EXPERIMENTAL AND CLINICAL TRANSPLANTATION

De novo hepatitis B infection in patients receiving liver transplants from hepatitis B core antibody-positive donors is well known, but the effective prevention strategy has not been well established. In our hospital, recipients receive hepatitis B immunoglobulin monotherapy if they are hepatitis B surface antigen negative at the time of transplant and are receiving a liver from a hepatitis B core antibody-positive donor. Since August 2006, we have had 4 patients who were naïve to hepatitis B virus and received a hepatitis B core antibody-positive graft. Two patients died of other causes, and 2 patients, who had liver transplant in October 2006 and October 2009, developed de novo hepatitis B. Both patients were tested annually for serum hepatitis B surface antigen as part of routine visit. Tests were negative; however, both patients recently became hepatitis B surface antigen positive. Other laboratory results, including liver function test, were unremarkable, except HBsAb titer was undetectable even though hepatitis B immunoglobulin monotherapy had been administrated 2 months previously in both patients. The patients had hepatitis B virus DNA levels of 3.07E+08 copies/mL and 1.51E+08 copies/mL. We suggest that additional prophylactic therapies above hepatitis B immunoglobulin monotherapy are needed for these recipients.

Key words : Liver transplant, Recurrence, De novo infection, Outcome

De novo hepatitis B infection in patients who receive liver transplant from hepatitis B core antibody-positive (HBcAb-positive) donors is well known,^1-5 but the effective prevention strategy has not been well established. Prophylactic therapy can include either hepatitis B immunoglobulin (HBIG),^6-8 or a nucleoside analogue alone,^9-11 or a combination of HBIG and nucleoside analogues.^12-14 In this article, we present 2 cases of hepatitis B-naïve recipients who received HBcAb-positive grafts and who developed de novo hepatitis B infection during prophylaxis with HBIG alone, as well as a review of the literature.

Since August 2006, fifty patients have received liver transplants at our hospital. Of these, we had 4 recipients who were naïve to hepatitis B virus (HBV) infection and received HBcAb-positive grafts. Our institution’s protocol is to treat these patients with 10 000 IU of intravenous HBIG for 4 days, including the operative day, and then to continue with intra-venous HBIG to maintain serum hepatitis B surface antigen (HBsAg) levels greater than 100 IU/L, with HBsAg levels tested annually. Of the 4 recipients, 2 died of other causes shortly after liver transplant, and 2 patients experienced de novo hepatitis B infection.

Case 1
In October 2006, a 48-year-old man who presented with alcoholic liver cirrhosis and hepatocellular carcinoma received a liver transplant from his brother. The recipient’s serologic tests for HBV showed that HBsAg, hepatitis B e-antigen (HBeAg), hepatitis B e-antibody (anti-HBe), hepatitis B c-antibody, and hepatitis B s-antibody were all negative. The donor had negative HBsAg and HBeAg results and positive anti-HBe, hepatitis B c-antibody, and hepatitis B s-antibody results. The recipient’s recovery after transplant was uneventful, including no rejection or recurrence of hepatocellular carcinoma. Routine HBsAg results were negative for this patient until January 2014, when his serum became positive for HBsAg. Other laboratory findings, including liver function test, were unre-markable, except HBsAb titer was undetectable even though 10 000 IU of HBIG had been administrated intravenously 2 months earlier. His last 2 consecutive HBsAb titers were 332.68 IU/L and 99.86 IU/L. HBeAg was reactive in his serum, anti-HBe was nonreactive, and HBV DNA quantification showed 3.07E+08 copies/mL.

Case 2
In October 2009, a 50-year-old man who presented with alcoholic liver cirrhosis and hepatocellular carcinoma received a liver transplant from a deceased donor. Serologic results for the donor and recipient were the same as for case 1. In September 2013, his serum became positive for HBsAg. Other laboratory findings, including liver function tests, were unremarkable, except HBsAb titer was undetectable, even though 10 000 IU of HBIG had been administrated 2 months earlier. The patient’s last 2 consecutive HBsAb titers were 115.60 IU/L and 49.94 IU/L. HBeAg was reactive in his serum, anti-HBe was negative, and HBV DNA quantification showed 1.51E+08 copies/mL.

Despite long-term use of HBIG prophylaxis, 2 patients who received grafts from HBcAb-positive donors developed de novo hepatitis B infection at our institution. Hepatitis B immunoglobulin monotherapy is our standard strategy for these patients, both because HBIG has been previously thought of as a sufficient prophylactic for de novo hepatitis B and because of the medical insurance in Korea. In Korea, medical insurance allows use of HBIG and nucleoside analogues for HBV recurrence in patients who are HBsAg positive at the time of liver transplant but only allows HBIG prophylaxis in this clinical setting. Thus far, 3 strategies in this setting of adult liver transplant have been published, which include use of HBIG alone,^6-8 nucleoside analogue alone,^9-11 and both HBIG and nucleoside analogues.^12-14 Table 1 summarizes the results of these studies.

The time from liver transplant to development of de novo hepatitis B infection is varied. In our report, 1 patient had de novo hepatitis B infection at 7 years and 3 months after liver transplant and the other at 3 years and 11 months. Donataccio and associates⁷ reported that the time of de novo hepatitis B infection after liver transplant was approximately 12 to 60 months. Uemoto and associates¹ reported 15 cases of de novo hepatitis B that occurred approximately 6 to 24 months after liver transplant. It was not possible to find a perfect prophylactic method in the literature. This might be because of the small number of patients and relatively short follow-up in each report. Patients treated with either HBIG mono-therapy or lamivudine monotherapy also may develop resistance.² In addition, prophylaxis with HBIG and lamivudine is costly. Further studies with new nucleoside analogues are needed. To prevent de novo hepatitis B, we suggest that patients need other prophylactics in addition to HBIG monotherapy. Furthermore, we advocate that the same strategy could be used to prevent recurrence of hepatitis B in hepatitis B patients after liver transplant.

Volume: 14 Issue: 1 February 2016

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