Elsevier

Journal of Hepatology

Volume 30, Issue 4, April 1999, Pages 715-721
Journal of Hepatology

High pre-treatment serum hepatitis B virus titre predicts failure of lamivudine prophylaxis and graft re-infection after liver transplantation

https://doi.org/10.1016/S0168-8278(99)80204-9Get rights and content

Abstract

Background/Aims: Orthotopic liver transplantation has an established role for the treatment of patients with chronic liver failure secondary to hepatitis B virus (HBV)infection. Unfortunately, recurrent infection of the graft can be associated with aggressive disease, and with diminished graft and patient survival. Currently, the role of nucleoside analogues for prevention of graft re-infection is being evaluated. Preliminary results are encouraging, but treatment failure has been associated with emergence of drug-resistant virus.

Methods: We have studied ten consecutive patients who received lamivudine prophylaxis for prevention of HBV graft reinfection. Sequential sera, collected prelamivudine then during treatment before and after liver transplantation, were examined. Conventional serological markers were measured, as were serum viral DNA levels with a sensitive quantitative polymerase chain reaction assay.

Results: Lamivudine treatment effected a reduction in serum HBV levels, but six patients still had measurable viral DNA at the time of transplantation. Five patients developed graft re-infection with lamivudineresistant virus. Resistant virus emerged 8 to 15 months post-transplant. The likelihood of emergence of resistant virus was related to the pre-treatment serum HBV titre. Persistent serum viral DNA positivity and evidence of graft re-infection during the early post-transplant period did not predict the subsequent emergence of resistant virus.

Conclusions: Our observations suggest that the resistant species may be present in the viral quasispecies in the serum and liver of patients with high-level replication prior to lamivudine exposure. The resistant species can persist during lamivudine treatment prior to transplantation, and emerge following transplantation. These observations suggest strategies which might prevent the emergence of drug-resistant species, and imply that graft re-infection may be a preventable phenomenon.

Section snippets

Patients and Methods

Ten consecutively treated patients who survived at least 3 months after liver transplantation were studied. Eight of these patients participated in the aforementioned study which evaluated the use of lamivudine as prophylaxis against graft re-infection following transplantation for HBV-associated end-stage chronic liver disease (10). That study was approved by the research ethics committee, and patient consent was obtained. Another two patients were transplanted subsequent to closure of trial

Results

Ten HBsAg-positive patients were studied (see Table 1). Patients were studied from the time of commencement of lamivudine until 1/9/98. The median duration of lamivudine treatment prior to transplantation was 60 days (range 36–170). Two patients died of recurrent HBV infection, (both due to emergence of lamivudineresistant species) 505 and 704 days post-transplant respectively. For eight survivors, the median duration of follow-up post-transplant was 966 days (range 480–1557).

Discussion

Following liver transplantation, recurrent HBV infection is associated with significant morbidity, and with diminished graft and patient survival. To date, strategies to prevent graft re-infection have required the administration of HBV hyperimmune immunoglobulin (HBIg). HBIg prophylaxis has proven quite successful for prevention of recurrent infection in those patients with low levels of viral replication prior to transplantation. For patients with higher levels of replication (defined as

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