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Corticosteroid-Sparing and Optimization of Mycophenolic Acid Exposure in Liver Transplant Recipients Receiving Mycophenolate Mofetil and Tacrolimus: A Randomized, Multicenter Study

Saliba, Faouzi MD, PhD; Rostaing, Lionel MD, PhD; Gugenheim, Jean MD, PhD; Durand, François MD, PhD; Radenne, Sylvie MD; Leroy, Vincent MD, PhD; Neau-Cransac, Martine MD; Calmus, Yvon MD, PhD; Salamé, Ephrem MD, PhD; Pageaux, Georges-Philippe MD, PhD; Duvoux, Christophe MD, PhD; Taguieva, Naila MD; Sinnasse-Raymond, Gilles MD; Sebagh, Mylène MD; Samuel, Didier MD, PhD; Marquet, Pierre MD, PhD

doi: 10.1097/TP.0000000000001228
Original Clinical Science—Liver
Free

Background We conducted a randomized multicenter open-label trial in de novo liver transplant recipients to assess the feasibility and potential benefit of a corticosteroid (CS)-free regimen coupled with tacrolimus (Tac) and dose-intensified mycophenolate mofetil (MMF) further adjusted individually.

Methods Adult liver transplant recipients were randomized on the day of transplantation to a CS-free regimen with Tac and MMF starting at 3 g/d and dose adjusted from day 5 according to mycophenolic acid (MPA) exposure (arm A) or a regimen with CS maintained up to 6 months, Tac and fixed-dose MMF (2 g/d) (arm B). The primary end point was the proportion of patients who experienced treated biopsy-proven acute rejection (BPAR) during the first year posttransplant.

Results One hundred eighty-seven patients were randomized, and 174 comprised the per-protocol population (87 in each arm). The primary objective of noninferiority was met: 7 patients in arm A (8%) and 8 in arm B (9%) experienced treated BPAR in the first year. Two patients in arm A (2%) and 5 in arm B (6%) lost their graft, and 12-month patient survival was similar in both arms (90.8% vs 89.8%; P = 0.86). Adverse events were comparable between arms, except for a lower incidence of de novo diabetes (19.8% vs 32.6%, P = 0.049) and a higher incidence of leukopenia less than 2000/mm3 (28.6% vs 9.8%; P = 0.001) and neutropenia (26.7% vs 7.9%; P < 0.001) in arm A.

Conclusions Mycophenolate mofetil at intensified and individually adjusted dose in combination with Tac in de novo liver transplant recipients allows CS discontinuation from day 1 posttransplant with good tolerance and very low rejection incidence.

In this randomized multicenter open-label trial in liver transplant recipients, the authors show that a therapeutic protocol with mycophenolic acid AUC dose adjusted MMF in combination with tacrolimus allows early discontinuation of corticosteroid (at day 1) resulting in lower 1-year posttransplantation diabetes without increasing the incidence of acute rejection.

1 AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, France.

2 CHU de Toulouse, Hôpital Purpan, Département de Néphrologie et Transplantation d’Organes, Toulouse, France.

3 CHU l'Archet 2, Service de Chirurgie Digestive, Nice, France.

4 AP-HP, Hôpital Beaujon, Service d'Hépatologie, Clichy, France.

5 Hôpital de la Croix-Rousse, Service d’Hépatologie, Lyon, France.

6 Hôpital A. Michallon, Service d'Hépato-gastroentérologie, La Tronche, France.

7 Hôpital Pellegrin, Pôle d’hépatogastroentérologie, Bordeaux, France.

8 AP-HP, Hôpital Pitié-Salpétrière, Paris, France.

9 Hôpital Trousseau, Service de Chirurgie Digestive et Transplantation Hépatique, Chambray-Lès-Tours, France.

10 CHU Saint Eloi, Service d’HGE et Transplantation, Université de Montpellier, Montpellier, France.

11 AP-HP, Hôpital Henri Mondor, Service d'Hépatologie, Créteil, France.

12 Roche SAS, Boulogne-Billancourt, France.

13 CHU Limoges, UMR 850 INSERM, Univ. Limoges, Limoges, France.

Received 2 October 2015. Revision received 3 February 2016.

Accepted 5 March 2016.

Correspondence: Faouzi Saliba, MD, Hôpital Paul Brousse, Centre Hépato-Biliaire, 12, avenue Paul Vaillant Couturier, 94800 Villejuif-France. (faouzi.saliba@aphp.fr).

This work was supported by Roche SAS, France.

The authors declare no conflicts of interest.

Study registration number: NCT00545402 (ClinicalTrials.gov).

