Improved clinical outcomes for liver transplant recipients using cyclosporine monitoring based on 2-hr post-dose levels (C2)

Background. A prospective, open-label, study was conducted at 29 centers in 9 countries, involving 307 de novo liver transplant patients to compare the clinical usefulness of monitoring 2-hr post-dose cyclosporine (CsA) levels (C-2) with conventional trough cyclosporine blood levels (pre-dose) (C-0). Methods. Neoral oral therapy was initiated at 15 mg/kg/day and dose adjusted according to predetermined C-2 or C-0 target level ranges. The primary efficacy variable was treatment failure at 3 months, where evaluation was based on a composite endpoint of biopsy-proven rejection, treatment for rejection, graft loss, death, or premature withdrawal/discontinuation from the study. Results. Baseline characteristics were similar between groups. Graft loss at 12 weeks (retransplantation or death) occurred in 63% C-2 and in 7.0% C-0 patients. Overall incidence of treated acute rejection was lower for C-2 (23.6%) than C-0 patients (31.6%) (P=0.144, Cochran-Mantel-Haenszel [CMH] test). In hepatitis C virus (HCV)-negative patients, the incidence of rejection in the C, group was significantly less than in the C-0 group (21.2% vs. 33.0%, P<0.05), whereas in HCV-positive patients, the rejection rate was similar in both groups (26.7% for C-2 group vs. 27.3% for C-0 group: P=0.81). C-2 patients (n=16) who reached minimum target CsA levels by day 3 had a notably low incidence of rejection (12.5%), whereas there was no difference in the incidence of rejection in C-0 patients, irrespective of time to reach target level. For biopsy-proven acute rejections (21.6% for C-2 vs. 30.4% for C-0), the incidence of moderate and severe histological diagnosis was significantly lower in the C-2 group than in the C-0 group (47% vs. 73%; P=0.01). Safety profiles were similar between the two groups, with few patient withdrawals due to adverse events (9.5% for C-2; 7.0% for C-0). Conclusions. Using C-2 monitoring, the overall incidence of acute cellular rejection was lower compared with the C-0 group, and the histological severity of acute rejections was shown to be significantly milder for the C-2 group, indicative of good long-term prognosis. These data demonstrate that the use of C-2 monitoring is superior to C-0 and results in a reduction in the incidence and severity of acute cellular rejection without detrimental effect on the drug safety profile.