Effect of Immunosuppression Drug Weaning on Hepatitis C Virus (HCV)-Induced Liver Damage After Liver Transplantation
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|ClinicalTrials.gov Identifier: NCT00668369|
Recruitment Status : Completed
First Posted : April 29, 2008
Last Update Posted : December 20, 2013
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.
|Condition or disease||Intervention/treatment||Phase|
|Hepatitis C Virus Infection Liver Transplantation||Procedure: Gradual immunosuppression drug withdrawal.||Phase 2|
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:
- To test whether the magnitude of HCV-mediated inflammatory responses influence the acquisition of operational tolerance following liver transplantation.
- 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.
- 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.
- 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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||34 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Effect of Immunosuppression Drug Weaning on Hepatitis C Virus Induced Liver Damage After Liver Transplantation.|
|Study Start Date :||April 2008|
|Primary Completion Date :||September 2011|
|Study Completion Date :||September 2011|
Liver transplant recipients with HCV infection fulfilling inclusion criteria.
Procedure: Gradual immunosuppression drug withdrawal.
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.
- Proportion of hepatitis C virus positive liver recipients successfully withdrawing immunosuppressive drugs. [ Time Frame: 18 months ]
- Effects of immunosuppression withdrawal on hepatitis C virus induced liver damage. [ Time Frame: 18 months ]
- Influence of HCV-induced immune responses on the feasibility of successfully withdrawing immunosuppressive drugs in liver transplant recipients. [ Time Frame: 18 months ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00668369
|Hospital Clinic Barcelona, University of Barcelona|
|Barcelona, Spain, 08036|
|Principal Investigator:||Alberto Sanchez-Fueyo, MD||Hospital Clinic Barcelona / IDIBAPS, Barcelona, Spain|
|Study Chair:||Giuseppe Tisone, MD||University Tor Vergata, Rome, Italy|
|Study Chair:||Marina Berenguer, MD||HOSPITAL LA FE VALENCIA|