Elsevier

Journal of Hepatology

Volume 38, Issue 6, June 2003, Pages 811-817
Journal of Hepatology

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

https://doi.org/10.1016/S0168-8278(03)00087-4Get rights and content

Abstract

Background/Aims: To compare the efficacy in preventing hepatitis B virus (HBV) recurrence of lamivudine vs. lamivudine plus hepatitis B immune globulin (HBIg) after a short course of HBIg and lamivudine in liver transplanted chronic hepatitis B patients.

Methods: Forty-six patients with HBV cirrhosis received lamivudine before liver transplantation and were then randomized to receive lamivudine plus HBIg for 1 month followed by lamivudine or both drugs for 17 months.

Results: Thirty-two patients were transplanted and 29 were randomized to receive combination therapy (15 cases) or lamivudine monotherapy (14 cases). HBV DNA was undetectable in all cases (17 induced by lamivudine therapy) at the time of liver transplantation. After 18 months of follow-up, all patients survived without HBV recurrence: hepatitis Bs antigen and HBV DNA were negative; however, HBV DNA was detected by polymerase chain reaction in four cases (three with HBIg plus lamivudine and one with lamivudine). Alanine aminotransferase levels were normal except in six cases (one HCV and two HDV coinfections). There were no drug-related adverse events.

Conclusions: Lamivudine monotherapy after a short course of lamivudine and HBIg is equally as efficacious in preventing HBV recurrence as HBIg plus lamivudine during the first 18 months after liver transplantation. This strategy is more economic and convenient to administer than long-term HBIg plus lamivudine.

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)

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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.

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