• Incidence of biopsy proven acute rejection treated with corticoids or requiring a re-introduction of ICN in arm 1 -- or an increase of ICN in arm 2 -- 12 months after the interruption of ICN (arm 1) or after randomization (arm 2).
• Incidence of a composite end-point at 12 months, associating biopsy proven acute rejection treated with corticoids or requiring an increase and a re-introduction of ICN + chronic rejection + re-transplantation + death.
• Incidence of histological lesions of acute or chronic rejection at 12 months.
• Values of hepatic biological tests in each arm at 12 months.
• Evolution of side effects of the ICN in each arm at 12 months.
• Incidence of infectious and cancer complications in each arm at 12 months.

The aim of this project is to determine whether, in liver transplant patients with side effects due to ICN, the use of MMF in monotherapy can be optimised by dose adjustment based on the area under the curve (AUC) of mycophenolic acid (MPA). It involves a multicentre phase IV trial with direct individual benefit. A population of 130 liver transplant patients at 2 to 10 years post-transplant, showing significant clinical ICN side effects and being given bitherapy by ICN +MMF will be included and randomised 1:1 in two arms:

• Arm 1: progressive interruption of ICN after obtaining an AUC of MPA of 50 mg.h/l, followed by MMF monotherapy with dose adjustment based on the AUC of MPA,
• Arm 2: continuation of the ICN+MMF bitherapy without MMF therapeutic drug monitoring.

The main judgement criterion will be the incidence of acute rejection in the 2 groups at 6 months. The secondary judgment criterion will be the evaluation of the benefit of stopping ICN on the side effects caused by these drugs.

• Drug: Mycophénolate Mofétil
• Drug: Ciclosporine A
• Drug: Tacrolimus

Inclusion Criteria:

• Patient with first liver transplantion or retransplantation since more than 6 months: with a post-transplant lapse of time of 2 to 10 years and showing one of the following adverse effects of ICN:
• Renal insufficiency defined by a creatinine clearance <50ml/mn (calculated or estimated according to the Cockcroft formula)
• Arterial hypertension not controlled by an anti-hypertensive bitherapy
• Diabetes mellitus (fasting glycaemia >7.0mmol/l), whether treated or not
• Neuromuscular toxicity
• Immunosuppression by cyclosporine or tacrolimus and MMF
• Hepatic biopsy performed within the 6 months preceding the inclusion for the patients with a post-transplant period of <5 years and in the 12 months preceding the inclusion for patients with a post transplant period of >5 years.

Exclusion Criteria:

• Acute rejection within the 6 months preceding the screening
• Previous history of cortico-resistant rejection
• Chronic rejection
• Significant ductopenia (absence of inter-lobule biliary canals in more than 30% of the portal tracts) on the pre-screening biopsy.
• Existence of a pre-transplantation diabetes mellitus.
• Liver transplantation for auto-immune hepatitis or primary sclerosing cholangitis
• Patients transplanted for viral C cirrhosis with reinfection lesions of the transplanted organ, rendering treatment by ribarivine + interferon conceivable in the year following inclusion.
• Counter-indications to MMF (anaemia, leucopenia)
• Immunosuppression by sirolimus, everolimus, azathioprine or corticoids