End stage liver disease from hepatitis C is a leading indication for liver transplantation. Recurrent hepatitis C after liver transplant may lead to cirrhosis and graft failure in up to 25% of recipients five years after liver transplantation. Anti-viral therapy is challenging after liver transplantation due to increased side effects including cytopenias and decreased efficacy compared to the nontransplant population. Tacrolimus and cyclosporine are the most common immunosuppressants used to prevent graft rejection. Tacrolimus is more potent than cyclosporine and may be preferred to cyclosporine. However, cyclosporine may have activity against hepatitis C and may have a theoretical advantage to tacrolimus in hepatitis liver transplant recipients. Cyclosporine may inhibit NS5B and NS5A protein complexes and increase endogenous interferon activity. Cyclophilin inhibitors without immunosuppressive properties are under development and represent a novel mechanisms for inhibiting HCV replication.
References
[1]
F. Fernandes, I. H. Ansari and R. Striker, “Cyclosporine Inhibits a Direct Interaction between Cyclophilins and Hepatitis C NS5A,” PloS One, Vol. 5, No. 3, 2010, Article ID: e9815. doi:10.1371/journal.pone.0009815
[2]
A. Scribner, D. Houck, Z. Huang, S. Mosier, M. Peel and B. Scorneaux, “Synthesis and Biological Evaluation of [D-lysine] Cyclosporin A Analogs as Potential Anti-HCV Agents,” Bioorganic & Medicinal Chemistry Letters, Vol. 20, No. 22, 2010, pp. 6542-6546.
doi:10.1016/j.bmcl.2010.09.036
[3]
M. Berenguer, A. Royuela and I. Zamora, “Immunosuppression with Calcineurin Inhibitors with Respect to the Outcome of HCV Recurrence after Liver transplantation: Results of a Meta-analysis,” Liver Transplantation, Vol 13, 2007, pp. 21-29.
[4]
J. Gentzsch, B. Hinkelmann, L. Kaderali, H. Irschik, R. Jansen, F. Sasse, et al., “Hepatitis C Virus Complete Life Cycle Screen for Identification of Small Molecules with Proor Antiviral Activity,” Antiviral Research, Vol. 89, 2011, pp. 136-148. doi:10.1016/j.antiviral.2010.12.005
[5]
Q. Pan, H. J. Metselaar, P. de Ruiter, J. Kwekkeboom, H. W. Tilanus, H. L. Janssen and L. J. van der Laan, “Calcineurin Inhibitor Tacrolimus Does Not Interfere with the Suppression of Hepatitis C Virus Infection by Interferonα,” Liver Transplantation, Vol. 16, 2010, pp. 520-526.
[6]
R. Teixeira, G. V. Papatheodoridis and A. K. Burroughs, “Management of Recurrent Hepatitis C after Liver Transplantation,” Journal of Viral Hepatitis, Vol. 8, 2001, pp. 159-168. doi:10.1046/j.1365-2893.2001.00282.x
[7]
A. Frankel, “Letter: In Response to Treatment of Psoriasis with Cyclosporine in Patients with Hepatitis C Infection: Risk or Opportunity?” Journal of the American Academy of Dermatology, Vol. 64, No. 4, 2011, pp. 788-789.
[8]
ReViS-TC Study Group, “Cyclosporine A-Based Immunosuppression Reduces Relapse Rate after Antiviral Therapy in Transplanted Patients with Hepatitis C Virus Infection: A Large Multicenter Cohort Study,” Transplantation, Vol. 92, No. 3, 2011, pp. 334-340.
[9]
S. Pollard, “Calcineurin Inhibition and Disease Recurrence in the Hepatitis C Virus-Positive Liver Transplant Recipient,” Liver International, Vol. 24, 2004, pp. 402-206. doi:10.1111/j.1478-3231.2004.0987.x
[10]
K. Watashi and K. Shimotohno, “Chemical Genetics Approach to Hepatitis C Virus Replication: Cyclophilin as a Target of Anti-Hepatitis C Virus Strategy,” Reviews in Medical Virology, Vol. 17, 2007, pp. 245-252.
