A randomized study comparing lamivudine monotherapy after a short course of hepatitis B immune globulin (HBIg) and lamivudine with long-term lamivudine plus HBIg in the prevention of hepatitis B virus recurrence after liver transplantation☆
Introduction
Recurrence of hepatitis B virus (HBV) infection in patients transplanted for chronic hepatitis B is almost universal and is associated with poor survival rates if prophylaxis is not used. Prophylaxis of recurrent hepatitis B using either immune or antiviral therapies has some limitations. Hepatitis B immune globulin (HBIg) was the first therapy used to prevent HBV recurrence. Long-term HBIg administration reduces the rate of HBV recurrence to between 20 and 30% in patients without detectable hepatitis Be antigen (HBeAg) or HBV DNA [1], [2] but it is expensive, has to be administered parenterally, has side effects and is much less efficacious in patients with high levels of viremia before liver transplantation [1], [2], [3].
More recently, lamivudine, a nucleoside analogue, was introduced to prevent HBV recurrence. It has some advantages; it is a cheaper, oral drug, safe and capable of preventing HBV recurrence, even in some patients with high levels of HBV DNA before liver transplantation. Its main drawback is the development of YMDD mutants resistant to lamivudine which limits its long-term efficacy with recurrence rates of 25% after 1 year and possibly higher thereafter [4], [5], [6]. HBV recurrence is particularly frequent in patients with high serum HBV DNA levels treated with lamivudine and harboring YMDD mutants resistant to lamivudine before liver transplantation [7]. Patients with decompensated chronic hepatitis B and active viral replication are increasingly receiving lamivudine for a long time before liver transplantation, leading to the possible emergence of lamivudine resistant mutants, which increases the risk of HBV recurrence [7], [8], [9], [10], [11].
HBIg and lamivudine have different mechanisms of action and resistance profiles, which together could have a synergistic effect on the prevention of HBV recurrence. The combination of both drugs shows a higher efficacy than either of them alone and may allow the use of lower doses or shorter courses of HBIg. There have been two studies in which both drugs were combined and after a median follow-up of 15 months, no patients had HBV recurrence but the regimens used high doses of intravenous HBIg, which is an expensive strategy [12], [13]. Despite the high cost of HBIg and intravenous administration, the combination of HBIg and lamivudine has become the current standard prophylactic strategy in the prevention of HBV recurrence in most transplantation programs. There are, however, some unresolved questions, such as the optimal HBIg dose, the best method of HBIg administration, the optimal duration of both drugs, and whether patients with high levels of HBV DNA before liver transplantation need more aggressive prophylaxis [2], [13], [14].
The aim of this study was to compare the efficacy of a short schedule of HBIg plus lamivudine followed by lamivudine monotherapy versus the combination of HBIg and lamivudine in preventing HBV recurrence after liver transplantation in a prospective randomized study in patients with chronic hepatitis B and undetectable HBV DNA.
Section snippets
Patients
Candidates for transplantation for end-stage HBsAg-positive cirrhosis were considered for the study. The eligibility criteria included: decompensated liver disease, age between 13 and 70, HBsAg-positive for at least 6 months, HBeAg or antiHBe-positive and HBV DNA-negative. HBV DNA had to be undetectable by hybridization assay before liver transplantation in two separate determinations at least 15 days apart. Patients with detectable HBV DNA were included in the study, if it became undetectable
Results
Forty-six patients were included in the study, of whom 32 received a liver transplantation and 14 were withdrawn. Of the 14 withdrawn, eight died of liver complications before liver transplantation (six were HBV DNA-positive). Three developed contraindications for transplantation (one continued to be HBV DNA-positive after 3 months of lamivudine, one had a growing hepatocelullar carcinoma and one had an alcoholic relapse), while the remaining three patients were still on the waiting list when
Discussion
This is the first randomized clinical trial comparing the long-term prophylaxis of HBV recurrence after liver transplantation using two different schedules: lamivudine monotherapy versus lamivudine plus HBIg after a 1-month course of both drugs combined. The results of this study demonstrate that long-term lamivudine monotherapy is equally as efficacious as combination therapy for patients who received a liver transplantation with undetectable HBV DNA. Based on these findings, this prophylactic
Acknowledgements
Supported in part by Ministerio de Sanidad y Consumo of Spain, project Red Tematica Cooperativa C03/02.
References (33)
- et al.
immune globulin to prevent HBV graft reinfection following liver transplantation: a concise review
Hepatology
(2000) - et al.
Eurohep consensus report on the management of liver transplantation for hepatitis B virus infection. European Concerted Action on Viral Hepatitis
J Hepatol
(1994) - et al.
Lamivudine prophylaxis against reinfection in liver transplantation for hepatitis B cirrhosis
Lancet
(1996) - et al.
High pre-treatment serum hepatitis B virus titre predicts failure of lamivudine prophylaxis and graft re-infection after liver transplantation
J Hepatol
(1999) - et al.
Multicenter United States–Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B
Hepatology
(2001) - et al.
Lamivudine treatment is beneficial in patients with severely decompensated cirrhosis and actively replicating hepatitis B infection awaiting for liver transplantation. A comparative study using matched, untreated cohorts
Hepatology
(2001) - et al.
Management of hepatitis B: 2000 – summary of a workshop
Gastroenterology
(2001) - et al.
Role of hepatitis B, C and D viruses in dual and triple infection: influence of viral genotypes and hepatitis B precore and basal core promoter mutations on viral replicative interference
Hepatology
(2001) - et al.
Reduced doses of hepatitis B Immunoglobulin protect against hepatitis B virus recurrence after liver transplantation
Transplant Proc
(2001) - et al.
Randomized trial of lamivudine versus hepatitis B immunoglobulin for long-term prophylaxis of hepatitis B recurrence after liver transplantation
J Hepatol
(2001)
Combination low dose hepatitis B immune globulin and lamivudine therapy provides effective prophylaxis against posttransplantation hepatitis B
Liver Transpl
Prevention of hepatitis B virus recurrence after liver transplant in cirrhotic patients treated with lamivudine and passive immunoprophylaxis
J Hepatol
Liver transplantation and hepatitis B virus infection: the situation seems to be under control, but the virus is still there
J Hepatol
Clinical utility in quantifying HBV DNA levels using PCR assays
J Hepatol
Selection of mutations in the hepatitis B virus polymerase during therapy of transplant recipients with lamivudine
Hepatology
Hepatitis B virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation
Lancet
Cited by (0)
- ☆
Presented in part at the 36th Annual Meeting of the European Association for the study of the Liver, Prague, April 18–22, 2001, and published in abstract form in J Hepatol 2001;34(Suppl 1):441A.
- †
The authors declare that E. Cruz de Castro and C. Garı́a-Rey are employees of GlaxoSmithKline (Spain) but they did not receive funding from the manufacturers to carry out this study.