cleoside analogues, 8-10 the only established treatment option Hepatitis B virus (HBV) replicates via an intermediate to prevent reinfection is the administration of polyclonal hep-RNA step. High frequency of polymerase errors with adatitis B surface antigen antibody (anti-HBs) (hepatitis B imditional selection pressure leads to mutations in the mune globulin [HBIG]). HBIG reduces the rate of reinfection HBV genome. We investigated the number, type, and anfrom about 90% to less than 30% and improves the long-term tigenic effects of mutations in the coding region of the outcome of patients who underwent OLT for HBV-related HBV surface antigen in eight patients who underwent disease. 2-4 orthotopic liver transplantation (OLT) for HBV-related A number of explanations for graft infection have been end-stage liver disease and were experiencing infection proposed. First, virions from the explanted liver are circulatof the graft and who received hepatitis B surface antigen ing in the blood during or soon after transplantation. Second, antibody (anti-HBs) prophylaxis (hepatitis B immune virions are replicating at extrahepatic sites. HBIG interferes globulin [HBIG]) after OLT. Controls were chronic HBV with this process and probably prevents virions from entering patients who underwent kidney transplantation and rehepatocytes. 11 The mechanisms that lead to reinfection in ceived the same immunosuppressive regime but no 30% of patients receiving HBIG after OLT are not under-HBIG. The S-gene was amplified from serum before and stood. after transplantation, sequenced, and changes in the ge-HBV employs reverse transcriptase for its replication; this nome were analyzed. In the five patients who experilacks proofreading capability, and thus leads to a higher enced reinfection while receiving anti-HBs, clear mutanumber of mutations in the HBV genome. 12 Some of these tions occurred in the S-gene. In the patient who did not variants may have a replication advantage and become domireceive HBIG and those who experienced reinfection nant. From the pool of variants with similar replication poonly after termination of HBIG, no mutations were tential, some will be positively selected by forces such as found in the S-gene. In the kidney recipients, mutations the humoral or cellular immune response 13 ; these are termed in the S-gene occurred in only one of eight patients. Beescape mutants. Evolution of viruses under antibody prescause the a determinant contains neutralizing epitopes, sure, either monoclonal or polyclonal, has been well studied this region was chosen for antibody binding to quantify both in vitro and in vivo. The addition of neutralizing antibodantigenic effects of the mutations. The two patients who ies to virus cultures regularly results in isolates that are not selected mutations in the a determinant and became reneutralized by the added antibodies. This is particularly true infected while receiving HBIG had reduced antibody with monoclonal reagents, because the change in viral antibinding after OLT. Our results suggest that HBIG after genic structure required to avoid neutralization involves the OLT imposes a selection pressure on the S-gene, and loss of a single epitope. In some cases, removal of the selecting that mutations are one mechanism for reinfection while antibody allows back-selection of the wild-type strain. 14 receiving HBIG. (HEPATOLOGY 1996;24:489-493.)
A further humoral immune target of HBV is the a determinant, which is predominantly located between amino acids End-stage liver disease or fulminant hepatic failure associ-(aa)121 and 149 of the hepatitis B surface antigen (HBsAg). ated with hepatitis B virus (HBV) infection has a very poor A large proportion of the anti-HBs found in immune serum prognosis, and treatment options are limited. 1 Orthotopic is directed against this determinant, in particular the ''second liver transplantation (OLT) may help in this situation; howloop'' (aa139 to 147). 15 Mutations are selected in and around ever, reinfection of the graft is common, especially if there is this determinant in patients who received active and passive a high viral load pre-OLT. [2][3][4] HBV reinfection leads to a poor vaccination against HBV. [16][17][18][19][20] This includes mutations seen long-term outcome. [5][6][7] The prevention of HBV reinfection is in patients given a monoclonal antibody directed against the therefore crucial, and aside from encouraging trials with nua determinant after liver transplantation. 21 However, HBIG contains polyclonal antibody, and it would be reasonable to think that patients treated with polyclonal antibodies would be under less pressure to select mutations in the surface Abbreviations: HBV, hepatitis B virus; OLT, orthotopic liver transplantation; anti-HBs, antigen. The subject of variation in HBsAg has been recently hepatitis B surface antigen antibody; HBIG, hepatitis B immune globulin; aa, amino acid; reviewed. 22 Therefore, we investigated the selection pressure HBsAg, hepatitis B surface antigen.