doi:10.1002/rmv.534
[11]
M. Berenguer, V. Aguilera, F. San Juan, S. Benlloch, A. Rubin, R. López-Andujar, et al., “Effect of Ccalcineurin Inhibitors in the Outcome of Liver Transplantation in Hepatitis C Virus-Positive Recipients,” Transplantation, Vol. 90, 2010, pp. 1204-1209.
doi:10.1097/TP.0b013e3181fa93fa
[12]
G. Everson, “Impact of Immunosuppressive Therapy on Recurrence of Hepatitis C,” Liver Transplantation, Vol. 8 No. 10, 2002, pp. S19-S27. doi:10.1053/jlts.2002.35852
[13]
The US Multicenter FK506 Liver Study Group, “A Comparison of Tacrolimus (FK 506) and Cyclosporine for Immunosuppression in Liver Transplantation,” New England Journal of Medicine, Vol. 331, 1994, pp. 1110-1115.
doi:10.1056/NEJM199410273311702
[14]
K. Tanaka, J. Lake, F. Villamil, G. Levy , P. Marotta, S. Mies, B. de Hemptinne and C. Moench, “Comparison of Cyclosporine Microemulsion and Tacrolimus in 39 Recipients of Living Donor Liver Transplantation,” Liver Transplantation, Vol. 11, No. 11, 2005, pp. 1395-1402.
doi:10.1002/lt.20508
[15]
J. P. Liu, L. Ye, X. Wang, J. L. Li and W. Z. Ho, “Cyclosporine A Inhibits Hepatitis C Virus Replication and Restores Interferon-Alpha Expression in Hepatocytes,” Transplant Infectious Disease, Vol. 13, 2010, pp. 24-32.
doi:10.1111/j.1399-3062.2010.00556.x
[16]
X. Puyang, D. L. Poulin, J. E. Mathy, L. J. Anderson, S. Ma, Z. Fang, et al., “Mechanism of Resistance of Hepatitis C Virus Replicons to Structurally Distinct Cyclophilin Inhibitors,” Antimicrobial Agents and Chemotherapy, Vol. 54, No. 5, 2010, pp. 1981-1987.
doi:10.1128/AAC.01236-09
[17]
A. Pissaia, L. Aoudjehane, S. Ben Othman, O. Scatton, O. Soubrane, C. Housset, et al., “Cyclosporine Inhibits Profibrotic Effects of Interleukin-4 and Transforming Growth Factor β on Human Intrahepatic Fibroblasts Cultured in Vitro,” Transplantation proceedings, Vol. 42, 2010, pp. 4343-4346. doi:10.1016/j.transproceed.2010.09.124
[18]
F. Yang, J. M. Robotham, H. Grise, S. Frausto, V. Madan, M. Zayas, et al., “A Major Determinant of Cyclophilin Dependence and Cyclosporine Susceptibility of Hepatitis C Virus Identified by a Genetic Approach,” Public Library of Science: Pathogens, Vol. 6, No. 9, 2010, pp. 1-16.
[19]
The United States FK506 Study Group, “A Long-Term Comparison of Tacrolimus (FK506) versus Cyclosporine in Liver Transplantation: A Report of the United States FK506 Study Group,” Transplantation, Vol. 66, No. 4, 1998, pp. 493-499
[20]
R. M. Ghobrial, S. Colquhoun, H. Rosen, P. Hollis, S. Ponthieux, A. Pakrasi, D. G. Farmer, et al., “Retransplantation for Recurrent Hepatitis C Following Tacrolimus or Cyclosporine Immunosuppression,” Transplantation Pro- ceedings, Vol. 30, 1998, pp. 1470-1471.
doi:10.1016/S0041-1345(98)00320-0
[21]
R. Rabie, K. Mumtaz and E. L. Renner, “Efficacy of Antiviral Therapy for Hepatitis C Post Liver Transplant on Cyclosporine versus Tacrolimus: A Systematic Review and Meta-Analysis,” Liver Transplantation, 2012, in press.
doi:10.1002/lt.23516
[22]
R. Flisiak, S. V. Feinman, M. Jablkowski, A. Horban, W. Kryczka, M. Pawlowska, et al., “The Cyclophilin Inhibitor Debio 025 Combined with PEG IFN α2a Significantly Reduces Viral Load in Treatment-Na?ve Hepatitis C Patients,” Hepatology, Vol. 49, No. 5, 2009, pp 1460-1468.
doi:10.1002/hep.22835
