Hepatitis B virus surface mutations associated with infection after liver transplantation.
OBJECTIVE
Liver transplantation for chronic liver disease due to hepatitis B virus infection is associated with a high risk of graft infection, graft failure and death. Many centres restrict this procedure to those seronegative for HBV-DNA (by hybridisation assay) and use prophylactic polyclonal human hepatitis B specific immunoglobulin to prevent infection of the graft, despite the very high cost.


METHODS
We describe three patients who underwent liver transplantation for chronic HBV-related disease in whom death was due to fibrosing cholestatic hepatitis following graft infection with hepatitis B virus, despite receiving hepatitis B specific immunoglobulin. Variation within the immunodominant a epitope of HBsAg was sought by analysis of hepatitis B virus sequences and the use of a point mutation assay, following amplification from serum by the polymerase chain reaction.


RESULTS
Prior to transplantation, Cases 1 and 2 had mutations at nucleotide 1902 (codon 145), resulting in G-C substitutions, which persisted at a low level after transplantation. In Case 2 a second mutant type with a G-A substitution at nucleotide 1902, became the predominant viral type post transplant. Case 3 had exclusively wild type virus before and after transplantation. The emergence of mutant type virus in Case 2 may have occurred because of immune pressure exerted by high titre anti-HBs detectable for more than 7 months. Cases 1 and 3 received only brief courses of anti-HBs therapy. The mutant viral surface antigen was not detected by a monoclonal antibody-based assay, and therefore the choice of HBsAg assay for post-transplant monitoring of patients who receive liver grafts for hepatitis B virus disease is important.


CONCLUSIONS
A search for mutations affecting the a determinant prior to liver transplantation for HBV-related liver disease may help to identify those at risk of failure of prophylaxis. Monoclonal antibodies specific to the codon 145-mutant surface antigen might prevent graft infection, but other mutations might then emerge.
Hawkins
A E
AE
Academic Department of Genitourinary Medicine, University College London Medi
Gilson
R J
RJ
Gilbert
N
N
Wreghitt
T G
TG
Gray
J J
JJ
Ahlers-de Boer
I
I
Tedder
R S
RS
Alexander
G J
GJ
D001483:Base Sequence; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D006509:Hepatitis B / Q000821:virology*; D006514:Hepatitis B Surface Antigens / Q000032:analysis; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D016031:Liver Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D017354:Point Mutation
D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens