Immunosuppression and outcomes of patients transplanted for hepatitis C

Abstract

Liver disease caused by the hepatitis C virus (HCV) represents the most common indication for liver transplantation in adults throughout the world. As HCV re-infection is almost universal, the recurrence of hepatitis C following liver transplantation represents the most important clinical problem facing liver transplant physicians and surgeons [[1]Neumann U.P. Berg T. Bahra M. Puhl G. Guckelberger O. Langrehr J.M. et al.Long-term outcome of liver transplants for chronic hepatitis C: 1 10-year follow-up.Transplantation. 2004; 77: 226-231Crossref PubMed Scopus (260) Google Scholar]. Moreover, it has been suggested that recurrent hepatitis C is becoming an increasing problem post-transplant [[2]Forman L.M. Lewis J.D. Berlin J.A. Feldman H.I. Lucey M.R. The association between hepatitis C infection and survival after orthotopic liver transplantation.Gastroenterology. 2002; 122: 889-896Abstract Full Text Full Text PDF PubMed Scopus (944) Google Scholar]. Not only are recurrence of hepatitis C becoming increasingly recognized, and the percentage of transplants being performed for hepatitis C increasing, but there is also evidence that the disease severity and the outcomes of transplantation may be worsening [[3]Berenguer M. Ferrell L. Watson J. Prieto M. Kim M. Rayon M. HCV-related fibrosis progression following liver transplantation: increase in recent years.J Hepatol. 2000; 32: 673-684Abstract Full Text Full Text PDF PubMed Scopus (688) Google Scholar]. As the potency of our immunosuppressive regimens has increased during this era, it has been suggested that more potent immunosuppression may be, in part, responsible for this [[4]Lake J.R. The role of immunosuppression in the recurrence of hepatitis C.Liver Transpl. 2003; 9: S63-S66Crossref PubMed Scopus (110) Google Scholar]. The impact of specific immunosuppressive agents and regimens on the outcome of post-transplant hepatitis C has generally not been addressed prospectively in most large immunosuppressive trials. Thus, we have been left to retrospective analyses of large trials or registry data to guide us in our approach to immunosuppression in patients infected with HCV [[5]Lake J.R. David K.M. Steffen B.J. Chu A.H. Gordon R.D. Wiesner R.H. Addition of MMF to dual immunosupression does not increase the risk of malignant short-term death after liver transplantation.Am J Transplant. 2005; 5: 2961-2967Crossref PubMed Scopus (19) Google Scholar]. In the future, it will be mandatory that all immunosuppressive trials have built into the trial design, protocol assessment of liver histology and virologic studies.An optimal immunosuppression regimen should use the fewest agents at the lowest effective doses in order to reduce toxicity and cost, but still prevent rejection and disease recurrence. However, the liver is relatively unique amongst the solid-organ transplants in that, in general, there is no impact of acute cellular rejection on outcomes and chronic rejection occurs infrequently. This is certainly not true for kidney, heart or lung transplantation, where acute rejection is one of the more important predictors of long-term graft survival and chronic rejection is a relatively frequent cause of graft loss. For this reason, we are often able to push the lower limits of immunosuppression to a greater degree in liver recipients than in recipients of other organs.In this issue of the Journal, there are two studies, which examine, in one case, the impact of complete immunosuppression withdrawal on the progression of post-transplant hepatitis C [[6]Tisone G. Orlando G. Cardillo A. Palmieri G. Manzia T.M. Baiocchi L. et al.Complete weaning off immunosuppression in HCV liver transplant recipients is feasible and favourably impacts on the progression of disease recurrence.J Hepatol. 2006; 44: 702-709Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar] and in the other, the impact of eliminating all cortico-steroids from the post-transplant immunosuppressive regimen on post-transplant outcomes [[7]Llado´ L. Xiol X. Figueras J. Ramos E. Memba R. Serrano T. et al.Immunosuppression without steroids in liver transplantation is safe and reduces infection and metabolic complications: Results from a prospective multicenter randomized study.J Hepatol. 