An efficacy and cost-effectiveness analysis of combination hepatitis B immune globulin and lamivudine to prevent recurrent hepatitis B after orthotopic liver transplantation compared with hepatitis B immune globulin monotherapy

Abstract

Orthotopic liver transplantation (OLT) for hepatitis B virus (HBV) infectionO rthotopic liver transplantation (OLT) for hepatitis B virus (HBV) is complicated by a high rate of graft reinfection by HBV in the absence of prophylaxis. The consequences vary, ranging from asymptomatic infection with minimal graft dysfunction to fibrosing cholestatic hepatitis, graft failure, and patient death. The introduction of passive immunoprophylaxis with hepatitis B immune globulin (HBIG) post-OLT provided an initial approach to prevent recurrent HBV. [1][2][3][4][5] Despite HBIG, HBV still recurs in approximately 15% to 36% of the patients. 4,6 More recently, the advent of lamivudine, an oral purine nucleoside analogue with antiviral activity against HBV, has provided an alternative strategy to prevent recurrent HBV. Prophylaxis with lamivudine monotherapy has been shown to prevent initial HBV recurrence post-OLT. 7-9 Unfortunately, the emergence of lamivudine-resistant mutants with allograft reinfection also limits the efficacy of lamivudine monotherapy as a strategy to prevent HBV recurrence. 7,10,11 In previous studies, combination lamivudine and HBIG prevented HBV recurrence in all patients with no evidence of the development of lamivudine-resistant escape mutants during long-term follow-up. [12][13][14] In the present study, with our expanded experience in a larger cohort of patients administered combination HBIG and lamivudine to prevent recurrent HBV post-OLT, we evaluate the efficacy and cost-effectiveness of this strategy to prevent HBV recurrence compared with standard HBIG monotherapy.

Management of HBV Infection in Liver Transplantation Patients

“…Multiple studies showed that the mean reinfection rate was only 5.2% (range 0-18%) after 1 to 2 years, 14,15,18,28,43,48,49,75,80,81. Importantly, using highly sensitive PCR, circulating HBV DNA was undetectable in most patients after OLT 7,28,82.…”

“…Postulated mechanisms include the synergy of: 1) LAM reducing HBV replication and altering synthesis of HBsAg necessary for generation of HBIG escape mutations and 2) HBIG preventing the receptor-mediated entry of HBV into hepatocytes and extrahepatic cells required for production of escape mutations in the YMDD motif. In addition to efficacy, combination therapy is more cost effective because the dosage of expensive HBIG can be reduced 14,49. Combination therapy also permitted effective conversion of a high dose intravenous HBIG regimen to a lower dose intramuscular regimen in 98% of patients 74.…”

“…Pre-OLT inhibition of HBV replication using lamivudine (LAM) rendered patients with active replication eligible for transplantation, prevented recurrence post-OLT (unless LAM-resistant escape mutations developed) and improved the outcome of patients who became reinfected 13-17. The combination of HBIG and lamivudine enhanced prevention of HBV reinfection 14,18, and the advent of adefovir dipoxil (ADV) provided an safe and efficacious therapeutic option for patients with LAM-resistant infection 19. As a result of this progress in prevention and treatment of HBV reinfection, acute or chronic hepatitis B is now universally accepted as an excellent indication for OLT 8.…”

Low incidence of acute rejection in hepatitis B virus positive liver transplant recipients and the impact of hepatitis B immunoglobulin

“…Globally, 30% of cirrhosis and 53% of hepatocellular carcinoma cases are attributed to HBV, with liver transplantation (LT) as the main treatment option. From the mid-1990s until mid-2000s, the gold standard for prevention of HBV reinfection following LT has been hepatitis B immunoglobulin (HBIG) treatment with or without nucleos(t)ide antiviral analogues [2]. Over the past decade, more effective antiviral agents with low incidences of resistance (e.g.…”

Large Fragment Pre-S Deletion and High Viral Load Independently Predict Hepatitis B Relapse after Liver Transplantation

“…Furthermore, combination prophylaxis with the use of HBIG and antiviral agents has reduced the risk of hepatitis B relapse to 10% or less in the first 2 years following transplantation [8], [9], [10], [11], [12]. As a result, the outcomes of patients with acute and chronic HBV related liver diseases undergoing LT are now similar to or better than those with non-HBV related liver transplantation [13], [14].…”