LIVER TRANSPLANTATION 17:905-913, 2011

ORIGINAL ARTICLE

Conversion to Everolimus in Maintenance Liver Transplant Patients: A Multicenter, Retrospective Analysis ´ bastien Dharancy,2 Richard Lorho,3 Filome ´ na Conti,4 Sylvie Radenne,5 Faouzi Saliba,1 Se 6 7 ´ rome Dumortier9 Martine Neau-Cransac, Monika Hurtova, Jean Hardwigsen,8 Yvon Calmus,4 and Je 1 Centre He´pato-Biliaire, Hoˆpital Paul Brousse, Assistance Publique–Hoˆpitaux de Paris, Universite´ Paris-Sud, Villejuif, France; 2Service des Maladies de l’Appareil Digestif et de la Nutrition, Hoˆpital Claude Huriez, Centre Hospitalier Universitaire, Lille, France; 3Service des Maladies du Foie, Hoˆpital Pontchaillou, Centre Hospitalier Universitaire, Rennes, France; 4Unite´ de Transplantation He´patique, Hoˆpital St-Antoine, Assistance Publique–Hoˆpitaux de Paris, Paris, France; 5Service de Gastro-ente´rologie et d’He´patologie, Hoˆpital de la Croix Rousse, Lyon, France; 6Laboratoire d’Immunologie, Hoˆpital Pellegrin, Bordeaux, France; 7 Service d’He´pato-Gastro-ente´rologie, Hoˆpital Henri Mondor, Assistance Publique–Hoˆpitaux de Paris, Cre´teil, France; 8Service de Chirurgie et de Transplantation He´patique, Hoˆpital de la Conception, Marseilles, France; and 9Unite´ de Transplantation He´patique, Hoˆpital Edouard Herriot, Lyon, France

Data on the conversion of patients to everolimus after liver transplantation are sparse. A multicenter, retrospective study followed 240 maintenance liver transplant patients to analyze the current indications for everolimus conversion, the employed regimens and exposure levels, and the impact on efficacy and safety. The mean time from transplantation to the introduction of everolimus was 4.9 6 5.2 years. The mean everolimus trough level was 7.3 6 4.1 ng/mL at month 1 and 8.1 6 4.7 ng/ mL at month 12. At 12 months, 61.6% of the patients were no longer receiving calcineurin inhibitor (CNI) therapy. The mean estimated glomerular filtration rate (eGFR) according to the Cockcroft-Gault formula was 64.2 6 30.0 mL/minute on day 0 and 68.4 6 32.5 mL/minute at month 12 (P ¼ 0.007). Among patients with baseline serum creatinine levels
130 lmol/L, the eGFR values were 44.3 6 15.7 mL/minute on day 0 and 53.7 6 26.0 mL/minute at month 12 (P ¼ 0.003). Four patients (1.6%) developed mild or moderate biopsy-proven acute rejection. Adverse events led to everolimus discontinuation in 12.9% of the patients. After the initiation of everolimus, the mean white blood cell count decreased significantly, and the total cholesterol and triglyceride levels increased significantly. In this retrospective analysis of the largest cohort of maintenance liver transplant patients analyzed after their conversion to everolimus, more than 60% of the patients were kept free of CNIs with a very low risk of acute rejection and with an acceptable safety profile. Randomized trials in which maintenance liver transplant patients are switched to everolimus in response to clinical indications or preemptively are warranted. Liver Transpl 17:905-913, 2011. V 2011 AASLD. C

Received December 22, 2010; accepted February 20, 2011. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been shown in kidney1-6 and heart transplant patients7-11 to offer effective immunosuppression and to preserve renal function in de novo1,2,4-6 and maintenance settings.3,9,11,12

The initiation of everolimus with the discontinuation of calcineurin inhibitors (CNIs) or reduced exposure to CNIs can preserve renal function after kidney or heart transplantation if this initiation occurs early enough after transplantation3,9,12,13

Abbreviations: CNI, calcineurin inhibitor; C0/C2, cyclosporin trough blood level/2-hour cyclosporine blood level; eGFR, estimated glomerular filtration rate; HCC, hepatocellular carcinoma; MELD, Model for End-Stage Liver Disease; MPA, mycophenolic acid; mTOR, mammalian target of rapamycin; SD, standard deviation. Address reprint requests to Faouzi Saliba, M.D., Centre He´pato-Biliaire, Hoˆpital Paul Brousse, Assistance Publique–Hoˆpitaux de Paris, Universite´ Paris-Sud, 12 Avenue Paul Vaillant Couturier, 94800 Villejuif, France. Telephone: þ33 1 45 59 64 12; FAX: þ33 1 45 59 38 57; E-mail: [email protected] DOI 10.1002/lt.22292 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

C 2011 American Association for the Study of Liver Diseases. V

906 SALIBA ET AL.

and before CNI-related nephrotoxic effects have become irreversible.14 Experience with everolimus in liver transplant recipients, however, is more limited. There are no published data on the de novo use of everolimus after liver transplantation, although this is under investigation.15 One randomized trial assessed the impact of converting 78 patients from CNI therapy to everolimus very early (day 30) after liver transplantation.16 Renal function was significantly better at 1 year in the everolimus cohort, and this improvement was accompanied by a lower incidence of chronic kidney disease (stage 3 or higher); however, the rate of acute rejection was similar to the rate for the CNI arm. Single-arm studies have demonstrated that maintenance liver transplant patients can be converted from CNIs to everolimus safely at later time points with a low rate of acute rejection.17-22 Like kidney transplant recipients,23 liver transplant recipients with kidney dysfunction apparently need to be switched from CNI immunosuppression to everolimus either early after transplantation16 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.