F.S. and P.M.: conception and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, and final revision and approval of the manuscript. L.R., J.G., F.D., S.R., V.L., M.N.C., Y.C., E.S., C.D., G.-P.P., and D.S.: provision of patients, critical revision of the manuscript for important intellectual content, and approval of final draft. N.T. and G.S.-R.: conception and design; analysis and interpretation of data; administrative, technical, or logistic support. M.S.: central review of all study liver biopsies, critical revision of the article for important intellectual content, and approval of final draft.

Therapeutic protocols with immunosuppressive drugs have led in the last years to improvement in terms of reduction of acute rejections and better overall survival of patients and grafts. Still, treatment with corticosteroids and calcineurin inhibitors (CNI) is associated with frequent and sometimes severe side effects (eg, hypertension, diabetes, hypercholesterolemia, osteopenia/osteoporosis, cataract, obesity, and nephrotoxicity) increasing morbidity and mortality.1,2 Therefore, early corticosteroid-sparing protocols are increasingly favored.3,4 Data from a 3-year follow-up study in renal transplant confirmed that corticosteroid-sparing (dose reduced on day 4 and discontinued after day 7) was associated with excellent medium-term patient and graft outcomes, low incidence of posttransplant diabetes mellitus, and stable cardiovascular risk factors.5 In liver transplantation, several studies have shown that corticosteroid-sparing regimens could reduce the incidence of side effects without worsening graft losses.6,7

Mycophenolate mofetil (MMF), a potent, selective, uncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase, is indicated for prophylaxis of acute graft rejection after kidney, heart, or liver transplantation.4 Use of MMF in immunosuppressive protocols has been shown to decrease the risk of acute and late rejections.8-10 In liver transplantation, MMF has been used to reinforce the immunosuppressive action of the combination of CNI with corticosteroids at reduced doses11-15 or when reduced CNI exposure is used to prevent their side effects.16,17 Therefore, corticosteroid-sparing immunosuppressive protocols combining tacrolimus and MMF may be favored to improve safety.

The therapeutic drug monitoring (TDM) of mycophenolic acid (MPA, the active metabolite of MMF) has been recommended.18 The therapeutic efficacy and, to a lesser extent, the occurrence of adverse events are related to MPA area under the concentration-time curve (AUC0-12h).19 There is a linear relationship between MPA AUC and dose in renal transplant recipients but with a wide inter individual variability so that the relationship AUC-effects (efficacy and side effects) is more reliable than the relationship dose-effects,20 which justifies MMF TDM and individual dose adjustment in renal transplantation.21,22 Previous studies showed that with TDM, MPA AUC0-12h reached more rapidly the therapeutic range of exposure (30-60 mg.h/L) than patients receiving the standard fixed dose and had a better outcome.20 Furthermore, this individualization of MMF treatment may be used to reduce the other immunosuppressive agents, particularly corticosteroids and CNI, and reduce their cardiovascular toxicity.

A prospective pharmacokinetic study in liver transplantation has demonstrated that most patients (treated with MMF 2 g daily and tacrolimus) were underexposed to MMF until the third month, and 30% of the patients were still underexposed (AUC <30 mg.h/L) between 3 and 6 months after transplantation. Therefore, a dose of 2 g could not be enough to maintain an adequate level of immunosuppression.23

The aim of this study was to compare the efficacy and tolerance of a corticosteroid-free regimen with tacrolimus and individualized MMF dose versus a standard treatment with corticosteroids at decreasing doses (complete sparing at month 6), tacrolimus, and fixed dose MMF.

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MATERIALS AND METHODS

Design Overview

This was a prospective, open-label, comparative, randomized, parallel group study, conducted in 14 French centers between October 2007 and July 2011. The study protocol was approved by the relevant ethics committee, and the study was conducted in full agreement with the principles of the Declaration of Helsinki and the Good Clinical Practices guidelines. All patients signed an informed consent form before inclusion in the study.

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Patients and Settings

The patients could be screened while they were on the waiting list for liver transplant. Patients who fulfilled inclusion criteria (male or female, at least 18 years old, recipient of a first orthotopic [whole or partial] liver transplant from deceased or living donor) and none of the exclusion criteria were invited to participate. Exclusion criteria included history of organ transplants, multiorgan transplant, active gastroduodenal ulcer, history of malignant tumor within the past 5 years (except for successfully treated basal cell or squamous cell cancer, or in situ cervical cancer), hepatocellular carcinoma with greater than 3 nodules, nodules greater than 5 cm diameter, hepatic metastases or local invasion, condition not allowing corticosteroid withdrawal, HIV-positive blood test, serum creatinine of 180 μmol/L or greater, calculated creatinine clearance of 30 mL/min or less, leukocyte count of less than 2000/mm3, use of a prohibited treatment (immunosuppressant other than those used in the study, any temporary treatment protocol and temporary marketing authorizations, and induction therapy), pregnant or breast-feeding women, or women of childbearing age not using an effective contraception.

