Response to Lamivudine-Resistant Hepatitis B Virus Infection Postliver Transplantation from a Hepatitis B Core Antibody Donor

Abstract

To the Editor: We would like to respectfully respond to the comments of Dr. Hans Tillmann. We appreciate his interest in our case report and review. We would like to clarify that we do not believe that the liver initially harbored a lamivudine-resistant mutant, but that the mutation occurred during prolonged lamivudine exposure leading to de novo breakthrough hepatitis B virus infection. There is no reason to suspect the donor already had a lamivudine-resistant mutation, otherwise the recipient should have developed acute hepatitis B at a much earlier period due to the lack of protection by lamivudine and loss of anti-HBs after 6 months. Hepatitis B virus infection from a source other than the graft would also be very unlikely. Retrospective analysis of our cohort of 402 recipients (including the reported case), receiving 467 liver transplants between March 1998 and December 2001, revealed three cases of de novo Hepatitis B (0.6%) after a median follow up of 4.5 years (1Bonatti H Machicao V Dickson RC Mendez J Results of liver transplantation in HBV core antibody positive individuals and recipients of allografts from HBV core antibody positive individuals..Eur Surg. 2005; 37: 15Google Scholar). One case was acquired during unprotected intercourse. The second was an anti-HBc and anti-HBs negative recipient who developed acute hepatitis B 4 months after liver transplantation. Hepatitis B donor status was unknown at the time of transplantation and therefore no lamivudine prophylaxis was administered. The donor was subsequently found to be anti-HBc positive after retrospective analysis of stored serum. The third was the patient presented in the case report who developed HBV more than 3 years posttransplant while receiving continuous lamivudine prophylaxis. He was a heterosexual, elderly male without other viral exposures (HIV and HCV negative) or other viral risk factors pre- or posttransplantation. This data strongly support that the HBV infection was acquired from the graft. The development of lamivudine-resistant mutation after prolonged lamivudine therapy is not surprising. HBV DNA has been shown to persist after liver transplantation despite successful antiviral prophylaxis. Terrault et al. demonstrated HBV DNA in 8/9 patients a mean of 27 (range 13–33) months after liver transplantation for HBV despite successful HBIg prophylaxis (2Terrault NA Zhou S Combs C et al.Prophylaxis in liver transplant recipients using a fixed dosing schedule of hepatitis B immunoglobulin..Hepatology. 1996; 24: 1327-1333Crossref PubMed Google Scholar). In addition, the frequency of lamivudine resistance is known to increase with time in patients receiving lamivudine monotherapy for chronic Hepatitis B. Lai et al. described rates of 53% and 70% after 3 and 5 years of therapy (3Lai CL Dienstag J Schiff E et al.Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B..Clin Infect Dis. 2003; 36: 687-696Crossref PubMed Scopus (558) Google Scholar). The other patient in our series who developed de novo HBV from an anti-HBC graft also developed a lamiuvidine-resistant mutation after 1 year on lamivudine treatment. We agree with Dr. Tilman that the proof of our hypothesis might be possible if specimens from the liver and later on consecutive serum samples would be available for retesting. Unfortunately, we cannot provide these data. Four lessons should be learned form this case. First, donors must be tested for anti-HBc antibodies and these organs ideally should be allocated to Hepatitis B-exposed individuals. Second, serum and tissue from donors and recipients should be stored for retrospective studies. Third, a significant follow-up period is required to make any definitive statements about recurrent or de novo hepatitis B after liver transplant. Fourth, the risk for development of resistant mutations posttransplant must not be neglected.