and cholestasis but only minimal inflammation. This suggests that HBV may be directly cytopathic in the posttransplant setting.
Data from the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database show that patients undergoing liver transplantation in the years 1990-1992 for hepatitis B had the worst outcomes, along with transplantation for malignant disease4 (Fig. 1). However, even at that time, it was known that those who cleared HBsAg following transplantation generally had normal liver histology and a benign clinical course.5 However, things changed dramatically throughout the 1990s. With our ability to prevent reinfection in most recipients, survival has improved to the point that, at present, patients transplanted for hepatitis B enjoy the best outcomes in terms of patient and graft survival6 (Fig. 2).
ALD, alcoholic liver disease; anti-HBs, antibody to hepatitis B surface antigen; HBIg, hepatitis B hyperimmune globulin; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; OLT, orthotopic liver transplantation.
RISK FACTORS FOR REINFECTION
We have known for many years that the patients at risk for developing hepatitis B reinfection are those with the greatest degrees of viral replication, as indicated by the presence of hepatitis B e antigen and high-titer HBV DNA in serum. Patients who undergo transplantation for acute hepatitis B or who are coinfected with hepatitis D virus (HDV) are also at lower risk for reinfection.
Fortunately, we now have a number of effective antivirals (Table 1) that allow the physician to markedly decrease HBV DNA levels prior to transplantation. The goal of pretransplant antiviral therapy should be that HBV DNA is undetectable at the time of transplantation.
Table 1. Antivirals Against Hepatitis B Virus
Tested in Liver Transplant Recipients
The major advance for patients transplanted for hepatitis B was the ability to prevent reinfection with high doses of hepatitis B hyperimmune globulin (HBIg). A seminal paper published by a multicenter consortium in Europe5 demonstrated that giving very high doses of intravenous HBIg to maintain antibody to hepatitis B surface antigen (anti-HBs) titers > 100 IU/mL for periods of >1 year could prevent reinfection in the majority of patients. By the prevention of reinfection, the outcomes of transplantation for hepatitis B were markedly improved (Fig. 3). Using HBIg alone was most effective at preventing HBV reinfection in those at lower risk for recurrent infection, that is, patients with HDV coinfection, patients with acute hepatitis B, or patients who were HBV DNA(−) in serum.5, 7 Although the use of HBIg was never subjected to a randomized control trial, there certainly was no need because the differences in outcomes with HBIg versus outcomes without HBIg were so dramatic. No one needed convincing. However, the intravenous administration of HBIg is quite costly, that is, currently $74,320 for 8 daily doses of HBIg during the first week post–orthotopic liver transplantation and monthly doses thereafter in the United States and approximately $45,000 per annum after year 1 (local data). Moreover, it can lead to significant side effects such as back pain.8 It also requires a great deal of nurse coordinator time to be certain that patients are indeed scheduled for and receiving HBIg. In some programs, HBIg has been dosed on the basis of hepatitis B surface antibody titers, and this is even more time-consuming for the coordinators, who also have to track the antibody titers. Finally, when used alone, it may be required for life. Moreover, late breakthroughs have also occurred in patients who develop a variety of mutations in the HBV S gene.9
In the mid 1990s, antivirals began being used for the pretransplant and posttransplant management of patients undergoing liver transplantation. The goal of the therapy was to reverse the symptoms of decompensated liver disease, and this indeed occurred in many patients. In this way, the risk of liver-related mortality was reduced, and it even eliminated the need for liver transplantation for some patients. Most importantly, antiviral therapy decreased the risk of HBV reinfection post-transplant.
The first agent that was used for antiviral prophylaxis was lamivudine, which was discovered serendipitously in human immunodeficiency virus patients to have anti-HBV activity. Studies subsequently showed that lamivudine even used alone could decrease the number of hospital admissions, requirements for large-volume paracentesis, episodes of spontaneous bacterial peritonitis, and episodes of encephalopathy in patients with advanced hepatitis B.10 In fact, almost 85% of the patients improved with lamivudine to the point that approximately 20% could be removed from the wait list. However, the major problem with lamivudine is the development of drug resistance. The site of resistance is generally in the YMDD motif of the HBV polymerase.11 Resistance developed in as many as 30% of patients within the first year and in almost 80% of patients by 5 years. Resistance leads to HBV reinfection and then can lead to rapidly progressive liver disease and death.12 However, we now have other antivirals available (eg, adefovir) with different sites of resistance that can rescue such patients.13
Finally, it should be noted that the drugs are very well tolerated in transplant recipients with no interactions with the immunosuppressive agents and few if any side effects.