The eligible patients were assigned within 12 hours posttransplantation to 1 of the 2 treatment arms using centralized, balanced (1:1) adaptive randomization (minimization method), stratified on the following parameters: center, living or deceased donor, age of recipient, and presence or absence of hepatitis C virus (HCV).

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Study Treatments

In both treatment arms, the patients received a standard intravenous (IV) bolus of corticosteroids at day 0 in the peroperative period (10-15 mg/kg per day according to center practice) and were treated with tacrolimus (Prograf; Astellas Pharma, Levallois-Perret, France) adjusted to maintain a target trough level of 8 to 12 ng/mL from day 0 to month 1 and 3 to 8 ng/mL from months 1 to 12 (Figure 1). In addition, treatment regimens included the following:

FIGURE 1

FIGURE 1

In arm A (experimental treatment): MMF (CellCept; Roche, Boulogne-Billancourt, France) starting at 3 g/d from the day of transplantation (day 0), followed by dose adjustments based on total exposure (MPA AUC0-12h) using Bayesian estimation with limited sampling strategy (plasma samples drawn at 20 ± 10, 60 ± 15, and 180 ± 30 minutes after administration) (21), performed on days 5 and 14 and months 1, 3, 6, 9, and 12 (target MPA AUC: 45 mg.h/L).

In arm B (reference treatment): MMF 2 g/d (fixed dose, with clinical adjustment if necessary), corticosteroids (Cortancyl; Sanofi-Aventis, Compiègne, France) up to 6 months posttransplantation at a dose of 20 mg/d from day 0 to month 1, 15 mg/d from months 1 to 2, 10 mg/d from months 2 to 3, 5 mg/d from months 3 to 6, and discontinuation at month 7.

For all patients (irrespective of treatment arm), MPA plasma concentrations were measured locally in each center, whereas computer-assisted MPA AUC0-12h calculation and MMF dose recommendation were done centrally (at Limoges University Hospital, Limoges, France). During the study, the results were transmitted to the investigators only for patients in arm A via the study Web site and automatic emails, whereas results for patients of arm B were kept blinded to the investigators.

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Study Parameters and Visits

The main objective of this study was to demonstrate in de novo liver transplant patients the noninferiority in terms of incidence of treated biopsy-proven acute rejection (treated BPAR) (according to Banff classification {24}) up to 12 months of a strategy integrating corticosteroids avoidance and tacrolimus and MMF at intensified and individually adjusted dose, compared with a tritherapy with corticosteroids maintained for 6 months and tacrolimus and MMF at fixed usual dose.

The patients were treated and followed up in the study for 12 months posttransplantation, with a total of 9 visits (day of the transplantation (D0), days 5 and 14 and months 1, 2, 3, 6, 9, and 12). A safety monitoring visit was conducted within 28 days after the last administration of study treatment (MMF or corticosteroids).

A systematic liver biopsy was performed for all patients on day 0 and at month 12 for histological evaluation of the graft. These biopsies, and biopsies “for cause” taken during the trial, were read locally and reviewed centrally.

At each visit planned in the study protocol, hematological and biochemical analyses, and lipid profiles when appropriate, were performed to evaluate the incidence of cardiovascular risks, diabetes, and dyslipidemia. Renal function was assessed using the estimated glomerular filtration rate (GFR, calculated with the modification of diet in renal disease [MDRD] simplified formula) and creatinine clearance calculated using the Cockcroft-Gault formula.25 Blood pressure was measured at each visit. Data were collected using electronic case report forms.

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Study End Points

The primary end point was the incidence of treated, biopsy-proven acute rejection (where BPAR is defined as acute rejection with Banff score ≥ 4,24 following the central review) up to 12 months posttransplantation. Secondary end points included all acute rejection episodes (treated or not, biopsy proven or not), graft and patient survival up to 12 months posttransplantation, and histological evaluation of the graft from liver biopsies performed at month 12.

The safety assessment up to 12 months posttransplantation was based on the incidence of de novo diabetes, arterial hypertension, and dyslipidemia (which represent cardiovascular risk factors); the evolution of renal function; and the incidence of cancers, infections, osteoporosis, neurological disorders, hepatitis C recurrence, and all adverse events (overall safety).

