Effect of Immunosuppression Drug Weaning on Hepatitis C Virus (HCV)-Induced Liver Damage After Liver Transplantation
Condition: Hepatitis C Virus Infection; Liver Transplantation
MeSH terms: Hepatitis A; Virus Diseases; Hepatitis C; Hepatitis
Study type: Interventional
Phase: Phase 2

Summary: 
      Viral infections can profoundly influence alloimmune responses and hamper allograft tolerance
      induction. Persistent hepatitis C virus (HCV) infection occurs in 50% of liver and 20% of
      kidney transplant recipients, but the impact of HCV on the acquisition of allograft tolerance
      has not been elucidated. Liver transplantation constitutes a unique clinical model to address
      this question, given that up to 20% of liver recipients can completely discontinue
      immunosuppressive drugs and attain operational tolerance.

      The goal of our study is to determine the influence of HCV-driven immune responses on the
      acquisition of operational tolerance in liver transplant recipients following drug weaning,
      and to assess whether immunosuppression withdrawal ameliorates HCV-induced liver damage.

      This is a prospective trial in which immunosuppressive drug weaning will be offered to
      HCV-positive liver recipients (selected on the basis of a high likelihood of tolerance) as a
      strategy to improve HCV-mediated liver disease.
    

Detailed description: 
      Objective: To determine the influence of hepatitis C virus (HCV)-driven immune responses on
      the acquisition of operational tolerance in liver transplant recipients following drug
      weaning, and to assess whether immunosuppression withdrawal ameliorates HCV-induced liver
      damage.

      Background: Viral infections can profoundly influence alloimmune responses and hamper
      allograft tolerance induction. Persistent HCV infection occurs in 50% of liver and 20% of
      kidney transplant recipients, but the impact of HCV on the acquisition of allograft tolerance
      has not been elucidated. Liver transplantation constitutes a unique clinical model to address
      this question, given that up to 20% of liver recipients can completely discontinue
      immunosuppressive drugs and attain operational tolerance.

      Hypothesis/Specific Aims: We hypothesize that HCV positive patients failing to attain
      operational tolerance will exhibit both decreased anti-HCV specific T cell responses and
      exacerbated non-specific immunoactivation. Furthermore, we anticipate that successful
      immunosuppression withdrawal will decrease the progression of HCV-induced liver damage. Thus
      our aims are:

        1. To test whether the magnitude of HCV-mediated inflammatory responses influence the
           acquisition of operational tolerance following liver transplantation.

        2. To establish the impact of anti-HCV specific CD4+ and CD8+ T cell immune responses on
           the capacity of liver recipients to successfully withdraw immunosuppression.

        3. To determine how the immunophenotypic traits and functional properties of T cells, NK
           cells and antigen presenting cells affect the development of operational tolerance in
           HCV-positive liver recipients.

        4. To assess the effect of immunosuppression weaning on the histological progression of
           HCV-induced liver damage.

      Proposed methods: On the basis of a previously identified immunophenotypic signature of
      tolerance (high ratio of delta 1 to delta 2 gammadelta T cell in peripheral blood), drug
      weaning will be offered to HCV-positive liver recipients as a strategy to improve
      HCV-mediated liver disease. We estimate that patients selected on the basis of this biomarker
      will have a likelihood of successful weaning greater than 50%. Both peripheral blood and
      liver tissue samples will be collected for diagnostic purposes before the initiation of drug
      weaning in order to perform the following assays: measurement of anti-HCV CD4+ and CD8+ T
      cell immunity, peripheral blood and liver tissue gene expression profiling, peripheral blood
      cell phenotyping and functional assays and, in a subset of patients, measurement of
      anti-donor T cell responses. Immunosuppression drugs will be weaned over a period of 6
      months, and thereafter patients will be followed for 12 additional months. Patients not
      undergoing rejection during this 18 month period will be considered tolerant. Liver biopsies
      will be obtained before the beginning of the study and at the end. Progression of HCV-induced
      liver diseased will be compared to that of patients with a low delta1/delta2 ratio, in whom
      no changes in immunosuppressive drugs will be conducted and liver biopsies will be obtained
      yearly (according to our clinical guidelines).

      Expected results: We expect to precisely define how HCV influences the acquisition of
      operational tolerance after liver transplantation, and confirm the beneficial effect of
      immunosuppression withdrawal in these patients.
    

Intervention name(s): Gradual immunosuppression drug withdrawal.
Intervention type(s): Procedure
Intervention description(s): Ater obtention of biological samples (peripheral blood, liver tissue) enrolled patients undergo gradual decrease in the doses of immunosuppression drugs (tacrolimus, cyclosporine A and/or mofetil mycophenolate) until complete discontinuation or appearance of rejection.
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Liver Transplantation; Tolerance; Hepatitis C virus infection; Immune responses; Allograft tolerance; Immunosuppression weaning; Immunosuppression minimization