Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis

Abstract

Early studies found that orthotopic liver transplantation (OLT) for hepatitis B virus (HBV)-related liver failure was associated with a very high rate of reinfection and severe and rapidly progressive liver disease, resulting in a significant decrease in graft and patient survival compared with patients transplanted for other causes of liver disease. 1,2 Various measures have been tried in an attempt to reduce the rate of reinfection. The most promising results have come from the use of long-term (Ն 6 months) high-dose hepatitis B immune globulin (HBIG). 3,4 However, this regimen is expensive, and a significant reduction in the rate of reinfection is mainly seen in patients who have nonreplicative infection pre-OLT. Reinfection despite HBIG immunoprophylaxis may be caused by inadequate neutralization of overwhelming amounts of wildtype HBV, or to breakthrough infection by immune escape mutants.The major B-cell epitopes of hepatitis B surface antigen (HBsAg) have been shown to reside in the 'a' determinant region located at amino acid positions 124-149. 5,6 This region is conformational and is thought to consist of two loops held by disulfide bridges between cysteines 124 and 137, and cysteines 138 and 147. 7 The second loop is more conserved and confers most of the antigenicity of the 'a' determinant; this loop is sometimes referred to as the major hydrophilic region (MHR). HBV can be classified into four major subtypes: adr, adw, ayr, and ayw. Antibodies to the 'a' determinant confer protection against all subtypes of HBV. 8 Mutations in the HBV S gene have been reported in OLT recipients who developed HBV reinfection despite prophylaxis with monoclonal or polyclonal hepatitis B surface antibody (anti-HBs). McMahon et al. found amino acid substitutions in the 'a' determinant in all three patients who were reinfected despite monoclonal anti-HBs prophylaxis, 9 while the incidence of mutations in the 'a' determinant in OLT recipients who were reinfected despite HBIG prophylaxis varied from 0% to 33%. 10-12 Some of these mutations, including the glycine-to-arginine substitution at codon 145, have been shown to decrease binding to monoclonal antiHBs, suggesting that the breakthrough infections were caused by immune escape mutants. 9,11,13 The number of patients cited in the above studies ranged from three to seven patients; therefore, the significance of S escape mutants in HBV reinfection post-OLT remains unclear. It is also possible that additional mutations may be present in the HBV S gene outside the 'a' determinant in patients who received polyclonal anti-HBs (HBIG). Unfortunately, there are very few data on the sequence in the rest of the S gene. In addition, to date, there are no data on the reversibility of these mutations after withdrawal of HBIG therapy.

Clinical relevance of hepatitis B viral mutations

“…43 The incidence of surface gene mutations in isolates from 20 patients with HBV reinfection after liver transplantation despite HBIG administration was examined. 44 Pretransplantation, only 1 of 20 patients was found to exhibit mutations in HBV isolates affecting the a determinant of HBsAg. However, posttransplantation, 10 of 20 (50%) of patients exhibited surface gene mutations in isolates affecting the a determinant (with the majority of these mutations affecting the antigenicity of the surface protein).…”

Mutational pattern of hepatitis B virus on sequential therapy with famciclovir and lamivudine in patients with hepatitis B virus reinfection occurring under hbig immunoglobulin after liver transplantation

“…From previous studies, we know that certain amino acid changes are associated with failure of HBIg immunoprophylaxis. [29][30][31][32][33] Before the start of nucleoside analogue therapy, 8 patients (PR11, NR22, NR24, R01, R02, PR16, PR19, NR26) (Tables 11, 12, and 13) also showed such mutations within the S-gene. These mutations were a G145R mutation associated with a D144E mutation of the HBsAg corresponding to a W501E mutant of the HBV-DNA polymerase in 2 patients (R01, NR22), and a P120T mutation corresponding to a T476N mutation of the HBV-DNA polymerase in 6 (R01, PR11, NR24, PR 16, PR19, NR26), of whom 1 (R01) also had the G145R and D144E mutations.…”

Prevention of Hepatitis B Recurrence in Liver Transplant Patients Using Oral Antiviral Therapy without Long-Term Hepatitis B Immunoglobulin

“…However, the use of HBIG has been limited due to its indefinite use, significant cost, parenteral administration, persistent risk of recurrence, and development of HBV surface antigen (HBsAg) escape mutations [3][9][10][11]. Adverse effects include headaches, myalgias, flushing, pain, and even reports of mercury poisoning [12].…”