2006; 44: 710-716Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar]. These studies address two very important issues in this field, and both built in protocol histologic assessment of the impact of their interventions.While the complete withdrawal of immunosuppression has been previously achieved in liver recipients [[8]Devlin J. Doherty D. Thomson L. Wong T. Donaldson P. Portmann B. et al.Defining outcome of immunosuppressioon withdrawal after liver transplantation.Hepatology. 1998; 27: 926-933Crossref PubMed Scopus (210) Google Scholar], I am unaware of any previous studies that have specifically applied this to HCV (+) recipients and moreover, built in protocol biopsies to examine the effect of immunosuppression withdrawal on histologic progression. Tisone and colleagues [[6]Tisone G. Orlando G. Cardillo A. Palmieri G. Manzia T.M. Baiocchi L. et al.Complete weaning off immunosuppression in HCV liver transplant recipients is feasible and favourably impacts on the progression of disease recurrence.J Hepatol. 2006; 44: 702-709Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar] withdrew cyclosporine (CSA) from 34 recipients on CSA monotherapy. Most importantly, they were successful in <25% (8 of 34), while 35% rejected during the CSA taper and 41% rejected after the taper. Those who achieved immunosuppression did show a slower rate of fibrosis progression, a lower necro-inflammatory score, improved liver tests and lower HCV RNA levels as compared to those who did not achieve sustained withdrawal of immunosuppression. However, there was no control group in whom no immunosuppression withdrawal was attempted.The high incidence of ‘late’ rejection is a matter of concern. While, in general, the occurrence of acute cellular rejection does not have an important impact on long term outcomes in liver recipients, this is not true in patients transplanted for hepatitis C [[9]Charlton M. Seaberg E. Impact of immunosuppression and acute rejection on recurrence of hepatitis C: results of the national institute of diabetes and digestive and kidney diseases liver transplantation database.Liver Transpl. 1999; 5: S107-S114Crossref Scopus (22) Google Scholar]. HCV (−) recipients who experience an episode of rejection have only half the mortality rate when compared to HCV (−) recipients who do not experience an episode of rejection. By contrast, HCV (+) recipients have been shown to have a three-fold increase risk of death if they experience an episode of rejection and more than a 5-fold increase risk of death if they experience steroid refractory acute cellular rejection (Charlton). Moreover, others have shown that ‘late’ rejection may be associated with worse outcomes [[9]Charlton M. Seaberg E. Impact of immunosuppression and acute rejection on recurrence of hepatitis C: results of the national institute of diabetes and digestive and kidney diseases liver transplantation database.Liver Transpl. 1999; 5: S107-S114Crossref Scopus (22) Google Scholar]. While the authors of this study did not show any obvious negative impact of the attempt at immunosuppression withdrawal or the subsequent development of rejection, which in all cases was treated simply by re-instituting cyclosporine, one has to question whether it is reasonable to routinely subject patients to these potential risks when only <1/4 of patients stand to benefit in any way. Indeed, two recipients who developed rejection during the study died of recurrent hepatitis C during the follow-up period and disappointingly, there was no difference in renal function in those who did vs. those who did not achieve sustained withdrawal of CSA, which is generally the indication for cyclosporine withdrawal.Two additional cautionary comments need to be made. First, the follow-up is relatively short and there is no control group to determine if there will be long-term negative consequences of the CSA withdrawal. Second, there is data from other groups [[8]Devlin J. Doherty D. Thomson L. Wong T. Donaldson P. Portmann B. et al.Defining outcome of immunosuppressioon withdrawal after liver transplantation.Hepatology. 