Successful use of hepatitis B surface antigen–positive liver grafts in recipients with hepatitis B virus–related liver diseases^†

The worldwide discrepancy between the availability of suitable liver donors and the need for liver transplantation (LT) has forced many centers to accept so-called marginal grafts that previously might have been discarded. In this extended pool, liver grafts from hepatitis B surface antigen (HBsAg)–positive donors without significant liver disease may be suitable only for hepatitis B virus (HBV)–infected patients in the absence of ideal donor organs: these grafts inevitably lead to HBV reactivation or de novo hepatitis in the absence of immunoprophylaxis. However, the experience with the transplantation of these grafts into HBsAg-positive recipients is extremely limited, and the number of patients involved in these studies (mostly single case reports) is too small for firm conclusions to be drawn.

The prevalence of HBV in the general Chinese population is very high (the HBsAg-positive rate is approximately 10%), and a considerable number of potential donors are inactive HBV carriers without significant liver disease.1 In this study, we report our experience with the transplantation of liver grafts from HBsAg-positive donors into 6 HBV recipients; our goal is to evaluate more carefully whether posttransplant outcomes are affected when HBsAg-positive donor livers are matched to HBsAg-positive recipients.

Six patients with HBV-related end-stage liver disease received liver grafts from HBsAg-positive donors; they provided informed consent after they were warned about the potential for a poor prognosis and the increased risks for living donors. All procedures were approved by the West China Hospital Ethics Committee, and in accordance with the ethical guidelines of the Declaration of Helsinki. The initial hepatitis B prophylaxis regimen and the immunosuppression protocol adopted by our center have been described previously.2

The clinical characteristics of the 6 recipients are summarized in Supporting Table 1. There was no evidence of a coinfection with hepatitis C virus, hepatitis D virus, or human immunodeficiency virus in any of the patients, and no patient was confirmed to have developed tyrosine-methionine-aspartate-aspartate mutants at the time of LT. The mean length of the hospital stay after LT was 30.2 ± 17.6 days (range = 15-64 days). All recipients except recipient 3 recovered promptly after LT and experienced a quick normalization of their liver enzyme levels and blood coagulation function. Because of the severity of recipient 3's disease, his liver enzyme levels, blood coagulation function, and serum creatinine level normalized 2 months, 1 week, and 38 days after transplantation, respectively.

Unfortunately, all the patients still remained HBsAg-positive after LT. Their titers for the antibody to HBsAg were not increased to 100 IU/L even with 1200 IU of hepatitis B immunoglobulin (HBIG) every 2 weeks. Hence, HBIG was discontinued after LT (mean = 6 ± 1.9 months, range = 3-8 months), and the initial prophylaxis protocol was replaced with a therapy combining lamivudine and adefovir. Serum HBV DNA became undetectable in recipients 1, 2, and 3 in postoperative months 2, 1, and 3, respectively, and it remained undetectable. Recipients 4, 5, and 6 were always HBV DNA–negative. During a mean follow-up of 22.5 ± 19.3 months (range = 5-60 months), all 6 recipients remained alive and showed no evidence of a hepatitis flare-up or lamivudine or adefovir resistance, and 4 recipients with hepatocellular carcinoma showed no signs of tumor recurrence.

During the follow-up, recipients 1, 2, and 4 each suffered 1 episode of liver function deterioration, and the remaining patients continued to have stable liver function profiles. The deterioration of recipient 1's liver function occurred in posttransplant month 13. A liver biopsy sample demonstrated acute allograft rejection and a chronic HBV infection, but there was no evidence of a hepatitis flare-up [the presence of HBsAg (15%) in the absence of hepatitis B core antigen according to immunohistochemistry]. Her liver biochemistry results normalized after a single 3-day course of pulse intravenous methylprednisolone therapy (500 mg/day). For recipient 2, a postoperative anastomotic biliary stricture led to the deterioration of liver function in postoperative month 21. His liver biochemistry results normalized promptly after he underwent endoscopic nasal biliary drainage. For recipient 4, 1 episode of biopsy-confirmed acute allograft rejection with no evidence of a hepatitis flare-up occurred in postoperative month 11, and his liver biochemistry results also normalized after 2 separate 3-day courses of pulse intravenous methylprednisolone therapy (500 mg/day).