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Statistical Analysis

A sample size of 224 patients to be included in the per protocol (PP) population was calculated to detect a difference of 15% in the primary end point between the 2 treatment arms with a statistical power of 80% and a 1-sided significance level of 2.5%.

All randomized patients with at least 1 MMF intake were included in the intent-to-treat (ITT) population. All ITT patients without major protocol violations were included in the PP population. All patients with at least 1 MMF and/or corticosteroid intake were included in the safety population.

Statistical analysis was performed using SAS software version 9.1 (SAS Institute, Cary, NC). Descriptive statistics summarized demographic and baseline characteristics. Qualitative parameters were compared using the chi-square test or the Fisher exact test if any of the theoretical numbers of patients was less than 5. The type I error (α) was fixed at 2.5% for the 1-sided test of the main criterion and at 5% for the 2-sided tests for all other variables.

The main analysis compared the proportion of patients with treated BPAR up to 12 months posttransplantation (primary end point) between the 2 treatment arms. If the 1-sided confidence interval of the difference in treated BPAR between the 2 treatment arms was comprised in the interval]-∞, 15%], the inferiority hypothesis was rejected in favor of the noninferiority hypothesis. The primary analysis was done on the PP population and repeated on the ITT population. Graft survival and overall survival were analyzed using Kaplan-Meier method and compared between treatment arms using a log-rank test and Cox model.

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RESULTS

Patient Recruitment

A total of 266 patients were screened and among them, 79 (30%) could not be randomized. Among the 187 remaining patients, 94 were randomized in arm A (MMF adjusted dose, corticosteroid-free) and 93 in arm B (MMF fixed dose, corticosteroids up to 6 months posttransplantation). The safety population included 183 patients who received at least 1 MMF and/or corticosteroid intake: 91 in arm A and 92 in arm B. The ITT population was composed of 180 randomized patients with at least 1 MMF intake: 90 in each treatment arm. Three patients in each treatment arm presented with major protocol deviations. Therefore, the PP population included 174 patients, 87 in each treatment arm (Figure 2).

FIGURE 2

FIGURE 2

Among the ITT population, 63 patients (35%) prematurely withdrew from the study (34 in arm A and 29 in arm B), mostly because of permanent discontinuation of study treatment (26 patients), use of prohibited immunosuppressive drugs (15 patients), or death (12 patients), comparable between treatment arms.

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Patients’ Characteristics

The ITT population included patients aged from 24 to 69 years (median, 56 years), mainly male patients (81%). Baseline characteristics were similar in both treatment arms (Table 1).

TABLE 1

TABLE 1

Overall, 88% of the patients of the ITT population presented with at least 1 concomitant disease, the most frequent being diabetes mellitus type 1 or 2 (29%), hypertension (36%), and thrombocytopenia (24%).

The indication of liver transplantation was mostly hepatocellular carcinoma (HCC, 45%) and alcoholic cirrhosis (28%). It was HCV-related disease (without HCC) for 26 patients (14%), including 11 patients who also presented with alcoholic cirrhosis. The median (range) MELD score was comparable in both arms, 136-37 and 136-32 in arms A and B, respectively.

Most grafts were obtained from deceased donors (96%). Cold ischemia time ranged from 1 to 16 hours, with a mean (±SD) of 7.8 (±2.5) hours.

Serology at baseline was positive in 6% of the patients for HBV, 37% for HCV, 96% for EBV, and 61% for CMV. Donor/recipient cross results were mostly D+/R+ (92%) and D + R- (3%) for EBV and D-/R+ (31%), D+/R+ (29%), D + R- (19%), and D-R- (21%) for CMV without statistical significance among groups.

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Immunosuppressive Drug Dosing and Pharmacokinetics

The mean daily doses of MMF received at each study visit in each group are presented in Table 2. In arm A, the percentage of patients receiving a daily dose of 3 g or more decreased progressively: 81% on day 14 and 78%, 35%, and 21% at months 1, 6, and 12, respectively. At month 12, 43% of the patients received a daily dose lower than 2 g. In arm B, the planned daily dose of 2 g was received by more than 95% of the patients up to month 1, 85% at month 3, and around 67% at month 6. From month 6 on, more than a quarter of the patients received less than 2 g daily.

TABLE 2

TABLE 2

At month 1, 61% of the patients in arm A and 52% in arm B had reached the MPA therapeutic exposure range (≥30 mg.h/L), and 82% and 75%, respectively, had reached this threshold at month 6 (Figure 3). In arm A, adjustment of MMF dose was done according to AUC results for 44% to 66% of the patients over the evaluation period. Overall, 43% of the patients (49% in arm A and 38% in arm B) had a dose reduction because of the occurrence of an adverse event.