1998; 27: 926-933Crossref PubMed Scopus (210) Google Scholar] that have withdrawn immunosuppression that the ‘functional tolerance’ that is achieved may not be stable in that most of the patients, at least in one such study, have had to be placed on immunosuppression with several of those patients having a poor outcome. Thus, while one can regard this as an interesting experiment, I personally do not believe that programs should attempt this strategy except in the context of a carefully controlled clinical trial. Even then, it could be argued to wait for longer follow-up from this trial in order to assess the long-term benefit of immunosuppression withdrawal in HCV (+) recipients.In terms of the impact of specific immunosuppressive agents on long-term outcomes of patients transplanted for hepatitis C, there is little doubt that the use of corticosteroid boluses to treat acute cellular rejection is harmful to HCV infected recipients. Years ago, Ed Gane and colleagues at the Kings College Hospital showed that cortico-steroid boluses are associated with an increase in serum HCV RNA concentrations of 4- to 100-fold. The higher HCV RNA levels were also associated with increased histologic severity of recurrent hepatitis. They also have showed corticosteroid boluses are also associated with an increase frequency of acute hepatitis and earlier time to recurrence [[10]Gane E. Naoumov N. Qian K. Mondelli M.U. Maertens G. Portmann B.C. A longitudinal analysis of hepatitis C virus replication following liver transplantation.Gastroenterology. 1996; 110: 167-177Abstract Full Text PDF PubMed Scopus (410) Google Scholar].Similarly, the use of OKT3 to treat rejection is associated with a greater severity of recurrence of hepatitis C and also a greater risk of post-transplant graft loss [[11]Sheiner P.A. Schartz M.E. Mor E. Schluger L.K. Theise N. Kishikawa K. et al.Severe or multiple rejection episodes are associated with early recurrence of hepatitis C after orthotopic liver transplantation.Hepatology. 1995; 21: 30-34Crossref PubMed Google Scholar].However, when one looks at the effects of specific agents used for induction or maintenance immunosuppression, the impact of these agents on HCV outcomes is not so clear. For example, it is difficult to compare the calcineurin inhibitors cyclosporine and tacrolimus, in terms of their specific impact on outcome in HCV infected recipients. In the original US FK506 multi-center trial, there was a significant difference in patient survival at 5 years in favor of the group of HCV (+) recipients randomized to tacrolimus-based immunosuppression. Interestingly, there was no difference in either patient or graft survival in the HCV (−) recipients. One must recall the major differences in that study between groups randomized to tacolimus- vs. cyclosporine-based immunosuppression was that the incidence of acute cellular rejection was higher in the CSA group. However the more impressive difference was that OKT3 use was more than twice as great in the CSA group and more than 4× as many patients met the end-point of ‘refractory rejection’. Finally cortico-steroid use was twice as great in the CSA group of patients, largely reflecting the treatment of rejection. Beyond this study, no other has shown significant long terms differences in outcomes between HCV (+) recipients receiving CSA- vs. tacrolimus-based immunosuppression [[12]Levy G. Burra P. Cavallari A. Duvoux C. Lake J. Mayer J. et al.Improved clinical outcomes for liver transplant recipients using cyclosporine monitoring based on 2-hr post-dose levels (C2).Transplantation. 2002; 73: 953-959Crossref PubMed Scopus (164) Google Scholar].Similarly, data regarding the impact of mycophenylate mofetil (MMF) on outcomes in HCV (+) recipients is mixed. This is significant in that IMPDH inhibitors have been tested as antiviral agents in hepatitis C. A recent analysis of the SRTR suggested that the addition of MMF to a regimen of Tacrolimus and cortico-steroids led to improved outcomes in HCV (+) recipients [[5]Lake J.R. David K.M. Steffen B.J. Chu A.H. Gordon R.D. Wiesner R.H. Addition of MMF to dual immunosupression does not increase the risk of malignant short-term death after liver transplantation.Am J Transplant. 2005; 5: 2961-2967Crossref PubMed Scopus (19) Google Scholar]. However, in two large randomized trials that compared MMF to azathioprine in a maintenance immunosuppressive regimen, there were no significant differences in either rates of recurrence of hepatitis C or outcomes in HCV infected patients in the study patients versus controls [[13]Jain A. Kashyap R. Demetris A.J. Eghstesad B. Pokharna R. Fung J.J. A prospective randomized trial of Mycophenolate Mofetil in liver transplant recipients with hepatitis C.Liver Transpl. 2002; 8: 40-46Crossref PubMed Scopus (136) Google Scholar].Finally, the data on antibody induction is also mixed. One uncontrolled trial suggested that the use of anti-CD25 induction therapy has a negative impact on long-term outcomes in patients transplanted for hepatitis C. while two randomized trials found no impact. Similarly 2 recent publications from the University of Pittsburgh showed induction agents (in one case thymoglobulin and the other alemtuzumab), which lead to marked T-cell depletion, are associated with very severe recurrence leading a high risk of graft loss. By contrast, the use of lower doses of thymoglobulin for induction does not seem to lead to the same poor outcomes, as shown in study by Eason, et al. [[14]Eason J.D. Nair S. Cohen A.J. Blazek J.L. Loss G.E. Steroid-free liver transplantation using rabbit antithymocite globulin and early tacrolimus monotherapy.Transplantation. 