The clinical characteristics of the related donors are listed in Supporting Table 2. There was no evidence of a coinfection with hepatitis C or human immunodeficiency virus in any of the donors. The liver function was normal for all donors except donors 5 and 6, who had mildly elevated liver enzyme levels. Donor 2, who was a cousin of recipient 2, donated his right lobe liver graft without a middle hepatic vein (531 g); the graft-to-recipient weight ratio was 0.98%. After surgery, his liver enzyme parameters rapidly returned to the normal range. Although his viral marker status remained HBsAg-positive, there was no evidence of HBV replication during the follow-up.

In the English literature, there is a report by Franchello et al.,3 who in 2005 described their preliminary experience in Italy with the use of organs from HBsAg-positive deceased donors in 3 patients with hepatocellular carcinoma. The follow-up for this series ranged from 10 to 13 months, and 2 of the patients continued to have persistently elevated liver enzyme levels because of a hepatitis D virus coinfection. A group from Canada published a case report of an HBV-infected patient who was coinfected with hepatitis C virus and safely received an HBsAg-positive deceased donor graft.4 Subsequently, Hwang et al.5 and Soejima et al.6 reported 2 cases in which an HBsAg-positive living donor liver graft was successfully transplanted into a patient with HBV-related cirrhosis.

The most significant disadvantage for HBV-infected recipients of HBsAg-positive grafts is the persistent HBsAg-positive status after LT despite high-dose HBIG prophylaxis. One potential mechanism contributing to this phenomenon is the ability of an HBsAg-positive graft to continuously produce such large amounts of HBsAg that HBIG cannot by itself neutralize the circulating and intracellular HBsAg.7 For this reason alone, the early discontinuation of HBIG may be a reasonable choice for HBV-infected recipients of HBsAg-positive grafts, but the optimal withdrawal time still needs to be determined. After the discontinuation of HBIG, a therapy combining lamivudine and adefovir, which have different mechanisms of action and no cross-resistance, is regarded as the most common regimen for providing an effective barrier against the development of multidrug-resistant HBV. The outcomes of our study and other studies5, 6 also confirm the efficacy and safety of this approach. New drugs such as entecavir, telbivudine, and tenofovir are probably candidates for oral antiviral therapy in these special circumstances.

For us, a major issue is the possibility of a posttransplant hepatitis flare-up in HBV recipients of HBsAg-positive grafts, which could lead to rapid disease progression. We did not observe an association between these grafts and worse survival in this study. Even though 3 patients experienced a deterioration of their liver function, this was unrelated to a hepatitis flare-up. We have the same concern about living donors. Donor 2 recovered rapidly after hepatectomy and showed no signs of a hepatitis flare-up during his follow-up. However, until there is more definitive evidence, it is probably best to avoid the use of HBsAg-positive living donors because there is no reason to worry about donor safety when organs from deceased donors are being used.

The histological grade of chronic hepatitis B and its stage provide important information about hepatitis activity and the likelihood of progression to cirrhosis in HBsAg-positive liver grafts. However, this scoring system may be affected by sampling and observer variability. In addition, because chronic hepatitis B slowly progresses to cirrhosis, a liver biopsy sample taken at one point will not fully demonstrate the liver disease status.

In conclusion, the findings of this study imply that HBsAg-positive liver grafts may be an acceptable alternative for recipients with HBV-related end-stage liver disease when no other donor organs are available. However, until there is more definitive evidence, it is probably best to avoid the use of HBsAg-positive liver grafts, especially from living donors.