Prophylaxis against hepatitis B recurrence following liver transplantation using combination lamivudine and hepatitis B immune globulin

Abstract

Until recently, liver transplantation in patients with hepatitis B was associated with a high rate of graft loss and poor survival because of viral recurrence. 1-3 Favorable outcome following liver transplantation for hepatitis B virus (HBV)-related liver disease was made possible with long-term, high-dose, passive immunoprophylaxis using hepatitis B immune globulin (HBIG). 4,5 Hepatitis B still recurs, however, despite HBIG. Recurrence may be caused by saturation of the antibody binding capacity of HBIG by a high viral load, or by mutations in the hepatitis B surface antigen (HBsAg) molecule that render HBIG ineffective. 6,7 Overall recurrence rates with HBIG monotherapy vary from approximately 15% to 50%. 4,5,[8][9][10][11] Using a different dosing schedule, in early experience from our own institution HBV recurrence on HBIG was 44%. 12 The wide disparity in the data reflects differing patient populations, e.g., patients who are HBV-DNA-positive at the time of transplantation have higher rates of recurrence. Moreover, the different dosing regimens of HBIG are also likely to influence recurrence rates. 5,11,13 An alternative approach to preventing HBV recurrence became possible using the purine nucleoside analog reversetranscriptase inhibitor, lamivudine. Demonstration of its efficacy, in the nontransplantation setting, in suppressing HBV-DNA synthesis 14,15 led to studies using lamivudine following liver transplantation as prophylaxis against hepatitis B recurrence, 16,17 or as treatment of de novo or recurrent hepatitis B. 17,18 Although a DNA virus, HBV replicates via an RNA intermediate. As is seen in human immunodeficiency virus, 19 lamivudine escape mutations in the tyrosine, methionine, aspartate, aspartate (YMDD) locus of the HBV-DNA polymerase are increasingly being reported. [20][21][22][23] While prophylactic failures of HBIG have been treated successfully with lamivudine, there are no reports documenting successful treatment of patients with lamivudine-resistant HBV.Mechanistic evidence suggests that HBIG and lamivudine would be synergistic. By inhibiting viral replication with lamivudine, it would be less likely that the viral binding capacity of HBIG would be overwhelmed; furthermore, there would be little pressure to select for HBIG-resistant mutations in the HBsAg molecule. By providing humoral immunity, HBIG may limit viral spread, confining the virus to extraheAbbreviations: HBV, hepatitis B virus; HBIG, hepatitis B immune globulin; HBsAg, hepatitis B surface antigen; anti-HBs, antibodies against hepatitis B surface antigen; PCR, polymerase chain reaction; HCC, hepatocellular carcinoma; HBeAg, hepatitis B envelope antigen.From

Liver transplantation in patients with hepatocellular carcinoma

“…The issue with HBV has been largely overcome; with the routine use of passive immunoprophylaxis with hepatitis B immune globulin, reinfection occurs in only about 10% of cases, and antiviral drugs such as lamivudine and adefovir are effective in ameliorating its course should recurrent HBV develop. 25 Recurrence of hepatitis C is a much larger problem. Nearly 100% of patients who are HCV RNA(ϩ) before transplant remain so afterwards 26 ; about 50% will have chronic hepatitis at 1 year, 27 and 20% will have cirrhosis at 5 years.…”

Liver transplantation

“…For this reason, other strategies using nucleoside analogues for hepatitis B are being explored by many transplant centers. 45,46 Autoimmune hepatitis. This condition of unknown cause affecting primarily women can result in progressive inflammation and fibrosis of the liver, with subsequent cirrhosis and hepatic failure.…”

Liver transplantation for chronic hepatitis B infection with the use of combination lamivudine and low-dose hepatitis B immune globulin

“…Efficacy with this combination has recently been reported from Los Angeles, 25 with no reported instances of allograft reinfection in 13 long-term surviving patients. Our findings with combination lamivudine and HBIG are similarly favorable.…”