2003; 75: 1396-1399Crossref PubMed Scopus (157) Google Scholar].One of the most hotly debated topics in liver transplantation is how to handle maintenance cortico-steroids. There are three options available. First, maintain the use of low dose (∼5 mg prednisone) steroids. Second, slowly taper the patients off the maintenance steroids. Third, completely avoid the use of any cortico-steroids. While, I would venture to say that the second approach is what liver transplant programs most commonly use, the existing data would suggest that either the first or third options are best supported. For example, there is data that suggests that complete avoidance of corticosteroids may be beneficial for patients with HCV infection undergoing liver transplantation [[14]Eason J.D. Nair S. Cohen A.J. Blazek J.L. Loss G.E. Steroid-free liver transplantation using rabbit antithymocite globulin and early tacrolimus monotherapy.Transplantation. 2003; 75: 1396-1399Crossref PubMed Scopus (157) Google Scholar]. By contrast, at least four publications suggest that ‘late’ withdrawal of corticosteroids (i.e. beyond 3 months post-transplant) may be harmful to HCV infected patients undergoing liver transplantation.In this issue of the Journal, Llado and colleagues [[7]Llado´ L. Xiol X. Figueras J. Ramos E. Memba R. Serrano T. et al.Immunosuppression without steroids in liver transplantation is safe and reduces infection and metabolic complications: Results from a prospective multicenter randomized study.J Hepatol. 2006; 44: 710-716Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar] randomized 198 liver recipients to immunosuppression with anti-CD25 induction and cyclosporine (C2 therapeutic monitoring), with or without cortico-steroids. While they showed there were no differences in rejection rates, or patient or graft survival there were significant differences in outcomes. First, not surprising, hypertension was more common in steroid group. However, de novo diabetes was more common in the steroid group. Moreover, the diabetics in the steroid arm experienced more bacterial infections. The finding that the incidence of new onset diabetes mellitus (NODM) was less in the steroid avoidance arm has been a consistent finding in studies of steroid avoidance both in liver and kidney populations [14Eason J.D. Nair S. Cohen A.J. Blazek J.L. Loss G.E. Steroid-free liver transplantation using rabbit antithymocite globulin and early tacrolimus monotherapy.Transplantation. 2003; 75: 1396-1399Crossref PubMed Scopus (157) Google Scholar, 15Navasa M. Bustamante J. Marroni C. González E. Andreu H. Esmatjes E. et al.Diabetes mellitus after liver transplantation: prevalence and predictive factors.J Hepatol. 1996; 25: 64-71Abstract Full Text PDF PubMed Scopus (141) Google Scholar]. I believe this is a very significant finding and will prove to be the major benefit of steroid avoidance protocols. While the benefit of avoiding NODM may be obvious, it is important to emphasize that diabetes is a major risk factor for the development of post-transplant renal failure and may also contribute to more aggressive post-transplant hepatitis C [[16]Baid S. Cosimi A.B. Farrell M.L. Schoenfeld D.A. Feng S. Chung R.T. et al.Posttransplant diabetes mellitus in liver transplant recipients: risk factors, temporal relationship with hepatitis C virus allograft hepatitis, and impact on mortality.Transplantation. 2001; 72: 1066-1072Crossref PubMed Scopus (246) Google Scholar]. Thus, while the follow-up period in this trial is relatively short, one might expect the benefits of steroid avoidance to become even more pronounced over time.Discussions regarding the differential impact of various immunosuppressive regimens on post-transplant hepatitis C will continue. Overriding these discussions is the fact that hepatitis C studies must now be an important aspect of any trial of a new immunosuppressive agent or regimen. Clearly, one needs to build HCV studies into the study design such that protocol biopsies are performed and appropriate virologic data is obtained. In fact, one could argue that the impact of new agents or