Incidence and severity of acute allograft rejection in liver transplant recipients treated with alfa interferon

Abstract

Interferon alfa-2b (IFN-alpha) therapy has been shown to be effective in the treatment of viral hepatitis B (HBV) or viral hepatitis C (HCV) in patients who did not undergo transplantation. However, in allograft recipients, treatment with IFN-alpha often leads to allograft rejection. The aim of the present study was to determine if IFN-alpha therapy increases the incidence or severity of acute rejection in human liver allograft recipients. One hundred five orthotopic liver transplant (OLT) recipients with HBV (n = 32), HCV (n = 58), or Non A Non B Non C (n = 15) viral infections were treated with a 6-month course of IFN-alpha, 5 million U subcutaneously three times a week, which began 2 to 97 months after transplantation. The mean hepatitis activity index (HAI) at the beginning of the therapy was 10.1 +/- 3.0. The baseline immunosuppression was achieved by tacrolimus in 77 patients and by cyclosporine A (CyA) in 28 patients. Contemporaneous controls consisted of 132 OLT patients (100 who received tacrolimus and 32 who received CyA) who did not receive IFN-alpha. A retrospective analysis was performed on this group of patients. The incidence of rejection and the baseline immunosuppression were compared. All biopsies were reviewed without knowledge of clinical data and scored for HAI and for rejection activity index (RAI). The biochemical response to IFN-alpha was also examined. The mean baseline maintenance dose of prednisone was greater by 2 mg daily in patients who received IFN-alpha with tacrolimus compared with control patients who did not receive IFN-alpha with tacrolimus (IFN-alpha 5. 3 +/- 5.2 mg daily v controls 3.3 +/- 4.9 mg daily; P </= .05). Similarly, the mean maintenance dose of prednisone was greater by 2.5 mg daily in patients who received IFN-alpha compared with controls who received CyA-based immunosuppression (IFN-alpha 9.8 +/- 3.1 mg daily v controls 7.3 +/- 3.3 mg daily; P = .01). Acute rejection episodes were detected in 10.5% (n = 11) of IFN-alpha-treated patients compared with 8.8% of controls for the similar time period from OLT and period of exposure to risk of rejection. Mean RAI was 2.0 +/- 2.4 for the IFN-alpha-treated group and 2.1 +/- 1.7 for controls. Rejection episodes with IFN-alpha treatment were mild and responded to steroid therapy. In OLT recipients, the risk of acute rejection was not increased by the introduction of IFN-alpha. However, in this study, patients were exposed to greater levels of immunosuppression.

Figure 1

(A) An example of a patient with chronic hepatitis, showing portal lymphocytic inflammation with mild interface activity. Note the lack of bile duct damage and endothelitis of portal veins. (B) This patient experienced an episode of acute rejection during lFN-α treatment. Note that the portal mononuclear inflammation is now directed at the bile ducts and portal vein endothelitis has appeared. (C) After 1 g of methylprednisone, the portal infiltrate has lessened and the duct damage and endothelitis have largely disappeared. There is, however, some residual interface activity (hematoxylin-eosin stain ×200).

Figure 2

(A) Tacrolimus dose and (B) level and (C) prednisone dose in control patients and in patients who received IFN-α therapy from 2 to 12 months, 12 to 24 months, and 24 to 36 months after liver transplantation. *P < .05 v controls; **P < .05 v controls and before IFN-α; ***P < .05 v before IFN-α.