Conversion to everolimus monotherapy in maintenance liver transplantation: feasibility, safety, and impact on renal function

Abstract

We present the 12-month results of a prospective trial of conversion from calcineurin inhibitors (CNI) to everolimus (EVL) in maintenance liver transplant (LT) recipients. Forty (M:F = 28:12; 54.9 +/- 11 years) patients were enrolled at a mean interval of 45.5 +/- 31.2 months from transplantation. Conversion was with EVL at a dosage of 0.75 mg b.i.d., withdrawal of antimetabolites, and a 50%-per-week reduction of CNI to a complete stop within 4 weeks. The treatment success was conversion to EVL monotherapy at 12 months while failure was presence of CNI, death, and graft loss. Indication to conversion was deteriorating renal function in 36 (90%). At 12 months, patient- and graft survival were 100% and the success rate was 75% (30/40). Ten patients (25%) were failures: four (10%) for acute rejection; three hepatitis C virus-RNA positive patients (7.5%) for hypertransaminasemia; one (2.5%) for acute cholangitis; and two (5%) due to persistent pruritus and oral ulcers. In patients on EVL monotherapy, at 12 months the mean change of calculated creatinine clearance (cCrCl) was 4.03 +/- 12.6 mL/min and the only variable correlated with the probability of improvement was baseline cCrCl (P < 0.0001). Conversion from CNI to EVL is feasible in 75% of the cases and associated with improvement in renal function for patients with higher baseline cCrCl

Conversion to everolimus in maintenance liver transplant patients: A multicenter, retrospective analysis

“…A multivariate analysis showed that baseline creatinine clearance was the only clinical variable significantly correlating with the probability of renal function improvement 12 months after the conversion to everolimus. 17 Another prospective study by De Simone et al 29 found no change in renal function 6 months after CNI withdrawal (or CNI reduction in 20% of the patients) with the introduction of everolimus, even though the time since transplantation was shorter than the time in the current study ($3 years), most likely because of the poor baseline renal function (creatinine clearance ¼ 51 mL/minute). Together, these studies suggest that liver transplant patients can receive a renal benefit from everolimus initiation with CNI withdrawal even at a relatively late stage after transplantation unless renal deterioration is profound.…”

“…17 In the current study, in which there were no protocol-specified withdrawals of other agents, there was a very low rate of acute rejection (<2.0%).…”

“…These improvements can be regarded as clinically relevant. 28 De Simone et al 17 reported a mean eGFR increase of 4 mL/minute in a prospective study of 40 maintenance liver transplant patients converted to everolimus with CNI withdrawal. In that study, 90% of the patients were converted because of poor kidney function; they had a mean baseline eGFR value similar to that of the current population and a slightly shorter mean time post-transplant (3.8 versus 4.9 years for the current cohort).…”

“…[17][18][19][20][21][22] Like kidney transplant recipients, 23 liver transplant recipients with kidney dysfunction apparently need to be switched from CNI immunosuppression to everolimus either early after transplantation 16 or before the establishment of severe dysfunction. 17 In clinical practice, some centers now initiate everolimus in maintenance liver transplant patients who develop kidney dysfunction or, less frequently, posttransplant neoplasms and attempt to withdraw CNI therapy. The aim of this multicenter, retrospective study was to analyze the current indications for the conversion of liver transplant recipients to everolimus, the employed regimens and exposure levels, and the impact on efficacy and safety.…”

De Novo Sirolimus and Reduced-Dose Tacrolimus Versus Standard-Dose Tacrolimus After Liver Transplantation: The 2000–2003 Phase II Prospective Randomized Trial

“…Furthermore, subsequent single-center observational studies (not clinical trials) comparing de novo sirolimus initiation at time of LTx have not shown an increased risk of graft failure or HAT as compared to other strategies, which underscore the importance of making the data of this multicenter study available to clinicians (15,20). Second, given emerging literature on the role of another mTOR inhibitor, everolimus, it is important to gauge whether similarities exist in the risk and benefit profile for these two medications (21)(22)(23)(24)(25)(26)(27). Above all, transparency in the full presentation of the results of the study are important given that it may impact our current approach to management of immunosuppression after LTx.…”