regimens on hepatitis C will dictate to what degree such agents or regimens are accepted for use as liver transplant immunosuppression.While post-transplant immunosuppression clearly impacts post-transplant hepatitis C severity, it cannot be emphasized enough that until we have effective therapy for post-transplant hepatitis C or even better, therapy which can prevent HCV re-infection of the allograft, we will be unlikely to impact in a major way the long-term outcomes of recipients transplanted for this disease. Liver disease caused by the hepatitis C virus (HCV) represents the most common indication for liver transplantation in adults throughout the world. As HCV re-infection is almost universal, the recurrence of hepatitis C following liver transplantation represents the most important clinical problem facing liver transplant physicians and surgeons [[1]Neumann U.P. Berg T. Bahra M. Puhl G. Guckelberger O. Langrehr J.M. et al.Long-term outcome of liver transplants for chronic hepatitis C: 1 10-year follow-up.Transplantation. 2004; 77: 226-231Crossref PubMed Scopus (260) Google Scholar]. Moreover, it has been suggested that recurrent hepatitis C is becoming an increasing problem post-transplant [[2]Forman L.M. Lewis J.D. Berlin J.A. Feldman H.I. Lucey M.R. The association between hepatitis C infection and survival after orthotopic liver transplantation.Gastroenterology. 2002; 122: 889-896Abstract Full Text Full Text PDF PubMed Scopus (944) Google Scholar]. Not only are recurrence of hepatitis C becoming increasingly recognized, and the percentage of transplants being performed for hepatitis C increasing, but there is also evidence that the disease severity and the outcomes of transplantation may be worsening [[3]Berenguer M. Ferrell L. Watson J. Prieto M. Kim M. Rayon M. HCV-related fibrosis progression following liver transplantation: increase in recent years.J Hepatol. 2000; 32: 673-684Abstract Full Text Full Text PDF PubMed Scopus (688) Google Scholar]. As the potency of our immunosuppressive regimens has increased during this era, it has been suggested that more potent immunosuppression may be, in part, responsible for this [[4]Lake J.R. The role of immunosuppression in the recurrence of hepatitis C.Liver Transpl. 2003; 9: S63-S66Crossref PubMed Scopus (110) Google Scholar]. The impact of specific immunosuppressive agents and regimens on the outcome of post-transplant hepatitis C has generally not been addressed prospectively in most large immunosuppressive trials. Thus, we have been left to retrospective analyses of large trials or registry data to guide us in our approach to immunosuppression in patients infected with HCV [[5]Lake J.R. David K.M. Steffen B.J. Chu A.H. Gordon R.D. Wiesner R.H. Addition of MMF to dual immunosupression does not increase the risk of malignant short-term death after liver transplantation.Am J Transplant. 2005; 5: 2961-2967Crossref PubMed Scopus (19) Google Scholar]. In the future, it will be mandatory that all immunosuppressive trials have built into the trial design, protocol assessment of liver histology and virologic studies. An optimal immunosuppression regimen should use the fewest agents at the lowest effective doses in order to reduce toxicity and cost, but still prevent rejection and disease recurrence. However, the liver is relatively unique amongst the solid-organ transplants in that, in general, there is no impact of acute cellular rejection on outcomes and chronic rejection occurs infrequently. This is certainly not true for kidney, heart or lung transplantation, where acute rejection is one of the more important predictors of long-term graft survival and chronic rejection is a relatively frequent cause of graft loss. For this reason, we are often able to push the lower limits of immunosuppression to a greater degree in liver recipients than in recipients of other organs. In this issue of the Journal, there are two studies, which examine, in one case, the impact of complete immunosuppression withdrawal on the progression of post-transplant hepatitis C [[6]Tisone G. Orlando G. Cardillo A. Palmieri G. Manzia T.M. Baiocchi L. et al.Complete weaning off immunosuppression in HCV liver transplant recipients is feasible and favourably impacts on the progression of disease recurrence.J Hepatol. 2006; 44: 702-709Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar] and in the other, the impact of eliminating all cortico-steroids from the post-transplant immunosuppressive regimen on post-transplant outcomes [[7]Llado´ L. Xiol X. Figueras J. Ramos E. Memba R. Serrano T. et al.Immunosuppression without steroids in liver transplantation is safe and reduces infection and metabolic complications: Results from a prospective multicenter randomized study.J Hepatol. 