A second major advance was the recognition that combining antivirals with HBIg post-transplant could markedly decrease the rate of acquired drug resistance and, subsequently, reinfection.14, 15 Moreover, it was shown that by using combination therapy, one could use much lower doses of HBIg and still achieve effective prophylaxis against HBV reinfection. In fact, a group from Australia and New Zealand showed that using antivirals with much lower doses of HBIg (given intramuscularly) results in equivalent prevention of HBV reinfection at a fraction of the cost.16 With such regimens, the rate of HBV reinfection post-transplant has decreased to 5% or less.
With these sorts of results, one might question the wisdom of attempting to develop an HBIg-free regimen. However, not only did the introduction of adefovir to our HBV armamentarium in the early part of this century allow us to rescue patients who developed lamivudine resistance, but the combination of adefovir and lamivudine (a nucleoside and nucleotide analog combination) markedly decreased the risk of HBV-infected patients developing resistance. This then set the stage for several groups, including our own at the University of Minnesota,17 to explore the use of antivirals alone as HBV prophylaxis. What drives this research is predominantly the cost of HBIg. It also makes the job of transplant coordinators much easier, in that they do not have to monitor anti-HBs levels or coordinate the administration of HBIg. At the University of Minnesota, we have limited HBIg dosing to the first week; it is followed only by combination antivirals over the long term. Our protocol is to begin the patients on lamivudine and adefovir if they have an HBV DNA level that is greater than 104 IU/mL. If it is less than 104, we start with adefovir as a single agent. Post-transplant, recipients receive only 1 week of daily intravenous HBIg, and then they are maintained on oral lamivudine plus oral adefovir over the long term. In our initial report,17 we reported 32 patients: 77% had HBV alone, whereas about 23% were coinfected with hepatitis C virus. Thirty percent had concomitant hepatocellular carcinoma, and only 8% were HDV(+). Twenty-three percent were HBeAg(+); 70% were HBV DNA–positive with a mean viral load of approximately 107 IU/mL. Almost 90% received pretransplant antiviral therapy, and 80% of them had a documented decrease in viral load before they underwent transplantation.
This regimen has yielded excellent results.17 Thus far, we have 100% patient and graft survival in this group. All patients have normal liver tests with a mean follow-up of 2 years, and only 1 patient developed reinfection; that patient, with a HBV DNA level > 108 IU/mL, was transplanted 1 day after beginning his antiviral therapy. Similar data have now been generated by the Australia/New Zealand Liver Transplant Consortium (the study is in press), and I will not discuss it further in this article.
Clearly, the most important problem over the long term is going to be identification of the people who acquire drug resistance. Resistance can be detected in 4 major ways. First, the patient can experience clinical deterioration. Hopefully, we would have identified acquired resistance before that point in time. It may also be identified by a simple rise in alanine aminotransferase levels or a rising HBV DNA level and the appearance of HBsAg in serum. Finally, there are now assays for genotypic markers of drug resistance.
It is important to understand which mutations correlate with resistance to specific agents in the polymerase gene to know how best to rescue resistant patients. In general, the patients with lamivudine or telbivudine resistance will respond to adefovir or tenofovir. Entecavir can also rescue lamivudine-resistant recipients when used at double the standard dose. However, the exact rate of acquiring resistance to entecavir over the long term in this setting is not clear.
It is important to emphasize that the development of resistance in a transplant patient is much more significant than the development of resistance in a patient being treated for chronic hepatitis B in the nontransplant setting. The development of resistance in a transplant patient means reinfection and thus puts the patient at risk for downstream events of that reinfection, such as hepatitis and even hepatocellular carcinoma. Thus, one can argue that it is much more important to prevent reinfection in the transplant patient.
An additional way to provide long-term immunoprophylaxis against HBV without the use of HBIg is an active vaccination program. Some success has been obtained with second-generation vaccines. One series reported a response rate of 50% in lamivudine-treated posttransplant recipients.18 In most, the anti-HBs titer was >100 IU/mL, and it was sustained in approximately two-thirds of responders. In addition, the same group has demonstrated passive transfer of HBV-specific immunocompetent T and B cells from HBV immune live liver donors in almost 60% of recipients.19 In some of the recipients, there was spontaneous hepatitis B surface antibody production. It remains to be determined how this might be exploited and whether antibody production can be sustained (eg, using novel vaccines).
In summary, I believe that through the use of combinations of antiviral agents we now are able to avoid the use of long-term HBIg. By doing so, we will avoid its side effects and cost and still enjoy excellent outcomes in a most cost-effective way. It is important to recognize the resistance patterns that develop with these drugs in order to develop combinations that maximally diminish the likelihood of drug resistance.