The Impact of Everolimus Based Immunosuppression in the Evolution of Hepatitis C Fibrosis After Liver Transplantation
Condition: Hepatitis C Recurrence After Liver Transplant
MeSH terms: Hepatitis A; Hepatitis C; Hepatitis; Fibrosis; Recurrence
Study type: Interventional
Phase: Phase 3

Summary: 
      Background:

      Hepatitis C recurrence, which invariably occurs in viremic liver transplant (LT) recipients,
      associated with accelerated liver fibrosis leading to established graft cirrhosis in 40-20%
      of patients in 5 years with another 5% experiencing an aggressive form with cirrhosis and
      graft loss in 1 year. Since treatment after LT has a low efficacy, the overall survival of
      HCV-infected LT recipients is shorter than that of uninfected LT patients.

      New immunosuppressive agents such as mTOR inhibitors (Everolimus/Sirolimus) reduce the risk
      of liver graft rejection, have antifibrotic properties and do not worsen HCV recurrence.
      Moreover new directly-acting antiviral agents have increased efficacy of interferon-based
      treatment but their use in LT recipients may be limited by side effects.

      Hypothesis:

      Use of individualized immunosuppressive regimen and early personalized anti-viral treatment
      based on recipient and viral factors would improve outcome of HCV infected liver transplant
      recipients.

      Objectives:

        1. To evaluate safety and efficacy of two steroid-free immunosuppressive regimens to reduce
           hepatitis C recurrence associated to fibrosis progression (F≥2 under ISHAK score) at one
           year post-transplant.

        2. To identify viral and recipient factors associated with liver fibrosis progression using
           ultra-deep pyrosequencing (UDPS).
    

Detailed description: 
      Study design:

      A pilot, open-label, prospective, randomized and unicenter study. As pilot study, the number
      of patients expected to be included is n=40.

      Inclusion criteria:

        -  Age≥18 years

        -  First liver transplant

        -  RNA-HCV positive within 12 months previous to the transplant

      Exclusion criteria:

        -  Multiorgan transplant

        -  Split liver

        -  ABO incompatible

        -  HIV positive patients

        -  Glomerular Filtration rate ≤60mL/min/1.73m2

      Patients will receive double immunosuppression therapy at induction with tacrolimus (basal
      dose 0.1 mg/Kg/day) and mycophenolate mofetil (MMF, basal dose 2g/day) within the first 12
      hours after skin closure.

      Patients will be randomized in one of the following groups at day 28th post-transplant:

        1. MMF group (n=20): tacrolimus (levels 8-10ng/ml) and MMF (levels 1-3ng/mL).

        2. EVL group (n=20): tacrolimus (levels 8-10ng/ml) and everolimus (levels 2- 4 ng/mL).

      HCV monitorization:

        -  HVC-RNA detection and quantification. Serum samples will be taken immediately before
           liver transplantation, in the anhepatic phase, at the beginning and at the end of the
           reperfusion, and at 1h, 4h, 8h, 12h, 18h, 1d, 3d, 7d, 14d, 28d, 2m, 3m, 6m, 9m and 12m.
           Blood samples will be taken from the peripheral circulation and centrifugated within 2
           to 3 hours after extraction, aliquoted, and frozen at -80 ºC. The concentration of
           HCV-RNA will be determined by using a quantitative reverse-transcription polymerase
           chain reaction (RT-PCR) assay (Cobas Ampliprep/Cobas TaqMan; Roche Molecular
           Diagnostics, Barcelona, Spain) that achieves a sensitivity of 15 UI/mL and ultra deep
           pyrosequencing (UDSP) protocols will be used to study DNA genomic factor and viral RNA
           variability.

        -  Serum fibrosis markers. Serum samples will be taken at 3rd, 6th and 12th months
           post-transplant from peripheral circulation and frozen at -21ºC. Serum markers (HA,
           PIIINP, and TIMP-1) will be analyzed by a fully automated, two-site sandwich immunoassay
           using direct chemiluminometric technology (ADVIA Centayr XP, Siemens Healthcare
           Diagnositics). The algorithm including the three markers (3-M-ALG) {score= -7,412 + [ln
           (HA)x0,681] + [ln (PIIINP)x0.775] + [ln (TIMP-1)]x0,494} will be also obtained.

        -  Transient elastography (FibroScan). Liver stiffness measurements using Fibroscan
           (Echosens, Paris, France) will be performed in clinics at 6th and 12th months
           post-transplant.

        -  Liver biopsy. Liver biopsy will be performed at 12th months post-transplant. All biopsy
           specimens will be read by a single pathologist. Necroinflammatory activity and fibrosis
           stage will be scored using ISHAK classification.

      Follow-up and clinical data:

      After discharge, patients will be visited in the outpatient clinic monthly for the first 3
      months and every 3 months thereafter during the first 12 months post-transplant, at which
      time clinical and analytical variables will be recorded.Baseline characteristics, HCV
      genotype and viral load before transplant, surgical variables (type of liver transplant,
      donor age and steatosis, ischemia time), post-transplantation information and follow-up will
      be prospectively collected in an electronic database.

      Patient withdrawal:

        -  No consent form given by the patient

        -  Severe adverse events related to immunosuppressors used

        -  Steroids are required for long period of time

        -  Antiviral therapy given before during the first year post-transplant

        -  Lost follow-up

        -  Patient death
    

Intervention name(s): EVL arm; MMF arm
Intervention type(s): Drug; Drug
Intervention description(s): Patients will be randomized at day 28th post-transplant. This group will receive Tacrolimus+Everolimus.; Patients will be randomized at day 28th post-transplant. This group will continue of current immunosuppressive regimen (Tacrolimus+MMF) / no everolimus introduction.
Other intervention name(s): Everolimus; Mofetil Mycophenolate
Intervention MeSH terms: Everolimus
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Hepatitis C; Liver Fibrosis; m-TOR inhibitors