Comparison of Tacrolimus With Neoral as Primary Immunosuppression in Hepatitis C Patients After Liver Transplantation X.A. Zervos, D. Weppler, G.P. Fragulidis, M.B. Torres, J.R. Nery, M.F. Khan, A.D. Pinna, T. Kato, J. Miller, K.R. Reddy, and A.G. Tzakis E ND-STAGE liver disease secondary to hepatitis C is the most common indication for orthotopic liver transplantation (OLTx). Disease recurrence after trans- plantation is recognized as a major problem because there are no effective antiviral agents and immunosuppression (ISP) accelerates its course by increasing viral replica- tion. 1–5 There are conflicting reports regarding the role of the two most commonly used ISP agents, cyclosporine (CyA) and tacrolimus (T), impacting the course of the hepatitis C virus (HCV) after transplant. In a randomized, prospective study we compared the effects of these two immunosuppressive agents on patients who underwent OLTx for HCV. PATIENT AND METHODS Fifty consecutive HCV-positive liver transplant recipients were randomly assigned to either T (group I) or Neoral (N) (group II) based ISP between December 1995 and September 1996. Fol- low-up is through December 1997 (median 498 days, range 25 to 716 days). Group I consisted of 12 males and 13 females; age 34 to 69 years (median 51). Group II consisted of 15 males and 10 females; age 30 to 72 years (median 46). Group I received T 0.05 mg/kg PO preoperatively and a daily divided dose to maintain a serum level of approximately 15 ng/dL. Group II received N 3 mg/kg PO preoperatively and a daily divided dose to maintain a level of 300 to 400 ng/dL. Upon reperfusion of the liver allograft, 1 g of methylprednisone was given followed by a maintenance dose of 20 mg per day for 2 to 3 weeks two postoperatively, which was tapered off over the next 2 to 3 months. Patients with a positive T-cell lymphocytic crossmatch or whose liver function tests in- creased during the first postoperative week received a steroid cycle. This consisted of 200 mg of methylprednisone per day and was tapered over a 5-day period to a maintenance dose of 20 mg per day. Steroid doses were similar in both groups. Serial HCV-RNA titers (b-DNA, Chiron) were measured at 1, 2, 4, 12, 24, 52, and 72 weeks postoperatively. Protocol biopsies were performed at 12 and 18 months posttransplant and when transami- nases were greater than two times baseline or when there was an inappropriate response to alterations in ISP regimens. Definition of recurrent HCV posttransplant was through biochemical activity, histologic diagnosis, serum HCV-RNA titers greater than 10 million Eq/mL, and liver biopsy titers greater than 1000 copies/mg, which were correlated with the clinical course of the patient. Confirmation of histologic rejection or recurrent HCV was sup- ported by serum and liver biopsy HCV-RNA titers and to the response of ISP manipulation. ISP was augmented for rejection and decreased for recurrent HCV. Severe cholestasis secondary to HCV was defined as having progressive jaundice with a serum bilirubin greater than 5 mg/dL for more than a month with a liver biopsy that demonstrated cholestasis with progressive portal and periportal fibrosis. Cross- over from one ISP agent to the other was allowed if there was perceived advantage from it. Statistical analysis was performed using analysis of variance. RESULTS The demographic data was comparable between group I and group II. One patient was excluded from analysis in group II because of a preexisting immunoglobin G defi- ciency. Patient and graft survival in the two groups was 68% and 57% for the group I and 67% and 64% for II, respectively. There was no difference in HCV-RNA titers preoperatively and postoperatively through week 72, but there was a trend toward lower serum levels in the group I at 24 weeks. Four patients in group I developed severe recurrent cholestatic HCV 50 to 137 days (median: 104 days) post- transplant with 25% mortality (1 of 4) and five patients in the N group, 10 to 220 days posttransplant (median: 53 days) with 100% (5 of 5) mortality. No patients were retransplanted for recurrent HCV infection. The rejection rate was 24% in group I (six episodes in six patients; mild N = 4, moderate N = 2, severe N = 0) and 50% (14 episodes in 12 patients; mild N = 3, moderate N = 9, severe N = 2) in group II. The use of OKT3 was required by one patient in group II because of resistant, severe rejections, but there were none in group I. Cytomegalovirus (CMV) infection occurred in five pa- tients on T (viremia N = 5) and in six patients on N (viremia N = 5, fatal hepatitis N = 1). Epstein Barr virus (EBV) viremia was observed in one patient on N. No patients From the Department of Transplantation and Division of Med- icine, Miami, Florida, USA. Address reprint requests to Xaralambos A. Zervos, 1150 NW 14 Street, Suite 603, Miami, Florida 33136. © 1998 by Elsevier Science Inc. 0041-1345/98/$19.00 655 Avenue of the Americas, New York, NY 10010 PII S0041-1345(98)00291-7 Transplantation Proceedings, 30, 1405–1406 (1998) 1405