FIGURE 3

FIGURE 3

The mean tacrolimus trough concentration between day 0 and month 1 was within the 8- to 12-ng/mL interval defined by the protocol but above the target interval of 3 to 8 ng/mL between month 1 and month 6, without differences between arms (Figure 4).

FIGURE 4

FIGURE 4

In arm A (corticosteroid-sparing regimen), 10 patients (11%) were treated with corticosteroids during the first month mostly for occurrence of adverse events or rejection treatment. In arm B, 58% of the patients were still treated with corticosteroids at month 6 (Table 2).

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End Points

Fifteen patients of the PP population (9%) had a treated BPAR during the 12 months posttransplantation: 7 in arm A and 8 in arm B. The 1-sided 97.5% confidence interval of the difference between the 2 treatment arms was [-∞, 9.49]; thus, the upper limit was less than 15%, and the noninferiority hypothesis was demonstrated (Table 3). Similar results were obtained in the ITT population, with treated BPAR in 8 patients (9%) of each treatment arm resulting in a 1-sided 97.5% CI of [-∞, 8.31].

TABLE 3

TABLE 3

In addition, 3 patients in arm A (3%) and 4 patients in arm B (5%) had nontreated BPAR, and 9 (10%) and 11 patients (13%), respectively, had treated but not biopsy-proven acute rejection episodes.

In the PP population, 2 patients, 1 in each treatment arm, had 2 episodes of BPAR during the 12 months posttransplantation, whereas all other patients with BPAR only had 1 episode. The score of BPAR according to Banff criteria was mostly 5 (27%) or 6 (36%), with no significant difference between treatment arms (P = 0.341, Fisher test). There was no statistically significant difference between treatment arms in rejection rates, either reported by local pathologists or after central reading.

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Patient and Graft Survival

The overall survival rate at 1-year posttransplantation in arm A and arm B was 91.1% and 88.9% (P = 0.71, logrank test), respectively, in the ITT population and 90.8% and 89.7% (P = 0.86), respectively, in the PP population. Seven patients (4%) experienced graft loss: 2 (2%) in arm A and 5 (6%) in arm B. Graft survival was similar in ITT and PP populations, respectively, 97.7% and 94.3% (P = 0.26, logrank test) in arms A and B.

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Safety

All patients experienced at least 1 AE, except 1 in arm B. The most frequently reported adverse events were anemia (49%), hypertension (34%), diarrhea (31%), renal failure (26%) and acute renal failure (21%), pleural effusion (26%), and cholestasis (24%). Similar results were observed in both treatment arms. Most adverse events (71%) resolved without sequelae.

Overall, 19 patients died during the study: 9 in arm A (10%) and 10 in arm B (11%). Deaths were mostly consecutive to multi-organ failure (6 patients) or septic shock (4 patients).

Serious adverse events were reported for 139 patients (76%), the most frequent being acute renal failure (14 patients in arm A and 5 patients in arm B) and renal failure (6 patients in each arm). Serious hepatitis C was reported for 10 patients (3 and 7 patients, respectively) and serious diarrhea was reported for 8 patients (6 and 2 patients, respectively). The incidence of all serious adverse events was similar in both treatment arms.

Overall, 62% of the patients experienced adverse events considered to be related to MMF, the most frequent being blood disorders including anemia (19%), thrombocytopenia (9%), neutropenia (8%), pancytopenia (8%), and leukopenia (7%). Mycophenolate mofetil–related diarrhea was reported for 22% of the patients. Thirteen patients in arm A and 6 patients in arm B had to permanently discontinue MMF because of treatment-related adverse events.

The most frequent adverse events related to tacrolimus were renal failure (18% of the patients) and acute renal failure (13%), hypertension (9%), anemia (8%), and diarrhea (7%). Treatment-related adverse events led to permanent discontinuation of tacrolimus for 8 patients in arm A and 5 patients in arm B. Adverse events related to corticosteroids were mostly hyperglycemia, diabetes mellitus, and hypertension.

The analysis of adverse events of special interest showed no statistically significant difference between treatment arms in the incidence of hypertension (32% of the patients overall); diarrhea (32%); and bacterial (55%), viral (19%), and fungal (9%) infections. Less cases of diabetes were reported in arm A: 20% of the patients compared with 33% of the patients in arm B (P = 0.049). Low values of hemoglobin concentration (<10 g/dL) and leukocyte (<2. 109/L) and neutrophil (<1. 109/L) counts were significantly more frequent in arm A than in arm B (Table 4). Estimated renal function was similar in both treatment arms. At 1 year posttransplantation, the mean (±SD) estimated GFR (MDRD formula) was 79 (±22) mL/min per 1.73 m2 (Figure 5), and the median [Q1; Q3] was 77 [62;90] mL/min per 1.73 m2.

