Introduction: The majority of immunosuppressive agents are administered according to trough levels (C0-levels). Avoiding both over- and underimmunosuppression is crucial to achieve an optimal balance between efficacy and safety. Although many studies have been performed to optimize immunosuppression, it has been revealed that pre-defined C0-levels are often not kept for distinct reasons. The  aim of the Hephaistos study⁽¹⁾ was to investigate the impact  of a reduced calcineurin inhibitor (CNI) regimen on renal function as well as CNI-induced nephrotoxicity following liver transplantation (LTx).
Materials and Methods: The primary endpoint of this 12 months (M) open-label, prospective, randomized de novo liver transplant study was to show that at M12 immunosuppressive therapy based on everolimus (EVR: 3-5ng/ml) combined with reduced tacrolimus (rTAC: <5ng/ml) yields superior renal functionality compared to TAC alone (TAC-C: 6-10ng/ml). In this study, a numerical yet not significant improvement was shown in the full analysis set. Nevertheless, TAC C0-levels of 31-42% of patients in the EVR+rTAC arms  were detected to be above the pre-defined range at various time points. Therefore, a posthoc analysis of a compliance set was conducted in which patients were only included if their C0-levels were within the TAC target range for a minimum of three different time points during the study.
Results and Discussion: Out of 333 randomized patients, 59 of 164 in the TAC-C arm and 74 of 169 patients in the EVR+rTAC made up the compliance set. At M12 a significantly higher mean eGFR (MDRD4) was obtained with EVR+rTAC (adjusted mean difference of 8.03 ml/min/1.73m2; p=0.0333). Contrarily, a difference of only 1.20 ml/min (p=0.7154) was observed in the non-compliance set (95 EVR+rTAC, 105 TAC-C). Regarding efficacy and safety, no difference was seen irrespective of compliance or treatment regimen.    

Conclusion: This compliance set analysis clearly revealed that when TAC C0-levels did not exceed the pre-defined range, renal function was significantly improved at M12 in the EVR+rTAC arm compared to the TAC-C group, with efficacy and safety being unaffected. Hence, EVR plus rTAC is an effective and well-tolerated regimen, allowing CNI minimization and yielding renal benefit after LTx.