PATIENTS AND METHODS This was a retrospective, multicenter analysis undertaken at 9 liver transplant centers in France. The analysis included all maintenance liver transplant patients in whom everolimus treatment was initiated from October 2005 to November 2008, regardless of the preceding immunosuppressive regimen or the indication for the introduction of everolimus. No Institutional Review Board approval was necessary. Data were obtained from patients’ medical records at the baseline (ie, the day of their conversion to everolimus), 1 month after conversion, and every 3 months after conversion until the end of the study period. The following information about the original transplant procedure and each patient’s status at the time of transplantation was obtained: the time since transplantation, the indication for primary transplantation or retransplantation, the Model for End-Stage Liver Disease (MELD) score, the serum creatinine and total bilirubin levels, the international normalization ratio, the body weight, the presence or absence of diabetes and the type of antidiabetic therapy, the presence of hypertension, the donor type and age, the graft type, and the recipient/donor cytomegalovirus status. The reason for the introduction of everolimus (including details about the location of any cancer leading to everolimus initiation and previous

LIVER TRANSPLANTATION, August 2011

cancer treatment) was recorded. On day 0 and at all post-baseline visits, the following data were collected: the current types, doses, and blood concentrations of immunosuppressive agents; hematological data; the serum creatinine and liver enzyme levels (total bilirubin, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltransferase); the prothrombin time activity; the presence or absence of diabetes and the type of antidiabetic therapy; the glucose, total and low-density lipoprotein cholesterol, and triglyceride levels; the use of antihyperlipidemic therapy; the 24-hour urinary protein level; the body weight; the arterial blood pressure and the presence of hypertension; and the alpha-fetoprotein and hepatitis C RNA levels in patients with hepatocellular carcinoma (HCC) and in patients with hepatitis C infections, respectively. The glomerular filtration rate was estimated with the Cockcroft-Gault formula.24 The estimated glomerular filtration rate (eGFR) was analyzed for the total population and specifically for 2 subpopulations of patients: (1) those who had been converted to everolimus because of chronic renal failure (established by the investigator) and (2) those who had a baseline eGFR value < 60 mL/minute. The primary objective of the analysis was to describe the current indications for everolimus use in maintenance liver transplant patients in routine clinical practice. The secondary objectives were (1) to determine the effect of everolimus conversion on renal function in patients with or without chronic renal failure, (2) to examine the effect of everolimus conversion on the risk of biopsy-proven acute rejection, (3) to assess the doses and trough levels of everolimus, (4) to identify the modifications made to the CNI-based regimen, and (5) to evaluate adverse events and tolerability after everolimus conversion in this setting.

Statistical Analysis For comparisons between patients, the v2 test was used for categorical data, and the independent sample t test was used for continuous data. Biological values and immunosuppressive doses on day 0 and at subsequent time points were compared with the paired t test. Overall survival probabilities were determined with the life-table method and were compared with the log-rank test. A P value 8 mL/minute (18.2%) in patients diagnosed with renal failure by investigators and >9 mL/minute (21.2%) in patients with serum creatinine levels
130 lmol/L at the baseline. 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). 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. The remarkable improvement in eGFR (almost 30 mL/minute) reported by Masetti et al.16 after CNI withdrawal on day 30 in everolimus-treated patients versus CNI-treated patients highlights that early, preemptive conversion may be a more promising strategy.

LIVER TRANSPLANTATION, Vol. 17, No. 8, 2011

The second major indication for the introduction of everolimus was the prevention or treatment of malignancies; this reflects current interest in the role of mTOR inhibitors in the management of posttransplant tumors.30-32 The mode of action of mTOR inhibitors33 suggests that they may be associated with a direct impact on malignant cells and may also exert an antiangiogenesis effect,34 as demonstrated in animal models.35-38 A phase 3 trial of everolimus in patients with advanced renal cell carcinoma39 and a series of phase 2 studies in patients with various other types of malignancies40-44 have consistently demonstrated an antitumor effect of everolimus. Although the data remain preliminary, a series of uncontrolled trials have shown markedly lower rates of HCC recurrence after liver transplantation in patients receiving sirolimus-based immunosuppression versus a standard CNI regimen.45-48 Chinnakotla et al.45 documented a 5-year survival rate of 80% in 121 patients receiving sirolimus after they underwent liver transplantation for HCC and a 5-year survival rate of 59% in 106 case controls receiving a CNI (P ¼ 0.001). In a large registry analysis of 2491 patients who underwent transplantation for HCC, sirolimus-based maintenance therapy was also associated with improved survival and conferred a 15% 5-year survival advantage in comparison with CNI-based immunosuppression.49 Here, however, the retrospective nature of the data collection, the heterogeneity of the patients in terms of the type of cancer and the site of recurrence, the differences in the therapeutic strategies (including surgery and chemotherapy regimens) at the various participating centers, and the short duration of follow-up prohibit any conclusions regarding the impact of everolimus therapy on the progression of either HCC recurrence or de novo neoplasms. Previous reports have described no rejection episodes after the introduction of everolimus,19-21 but in 2 trials in which CNI therapy and adjuvant immunosuppressants were withdrawn relatively aggressively, the rates of rejection were 7%18 and 10%.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 (