TABLE 4

TABLE 4

FIGURE 5

FIGURE 5

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DISCUSSION

This randomized study has shown that a corticosteroid-sparing regimen with tacrolimus and MMF at dose intensified and adjusted on MPA AUC0-12h is not inferior to the standard regimen with corticosteroids maintained for 6 months, tacrolimus, and fixed dose MMF with regard to the incidence of treated BPAR over 12 months posttransplantation. The rate of treated BPAR was low in both treatment arms: 8% with the corticosteroid-sparing regimen versus 9% with the reference regimen.

A meta-analysis of randomized trials comparing steroid-free with steroid-based immunosuppression in liver transplantation has shown benefits in terms of cardiovascular risk factors, without increased rejection rates when steroids were replaced by another immunosuppressive agent. Still, these trials were very heterogeneous, so that large, conclusive trials were needed.27 In a recent study conducted on HCV-positive liver transplant patients, the rate of BPAR was 16.4% with a steroid-free treatment including tacrolimus and daclizumab.28 Steroid-sparing regimens have been evaluated in several studies conducted on kidney transplant recipients. In a large trial involving 538 renal transplant recipients, a corticosteroid-free regimen with tacrolimus, MMF, and daclizumab led to the same incidence of BPAR (16.5%) after 6 months as treatment with tacrolimus, MMF, and corticosteroids, with added safety benefits.3 In the present study, the rate of acute rejections was low, probably because of improvement in treatment efficacy of the combination of dose-intensified and adjusted MMF and tacrolimus and to the inclusion/noninclusion criteria that excluded some patients with higher risk of rejection, for whom it was difficult to consider a corticosteroid-free protocol. In addition, the mean trough concentration of tacrolimus was in the 8- to 12-ng/mL interval defined by the protocol during the first month posttransplantation and above the 3- to 8-ng/mL target interval between months 1 and 6. Therefore, very few patients were underexposed to tacrolimus over the study period.

This study showed that a higher initial dose of MMF followed by dose adjustment according to MPA AUC0-12h allowed patients to reach more rapidly the MPA AUC target chosen (≥30 mg.h/L) than the standard fixed dose of MMF. This AUC0-12h target was chosen based on evidence in renal transplantation,19,29-32 and in autoimmune diseases33,34 with the hypothesis that MPA pharmacodynamics in lymphocytes35 are the same whatever the condition (as is the case for calcineurin inhibitor for instance). The mean MPA AUC was higher (although the difference was not statistically significant) in arm A until M6 and then similar in both groups. In a first randomized study in renal transplantation, we previously showed that TDM of MMF significantly decreased patient failure,30 whereas in a second, we found that it does not improve the outcomes for low-risk patients given 3 g/d as the starting dose and that it might be reserved to patients with a higher immunological risk who could benefit from greater MPA exposure.29

Investigators’ compliance with the MMF dose recommended was poor. Over the evaluation period, only 44% to 66% of recommended dose adjustments were actually applied. In a number of cases, the occurrence of adverse events may have interfered with the planned dose adjustment, so much so that the laboratory results usually arrived several days after sampling. In this study, 43% of the patients (49% in arm A and 38% in arm B) had a dose reduction because of adverse events attributed to MMF by the investigator. Similar difficulties to achieve the adjustment according to target MPA AUC were reported in yet another study comparing fixed and concentration-controlled doses of MMF in renal transplant recipients, and it was put forward that physicians were sometimes reluctant to implement dose changes.36 However, investigators’ motivation is probably key, as their compliance was much better (>70%) in our previous 2 studies in renal transplantation, using the same computer tools.29,30 The impact of MMF therapeutic drug monitoring per se in the context of corticosteroid-sparing regimen has never been studied in liver transplantation. Unfortunately, in the present study, it cannot be detangled from that of the high starting dose, as there was no comparative group without TDM.

The avoidance of corticosteroids with adjusted MMF dose did not lead to a higher incidence of graft loss or worse patient survival: graft loss was experienced by 2 patients in arm A (2%) and 5 patients in arm B (6%), and overall survival at 12 months was 90% in both treatment arms.