2006; 44: 710-716Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar]. These studies address two very important issues in this field, and both built in protocol histologic assessment of the impact of their interventions. While the complete withdrawal of immunosuppression has been previously achieved in liver recipients [[8]Devlin J. Doherty D. Thomson L. Wong T. Donaldson P. Portmann B. et al.Defining outcome of immunosuppressioon withdrawal after liver transplantation.Hepatology. 1998; 27: 926-933Crossref PubMed Scopus (210) Google Scholar], I am unaware of any previous studies that have specifically applied this to HCV (+) recipients and moreover, built in protocol biopsies to examine the effect of immunosuppression withdrawal on histologic progression. Tisone and colleagues [[6]Tisone G. Orlando G. Cardillo A. Palmieri G. Manzia T.M. Baiocchi L. et al.Complete weaning off immunosuppression in HCV liver transplant recipients is feasible and favourably impacts on the progression of disease recurrence.J Hepatol. 2006; 44: 702-709Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar] withdrew cyclosporine (CSA) from 34 recipients on CSA monotherapy. Most importantly, they were successful in <25% (8 of 34), while 35% rejected during the CSA taper and 41% rejected after the taper. Those who achieved immunosuppression did show a slower rate of fibrosis progression, a lower necro-inflammatory score, improved liver tests and lower HCV RNA levels as compared to those who did not achieve sustained withdrawal of immunosuppression. However, there was no control group in whom no immunosuppression withdrawal was attempted. The high incidence of ‘late’ rejection is a matter of concern. While, in general, the occurrence of acute cellular rejection does not have an important impact on long term outcomes in liver recipients, this is not true in patients transplanted for hepatitis C [[9]Charlton M. Seaberg E. Impact of immunosuppression and acute rejection on recurrence of hepatitis C: results of the national institute of diabetes and digestive and kidney diseases liver transplantation database.Liver Transpl. 1999; 5: S107-S114Crossref Scopus (22) Google Scholar]. HCV (−) recipients who experience an episode of rejection have only half the mortality rate when compared to HCV (−) recipients who do not experience an episode of rejection. By contrast, HCV (+) recipients have been shown to have a three-fold increase risk of death if they experience an episode of rejection and more than a 5-fold increase risk of death if they experience steroid refractory acute cellular rejection (Charlton). Moreover, others have shown that ‘late’ rejection may be associated with worse outcomes [[9]Charlton M. Seaberg E. Impact of immunosuppression and acute rejection on recurrence of hepatitis C: results of the national institute of diabetes and digestive and kidney diseases liver transplantation database.Liver Transpl. 1999; 5: S107-S114Crossref Scopus (22) Google Scholar]. While the authors of this study did not show any obvious negative impact of the attempt at immunosuppression withdrawal or the subsequent development of rejection, which in all cases was treated simply by re-instituting cyclosporine, one has to question whether it is reasonable to routinely subject patients to these potential risks when only <1/4 of patients stand to benefit in any way. Indeed, two recipients who developed rejection during the study died of recurrent hepatitis C during the follow-up period and disappointingly, there was no difference in renal function in those who did vs. those who did not achieve sustained withdrawal of CSA, which is generally the indication for cyclosporine withdrawal. Two additional cautionary comments need to be made. First, the follow-up is relatively short and there is no control group to determine if there will be long-term negative consequences of the CSA withdrawal. Second, there is data from other groups [[8]Devlin J. Doherty D. Thomson L. Wong T. Donaldson P. Portmann B. et al.Defining outcome of immunosuppressioon withdrawal after liver transplantation.Hepatology. 