Study of Sirolimus Versus Mycophenolate Liver Transplant Recipients With Recurrent Hepatitis C Virus (HCV)

Study Overview
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Brief Summary
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Different immunosuppressive drugs used in transplantation may reduce the body's defences against infection differently. It is known that patients with Hepatitis C virus, known as HCV, who switched from azathioprine to mycophenolate mofetil experienced an increase in viral load. Despite this, mycophenolate mofetil is used because it prevents rejection more reliably than azathioprine. Sirolimus is an another immunosuppressive agent that reliably prevents rejection and may have antiviral activity. This study is designed to see if the viral load of HCV and other viruses is reduced by switching from mycophenolate to sirolimus.

Detailed Description
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Hepatitis C virus (HCV) persistence after liver transplantation for HCV end-stage liver disease is universal and in this clinical setting, HCV mediated liver injury has been reported to follow a more progressive course compared to the non-immunosuppressed patient. Additionally, patients with recurrent chronic hepatitis C develop higher viral load compared to pre-transplant levels. Such persistently high viral burden post transplant may contribute to allograft damage. The choice of calcineurin inhibitor (CNI) does not effect recurrence rates of HCV hepatitis. HCV is also associated with renal dysfunction so that reduction in exposure to calcineurin inhibitors (CNI) is desirable. Unfortunately steroids are associated with a marked increase in HCV replication and cannot be used to reduce CNI doses. Mycophenolate mofetil (MMF) increases HCV viral load. A recent increase in the severity of recurrent hepatitis in patients with HCV receiving liver transplants has been attributed to MMF and interleukin-2 receptor blockers. Increased fibrosis of the liver occurs during antiviral anti HCV treatment in patients taking mycophenolate but patients on azathioprine develop cirrhosis faster, possibly because of rejection. A large industry sponsored phase III clinical trial has been underway for several years where patients have substituted sirolimus (SRL) for calcineurin inhibitors after liver transplantation. The object of that study is to determine impact of conversion on renal function. No detrimental effect (thrombosis, rejection or recurrent viral infection) was apparent to the safety board after two reviews. No study has compared SRL to MMF after liver transplantation. SRL, an immunosuppressive drug that inhibits the activation and proliferation of T-lymphocytes, is associated with reduction of Epstein Barr Virus (EBV) post-transplantation viral load in children. Experimentally it inhibits the growth of EBV B-cell lymphoma. A pilot study of tacrolimus with SRL showed a powerful anti-rejection effect but a subsequent trial was halted early because of an increase in hepatic artery thrombosis even though the rates of thrombosis in either arm of the study was below that expected. A recent large series in patients with hepatocellular carcinoma (most of whom had HCV) who received large doses of SRL showed a beneficial anti-cancer effect without thrombosis. The randomised trials and the reported series all had large numbers of patients with HCV. The absence of obvious recurrent HCV hepatitis and the low rates of cytomegalovirus (CMV) disease coupled with the known inhibition of EBV replication gives hope that SRL has anti-viral properties at immunosuppressive doses. Early reports confirm that hope: 1) successful liver transplantation in patients with HIV and HCV. Significantly better control of HIV and HCV replication was found among patients taking RAPA monotherapy (P=0.0001 and 0.03, respectively); 2) switching to sirolimus in renal transplant recipients with hepatitis C virus: HCV replication reduced by switch to sirolimus; 3) sustained, spontaneous disappearance of serum HCV-RNA under immunosuppression after liver transplantation for HCV cirrhosis: two liver recipients who spontaneously cleared HCV after switch to sirolimus. SRL (2 mg/day) and MMF (2g/day) are licensed as adjuvant immunosuppressive agents to be used in kidney transplantation with cyclosporine so that immunosuppressive equivalent doses are 1mg SRL = 1g MMF.

Official Title
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A Prospective Cross-over Study Comparing the Effect of Sirolimus Versus Mycophenolate on Viral Load in Liver Transplant Recipients With Recurrent Chronic HCV Infection

Conditions
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Hepatitis C

Intervention / Treatment
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* Drug: Mycophenolate to sirolimus switch


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recurrent HCV after liver transplantation Taking mycophenolate mofetil Stable liver function Exclusion Criteria: Pregnant females or couples unwilling to use contraception Intolerance or allergy to sirolimus Patients taking anti-HCV therapy Patients taking medications known to alter the levels of sirolimus History of thromboembolic disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mycophenolate to sirolimus switch<br>Liver transplant recipients with Hepatitis C virus switched from mycophenolate mofetil (MMF) to sirolimus (SRL) for 3 months and then switched back to MMF | Drug: Mycophenolate to sirolimus switch<br>* Sirolimus given for 3 months instead of mycophenolate at a starting dose equivalent of 1 mg sirolimus equal to 1000 mg of mycophenolate.<br>* Other names: cellcept;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delta Hepatitis C Viral Load | Percent change in HCV load determined 3 months after switch from MMF to SRL. | 3 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Final Hepatitis C Viral Load | Percent change in HCV load determined 3 months after switch from SRL to MMF | 3 month | 
| Sirolimus Trough Level |  | 3 month | 
| Delta Tacrolimus Trough Level | Percent change determined 3 months after switch from MMF to SRL | 3 month | 
| Delta Bilirubin | Percent change determined 3 months after switch from MMF to SRL | 3 month | 
| Delta Alkaline Phosphatase | Percent change determined 3 months after switch from MMF to SRL | 3 month | 
| Delta Alanine Aminotransferase | Percent change determined 3 months after switch from MMF to SRL | 3 month | 
| Delta Hemoglobin | Percent change determined 3 months after switch from MMF to SRL | 3 month | 
| Delta Platelet Count | Percent change determined 3 months after switch from MMF to SRL | 3 month | 
| Delta Cholesterol Fasting Level | Percent change determined 3 months after switch from MMF to SRL | 3 month | 
| Delta Triglyceride Fasting Level | Percent change determined 3 months after switch from MMF to SRL | 3 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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everolimus, sirolimus, mycophenolic acid, hepatitis C virus, tacrolimus, viral load