Regarding safety, there was no difference in the overall incidence of adverse events between the 2 treatment arms. No new safety signal was highlighted. Renal failure attributed to tacrolimus was reported in 18% and acute renal failure in 13% of the patients. The combination of MMF and CNI has been shown to be safe; long-term studies did not show any increase in malignancies when MMF was added to a combination of cyclosporine and corticosteroids9 or tacrolimus and corticosteroids.37 In this study, low values of hemoglobin, leukocytes, and neutrophils were significantly more frequent with the MMF intensified dose and corticosteroid-sparing regimen. However, significantly less cases of diabetes were reported in arm A (20% vs 33%), confirming that corticosteroid-free regimens improve the safety profile of immunosuppressive treatments.

In conclusion, this study in liver transplant recipients showed that a therapeutic protocol with MMF started at 3 g/d and dose adjusted according to MPA AUC in combination with tacrolimus allows early discontinuation of corticosteroid (at day 1), resulting in a lower incidence of posttransplantation diabetes at 1 year posttransplantation without increasing the incidence of treated biopsy-proven acute rejection.

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ACKNOWLEDGMENTS

The authors thank the steering committee, Data Safety Monitoring Board, Euraxi Pharma for data monitoring, Lincoln France for editorial assistance, and all physicians and patients for their participation in the study.