1998; 27: 926-933Crossref PubMed Scopus (210) Google Scholar] that have withdrawn immunosuppression that the ‘functional tolerance’ that is achieved may not be stable in that most of the patients, at least in one such study, have had to be placed on immunosuppression with several of those patients having a poor outcome. Thus, while one can regard this as an interesting experiment, I personally do not believe that programs should attempt this strategy except in the context of a carefully controlled clinical trial. Even then, it could be argued to wait for longer follow-up from this trial in order to assess the long-term benefit of immunosuppression withdrawal in HCV (+) recipients. In terms of the impact of specific immunosuppressive agents on long-term outcomes of patients transplanted for hepatitis C, there is little doubt that the use of corticosteroid boluses to treat acute cellular rejection is harmful to HCV infected recipients. Years ago, Ed Gane and colleagues at the Kings College Hospital showed that cortico-steroid boluses are associated with an increase in serum HCV RNA concentrations of 4- to 100-fold. The higher HCV RNA levels were also associated with increased histologic severity of recurrent hepatitis. They also have showed corticosteroid boluses are also associated with an increase frequency of acute hepatitis and earlier time to recurrence [[10]Gane E. Naoumov N. Qian K. Mondelli M.U. Maertens G. Portmann B.C. A longitudinal analysis of hepatitis C virus replication following liver transplantation.Gastroenterology. 1996; 110: 167-177Abstract Full Text PDF PubMed Scopus (410) Google Scholar]. Similarly, the use of OKT3 to treat rejection is associated with a greater severity of recurrence of hepatitis C and also a greater risk of post-transplant graft loss [[11]Sheiner P.A. Schartz M.E. Mor E. Schluger L.K. Theise N. Kishikawa K. et al.Severe or multiple rejection episodes are associated with early recurrence of hepatitis C after orthotopic liver transplantation.Hepatology. 1995; 21: 30-34Crossref PubMed Google Scholar]. However, when one looks at the effects of specific agents used for induction or maintenance immunosuppression, the impact of these agents on HCV outcomes is not so clear. For example, it is difficult to compare the calcineurin inhibitors cyclosporine and tacrolimus, in terms of their specific impact on outcome in HCV infected recipients. In the original US FK506 multi-center trial, there was a significant difference in patient survival at 5 years in favor of the group of HCV (+) recipients randomized to tacrolimus-based immunosuppression. Interestingly, there was no difference in either patient or graft survival in the HCV (−) recipients. One must recall the major differences in that study between groups randomized to tacolimus- vs. cyclosporine-based immunosuppression was that the incidence of acute cellular rejection was higher in the CSA group. However the more impressive difference was that OKT3 use was more than twice as great in the CSA group and more than 4× as many patients met the end-point of ‘refractory rejection’. Finally cortico-steroid use was twice as great in the CSA group of patients, largely reflecting the treatment of rejection. Beyond this study, no other has shown significant long terms differences in outcomes between HCV (+) recipients receiving CSA- vs. tacrolimus-based immunosuppression [[12]Levy G. Burra P. Cavallari A. Duvoux C. Lake J. Mayer J. et al.Improved clinical outcomes for liver transplant recipients using cyclosporine monitoring based on 2-hr post-dose levels (C2).Transplantation. 2002; 73: 953-959Crossref PubMed Scopus (164) Google Scholar]. Similarly, data regarding the impact of mycophenylate mofetil (MMF) on outcomes in HCV (+) recipients is mixed. This is significant in that IMPDH inhibitors have been tested as antiviral agents in hepatitis C. A recent analysis of the SRTR suggested that the addition of MMF to a regimen of Tacrolimus and cortico-steroids led to improved outcomes in HCV (+) recipients [[5]Lake J.R. David K.M. Steffen B.J. Chu A.H. Gordon R.D. Wiesner R.H. Addition of MMF to dual immunosupression does not increase the risk of malignant short-term death after liver transplantation.Am J Transplant. 2005; 5: 2961-2967Crossref PubMed Scopus (19) Google Scholar]. However, in two large randomized trials that compared MMF to azathioprine in a maintenance immunosuppressive regimen, there were no significant differences in either rates of recurrence of hepatitis C or outcomes in HCV infected patients in the study patients versus controls [[13]Jain A. Kashyap R. Demetris A.J. Eghstesad B. Pokharna R. Fung J.J. A prospective randomized trial of Mycophenolate Mofetil in liver transplant recipients with hepatitis C.Liver Transpl. 