Study of Sirolimus Versus Mycophenolate Liver Transplant Recipients With Recurrent Hepatitis C Virus (HCV)
Information source: London Health Sciences Centre
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Hepatitis C
Intervention: Mycophenolate to sirolimus switch (Drug)
Phase: Phase 4
Status: Completed
Sponsored by: London Health Sciences Centre Official(s) and/or principal investigator(s): Vivian McAlister, MB, FRCSC, Study Director, Affiliation: London Health Sciences Centre Natasha Chandok, MD, FRCPC, Principal Investigator, Affiliation: London Health Sciences Centre
Summary
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.
Clinical Details
Official title: A Prospective Cross-over Study Comparing the Effect of Sirolimus Versus Mycophenolate on Viral Load in Liver Transplant Recipients With Recurrent Chronic HCV Infection
Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention
Primary outcome: Delta Hepatitis C Viral Load
Secondary outcome: Final Hepatitis C Viral LoadSirolimus Trough Level Delta Tacrolimus Trough Level Delta Bilirubin Delta Alkaline Phosphatase Delta Alanine Aminotransferase Delta Hemoglobin Delta Platelet Count Delta Cholesterol Fasting Level Delta Triglyceride Fasting Level
Detailed description:
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.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
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
Locations and Contacts
London Health Sciences Centre, London, Ontario N6A5A5, Canada
Additional Information
PI research website Transplant Program website
Related publications: Zekry A, Gleeson M, Guney S, McCaughan GW. A prospective cross-over study comparing the effect of mycophenolate versus azathioprine on allograft function and viral load in liver transplant recipients with recurrent chronic HCV infection. Liver Transpl. 2004 Jan;10(1):52-7. McAlister VC, Gao Z, Peltekian K, Domingues J, Mahalati K, MacDonald AS. Sirolimus-tacrolimus combination immunosuppression. Lancet. 2000 Jan 29;355(9201):376-7. Di Benedetto F, Di Sandro S, De Ruvo N, Montalti R, Ballarin R, Guerrini GP, Spaggiari M, Guaraldi G, Gerunda G. First report on a series of HIV patients undergoing rapamycin monotherapy after liver transplantation. Transplantation. 2010 Mar 27;89(6):733-8. doi: 10.1097/TP.0b013e3181c7dcc0. Gallego R, Henriquez F, Oliva E, Camacho R, Hernández R, Hortal L, Sablón N, Quintana B, Santana R, Gonzalez F, Palop L, Vega N. Switching to sirolimus in renal transplant recipients with hepatitis C virus: a safe option. Transplant Proc. 2009 Jul-Aug;41(6):2334-6. doi: 10.1016/j.transproceed.2009.06.064. Samonakis DN, Cholongitas E, Triantos CK, Griffiths P, Dhillon AP, Thalheimer U, Patch DW, Burroughs AK. Sustained, spontaneous disappearance of serum HCV-RNA under immunosuppression after liver transplantation for HCV cirrhosis. J Hepatol. 2005 Dec;43(6):1091-3. Epub 2005 Sep 15. Ballardini G, De Raffele E, Groff P, Bioulac-Sage P, Grassi A, Ghetti S, Susca M, Strazzabosco M, Bellusci R, Iemmolo RM, Grazi G, Zauli D, Cavallari A, Bianchi FB. Timing of reinfection and mechanisms of hepatocellular damage in transplanted hepatitis C virus-reinfected liver. Liver Transpl. 2002 Jan;8(1):10-20. Charlton M. Liver biopsy, viral kinetics, and the impact of viremia on severity of hepatitis C virus recurrence. Liver Transpl. 2003 Nov;9(11):S58-62. Review. Sindhi R, Webber S, Venkataramanan R, McGhee W, Phillips S, Smith A, Baird C, Iurlano K, Mazariegos G, Cooperstone B, Holt DW, Zeevi A, Fung JJ, Reyes J. Sirolimus for rescue and primary immunosuppression in transplanted children receiving tacrolimus. Transplantation. 2001 Sep 15;72(5):851-5. Nepomuceno RR, Balatoni CE, Natkunam Y, Snow AL, Krams SM, Martinez OM. Rapamycin inhibits the interleukin 10 signal transduction pathway and the growth of Epstein Barr virus B-cell lymphomas. Cancer Res. 2003 Aug 1;63(15):4472-80. Kneteman NM, Oberholzer J, Al Saghier M, Meeberg GA, Blitz M, Ma MM, Wong WW, Gutfreund K, Mason AL, Jewell LD, Shapiro AM, Bain VG, Bigam DL. Sirolimus-based immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma. Liver Transpl. 2004 Oct;10(10):1301-11. Iacob S, Cicinnati VR, Hilgard P, Iacob RA, Gheorghe LS, Popescu I, Frilling A, Malago M, Gerken G, Broelsch CE, Beckebaum S. Predictors of graft and patient survival in hepatitis C virus (HCV) recipients: model to predict HCV cirrhosis after liver transplantation. Transplantation. 2007 Jul 15;84(1):56-63. Kornberg A, Küpper B, Tannapfel A, Hommann M, Scheele J. Impact of mycophenolate mofetil versus azathioprine on early recurrence of hepatitis C after liver transplantation. Int Immunopharmacol. 2005 Jan;5(1):107-15. Haddad EM, McAlister VC, Renouf E, Malthaner R, Kjaer MS, Gluud LL. Cyclosporin versus tacrolimus for liver transplanted patients. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD005161. Review. Rostaing L, Izopet J, Sandres K, Cisterne JM, Puel J, Durand D. Changes in hepatitis C virus RNA viremia concentrations in long-term renal transplant patients after introduction of mycophenolate mofetil. Transplantation. 2000 Mar 15;69(5):991-4.
Starting date: June 2010
Last updated: February 6, 2015
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