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REFERENCES

1. Sheiner PA, Magliocca JF, Bodian CA, et al. Long-term medical complications in patients surviving ≥ 5 years after liver transplant. Transplantation. 2000;69:781–789.
2. Fisher NC, Malag M, Gonzles-Pinto I. The clinical impact of nephrotoxicity in liver transplantation. Transplantation. 2000;69:18–22.
3. Rostaing L, Cantarovich D, Mourad G, et al. Corticosteroid-free immunosuppression with tacrolimus, mycophenolate mofetil, and daclizumab Induction in renal transplantation. Transplantation. 2005;79:807–814.
4. Klupp J, Pfitzmann R, Langrehr JM, et al. Indications of mycophenolate mofetil in liver transplantation. Transplantation. 2005;80:S142–146.
5. Borrows R, Loucaidou M, Van Tromp J, et al. Steroid sparing in renal transplantation with tacrolimus and mycophenolate mofetil: three-year results. Transplant Proc. 2005;37:1792–1794.
6. Stegall MD, Everson GT, Schroter G, et al. Prednisone withdrawal late after adult liver transplantation reduces diabetes, hypertension and hypercholesterolemia without causing graft loss. Hepatology. 1997;25:173–177.
7. Ringe B, Braun F, Schutz E, et al. A novel management strategy of steroid-free immunosuppression after liver transplantation: efficacy and safety of tacrolimus and mycophenolate mofetil. Transplantation. 2001;71:508–515.
8. European mycophenolate mofetil cooperative study group. Mycophenolate mofetil in renal transplantation: 3-year results from the placebo-controlled trial. Transplantation. 1999;68:391–396.
9. Mathew TH. A blinded, long term-term randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation: results at three years. Tricontinental mycophenolate mofetil renal transplantation study group. Transplantation. 1998;66:817.
10. Meier-Kriesche HU, Steffen BJ, Hochberg AM, et al. Long-term use of mycophenolate mofetil is associated with a reduction in the incidence and risk of late rejection. Am J Transplant. 2003;3:68–73.
11. Eckhoff DE, McGuire BM, Frenette LR, et al. Tacrolimus (FK506) and mycophenolate mofetil combination therapy versus tacrolimus in a dult liver transplantation. Transplantation. 1998;65:180–187.
12. Wiesner RH, Shorr JS, Steffen BJ, et al. Mycophenolate mofetil combination therapy improves long-term outcomes after liver transplantation in patients with and without hepatitis C. Liver Transpl. 2005;11:750–759.
13. Wiesner RH, Steffen BJ, David KM, et al. Mycophenolate mofetil use is associated with decreased risk of late acute rejection in adult liver transplant recipients. Am J Transplant. 2006;6:1609–1616.
14. Pageaux G, Rostaing L, Calmus Y, et al. Mycophenolate mofetil in combination with reduction of calcineurin inhibitors for chronic renal dysfunction after liver transplantation. Liver Transpl. 2006;12:1755–1760.
15. Nashan B, Saliba F, Durand F, et al. Pharmacokinetics, efficacy, and safety of mycophenolate mofetil in combination with standard-dose or reduced-dose tacrolimus in liver transplant recipients. Liver Transpl. 2009;15:136–147.
16. Pfitzmann R, Klupp J, Langrehr JM, et al. Mycophenolate mofetil for Immunosuppression after liver transplantation: a follow-up study of 191 patients. Transplantation. 2003;76:130–136.
17. Reich DJ, Clavien PA, Hodge EE. The MMF renal dysfunction after liver transplantation working group. Mycophenolate mofetil for renal dysfunction in liver transplant recipients on cyclosporine or tacrolimus: randomized, prospective, multicenter pilot study results. Transplantation. 2005;80:18–25.
18. Le Meur Y, Borrows R, Pescovitz MD, et al. Therapeutic drug monitoring of mycophenolates in kidney transplantation: report of The Transplantation Society consensus meeting. Transplant Rev (Orlando). 2011;25:58–64.
19. Van Gelder T, Hilbrands LB, Vanrenterghem Y, et al. A randomized double-blind, multicenter plasma concentration controlled study of the safety and efficacy of oral mycophenolate mofetil for the prevention of acute rejection after kidney transplantation. Transplantation. 1999;68:261–266.
20. Le Meur Y, Borrows R, Pescovitz MD, et al. Therapeutic drug monitoring of mycophenolates in kidney transplantation: report of the transplantation society consensus meeting. Transplant Reviews. 2011;25:58–64.
21. Premaud A, Le Meur Y, Debord J, et al. Maximum a posteriori bayesian estimation of mycophenolic acid pharmacokinetics in renal transplant recipients at different postgrafting periods. Ther Drug Monit. 2005;27:354–361.
22. Kuypers DR, Le Meur Y, Cantarovich M, et al. Transplantation Society (TTS) Consensus Group on TDM of MPA. Consensus report on therapeutic drug monitoring of mycophenolic acid in solid organ transplantation. Clin J Am Soc Nephrol. 2010;5:341–58.
23. Brunet M, Cirera I, Martorell J, et al. Sequential determination of phamacokinetics and pharmacodynamics of mycophenolate acid in liver transplant patients treated with mycophenolate mofetil. Transplantation. 2006;81:541–546.
24. Demetris AJ, Batts KP, Dhillon AP, et al. Banff schema for grading liver allograft rejection: an international consensus document. Hepatology. 1997;25:658–663.
25. Froissart M, Rossert J, Jacquot C, et al. Predictive performance of the modification of diet in renal disease and Cockroft-Gault equations for estimating renal function. J Am Soc Nephrol. 2005;16:763–73.
26. Segev DL, Sozio SM, Shin EJ, et al. Steroid avoidance in liver transplantation: meta-analysis and meta-regression of randomized trials. Liver Transpl. 2008;14:512–525.
27. Krämer BK, Klinger M, Vítko S, et al. Tacrolimus-based, steroid-free regimens in renal transplantation: 3-year follow-up of the ATLAS trial. Transplantation. 2012;94:492–498.
28. Neumann U, Samuel D, Trunečka P, et al. A randomized multicenter study comparing a tacrolimus-based protocol with and without steroids in HCV-positive liver allograft recipients. J Transplant. 2012;2012:894215.
29. Le Meur Y, Thierry A, Glowacki F, et al. Early steroid withdrawal and optimization of mycophenolic acid exposure in kidney transplant recipients receiving mycophenolate mofetil. Transplantation. 2011;92:1244–51.
30. Le Meur Y, Büchler M, Thierry A, et al. Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation. Am J Transplant. 2007;7:2496–2503.
31. Daher Abdi Z, Essig M. Impact of longitudinal exposure to mycophenolic acid on acute rejection in renal-transplant recipients using a joint modeling approach. Pharmacol Res. 2013;72:52–60.
32. Daher Abdi Z, Prémaud A, et al. Exposure to mycophenolic acid better predicts immunosuppressive efficacy than exposure to calcineurin inhibitors in renal transplant patients. Clin Pharmacol Ther. 2014;96(4):508–15.
33. Zahr N, Arnaud L, Marquet P, et al. Mycophenolic acid area under the curve correlates with disease activity in lupus patients treated with mycophenolate mofetil. Arthritis Rheum. 2010;62:2047–54.
34. Woillard JB, Bader-Meunier B, Salomon R, et al. Pharmacokinetics of mycophenolate mofetil in children with lupus and clinical findings in favour of therapeutic drug monitoring. Br J Clin Pharmacol. 2014;78(4):867–76.
35. Prémaud A, Rousseau A, Johnson G, et al. Inhibition of T-cell activation and proliferation by mycophenolic acid in patients awaiting liver transplantation: PK/PD relationships. Pharmacol Res. 2011;63(5):432–8.
36. van Gelder T, Silva HT, de Fijter JW, et al. Comparing mycophenolate mofetil regimens for de novo renal transplant recipients: the fixed-dose concentration-controlled trial. Transplantation. 2008;86:1043–1051.
37. Lake JR, David KM, Steffen BJ, et al. Addition of MMF to dual immunosuppression does not increase the risk of malignant short-term death after liver transplantation. Am J Transplant. 2005;5:2961–2967.
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