title: Impact of immunosuppression minimization and withdrawal in long-term hepatitis C virus liver transplant recipients.
abstract: OBJECTIVE
  To investigate the effects of different immunosuppressive regimens and avoidance on fibrosis progression in hepatitis C virus (HCV) liver transplant (LT) recipients.
  
  
  METHODS
  We retrospectively compared the liver biopsies of well-matched HCV LT recipients under calcineurin inhibitors (CNI group, n = 21) and mycophenolate (MMF group, n = 15) monotherapy, with those patients who successfully withdrawn immunosuppression (IS) therapy from at least 3 years (TOL group, n = 10). To perform the well-matched analysis, all HCV transplanted patients from December 1993 were screened. Only those HCV patients who reached the following criteria were considered for the analysis: (1) at least 3 years of post-operative follow-up; (2) patients with normal liver graft function under low dose CNI monotherapy (CNI group); (3) patients with normal liver graft function under antimetabolite (Micophenolate Mofetil or coated mycophenolate sodium) monotherapy (MMF group); and (4) recipients with normal liver function without any IS. We excluded from the analysis recipients who were IS free or under monotherapy for < 36 mo, recipients with cirrhosis or with unstable liver function tests.
  
  
  RESULTS
  Thirty six recipients were enrolled in the study. Demographics, clinical data, time after LT and baseline liver biopsies were comparable in the three groups. After six years of follow-up, there was no worsening of hepatic fibrosis in the MMF group (2.5 ± 1.5 Ishak Units vs 2.9 ± 1.7 Ishak Units, P = 0.5) and TOL group (2.7 ± 10.7 vs 2.5 ± 1.2, P = 0.2). In contrast, a significant increase in the fibrosis score was observed in the CNI group (2.2 ± 1.7 vs 3.9 ± 1.6, P = 0.008). The yearly fibrosis progression rate was significantly worse in the CNI group (0.32 ± 0.35) vs MMF group (0.03 ± 0.31, P = 0.03), and TOL group (-0.02 ± 0.27, P = 0.02). No differences have been reported in grading scores for CNI group (2.79 ± 1.9, P = 0.7), MMF group (3.2 ± 1.5, P = 0.9) and TOL group (3.1 ± 1.4, P = 0.2). Twenty four patients were treated with low dose ribavirin (8 TOL, 7 MMF, 9 CNI). The hepatitis C titers were comparable in the three groups. No episodes of rejection have been reported despite differences of liver function test in the three groups during the observational period.
  
  
  CONCLUSIONS
  IS withdrawal and MMF monotherapy is safe and seems to be associated with the slowest fibrosis progression in HCV LT recipients.
authors.affiliation: Tommaso Maria Manzia, Roberta Angelico, Paolo Ciano, Daniele Sforza, Luca Toti, Giuseppe Tisone, Department of Experimental Medicine and Surgery, Section of Transplantation, Tor Vergata University of Rome, 00133 Rome, Italy.
authors.forename: Tommaso Maria
authors.initials: TM
authors.lastname: Manzia
authors.affiliation: Tommaso Maria Manzia, Roberta Angelico, Paolo Ciano, Daniele Sforza, Luca Toti, Giuseppe Tisone, Department of Experimental Medicine and Surgery, Section of Transplantation, Tor Vergata University of Rome, 00133 Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Angelico
authors.affiliation: Tommaso Maria Manzia, Roberta Angelico, Paolo Ciano, Daniele Sforza, Luca Toti, Giuseppe Tisone, Department of Experimental Medicine and Surgery, Section of Transplantation, Tor Vergata University of Rome, 00133 Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ciano
authors.affiliation: Tommaso Maria Manzia, Roberta Angelico, Paolo Ciano, Daniele Sforza, Luca Toti, Giuseppe Tisone, Department of Experimental Medicine and Surgery, Section of Transplantation, Tor Vergata University of Rome, 00133 Rome, Italy.
authors.forename: Jon
authors.initials: J
authors.lastname: Mugweru
authors.affiliation: Tommaso Maria Manzia, Roberta Angelico, Paolo Ciano, Daniele Sforza, Luca Toti, Giuseppe Tisone, Department of Experimental Medicine and Surgery, Section of Transplantation, Tor Vergata University of Rome, 00133 Rome, Italy.
authors.forename: Kofi
authors.initials: K
authors.lastname: Owusu
authors.affiliation: Tommaso Maria Manzia, Roberta Angelico, Paolo Ciano, Daniele Sforza, Luca Toti, Giuseppe Tisone, Department of Experimental Medicine and Surgery, Section of Transplantation, Tor Vergata University of Rome, 00133 Rome, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Sforza
authors.affiliation: Tommaso Maria Manzia, Roberta Angelico, Paolo Ciano, Daniele Sforza, Luca Toti, Giuseppe Tisone, Department of Experimental Medicine and Surgery, Section of Transplantation, Tor Vergata University of Rome, 00133 Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Toti
authors.affiliation: Tommaso Maria Manzia, Roberta Angelico, Paolo Ciano, Daniele Sforza, Luca Toti, Giuseppe Tisone, Department of Experimental Medicine and Surgery, Section of Transplantation, Tor Vergata University of Rome, 00133 Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tisone
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D065095:Calcineurin Inhibitors / Q000008:administration & dosage; D018450:Disease Progression; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006526:Hepatitis C / Q000150:complications* / Q000175:diagnosis; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008103:Liver Cirrhosis / Q000175:diagnosis / Q000601:surgery* / Q000821:virology; D008111:Liver Function Tests; D016031:Liver Transplantation / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D012008:Recurrence; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents
keywords: Clinical operational tolerance; Hepatitis C virus recurrence; Immunosuppression withdrawal; Liver transplantation; Micofenolate mofetil; Minimization of immunosuppression