2002; 8: 40-46Crossref PubMed Scopus (136) Google Scholar]. Finally, the data on antibody induction is also mixed. One uncontrolled trial suggested that the use of anti-CD25 induction therapy has a negative impact on long-term outcomes in patients transplanted for hepatitis C. while two randomized trials found no impact. Similarly 2 recent publications from the University of Pittsburgh showed induction agents (in one case thymoglobulin and the other alemtuzumab), which lead to marked T-cell depletion, are associated with very severe recurrence leading a high risk of graft loss. By contrast, the use of lower doses of thymoglobulin for induction does not seem to lead to the same poor outcomes, as shown in study by Eason, et al. [[14]Eason J.D. Nair S. Cohen A.J. Blazek J.L. Loss G.E. Steroid-free liver transplantation using rabbit antithymocite globulin and early tacrolimus monotherapy.Transplantation. 2003; 75: 1396-1399Crossref PubMed Scopus (157) Google Scholar]. One of the most hotly debated topics in liver transplantation is how to handle maintenance cortico-steroids. There are three options available. First, maintain the use of low dose (∼5 mg prednisone) steroids. Second, slowly taper the patients off the maintenance steroids. Third, completely avoid the use of any cortico-steroids. While, I would venture to say that the second approach is what liver transplant programs most commonly use, the existing data would suggest that either the first or third options are best supported. For example, there is data that suggests that complete avoidance of corticosteroids may be beneficial for patients with HCV infection undergoing liver transplantation [[14]Eason J.D. Nair S. Cohen A.J. Blazek J.L. Loss G.E. Steroid-free liver transplantation using rabbit antithymocite globulin and early tacrolimus monotherapy.Transplantation. 2003; 75: 1396-1399Crossref PubMed Scopus (157) Google Scholar]. By contrast, at least four publications suggest that ‘late’ withdrawal of corticosteroids (i.e. beyond 3 months post-transplant) may be harmful to HCV infected patients undergoing liver transplantation. In this issue of the Journal, Llado and colleagues [[7]Llado´ L. Xiol X. Figueras J. Ramos E. Memba R. Serrano T. et al.Immunosuppression without steroids in liver transplantation is safe and reduces infection and metabolic complications: Results from a prospective multicenter randomized study.J Hepatol. 2006; 44: 710-716Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar] randomized 198 liver recipients to immunosuppression with anti-CD25 induction and cyclosporine (C2 therapeutic monitoring), with or without cortico-steroids. While they showed there were no differences in rejection rates, or patient or graft survival there were significant differences in outcomes. First, not surprising, hypertension was more common in steroid group. However, de novo diabetes was more common in the steroid group. Moreover, the diabetics in the steroid arm experienced more bacterial infections. The finding that the incidence of new onset diabetes mellitus (NODM) was less in the steroid avoidance arm has been a consistent finding in studies of steroid avoidance both in liver and kidney populations [14Eason J.D. Nair S. Cohen A.J. Blazek J.L. Loss G.E. Steroid-free liver transplantation using rabbit antithymocite globulin and early tacrolimus monotherapy.Transplantation. 2003; 75: 1396-1399Crossref PubMed Scopus (157) Google Scholar, 15Navasa M. Bustamante J. Marroni C. González E. Andreu H. Esmatjes E. et al.Diabetes mellitus after liver transplantation: prevalence and predictive factors.J Hepatol. 1996; 25: 64-71Abstract Full Text PDF PubMed Scopus (141) Google Scholar]. I believe this is a very significant finding and will prove to be the major benefit of steroid avoidance protocols. While the benefit of avoiding NODM may be obvious, it is important to emphasize that diabetes is a major risk factor for the development of post-transplant renal failure and may also contribute to more aggressive post-transplant hepatitis C [[16]Baid S. Cosimi A.B. Farrell M.L. Schoenfeld D.A. Feng S. Chung R.T. et al.Posttransplant diabetes mellitus in liver transplant recipients: risk factors, temporal relationship with hepatitis C virus allograft hepatitis, and impact on mortality.Transplantation. 2001; 72: 1066-1072Crossref PubMed Scopus (246) Google Scholar]. Thus, while the follow-up period in this trial is relatively short, one might expect the benefits of steroid avoidance to become even more pronounced over time. Discussions regarding the differential impact of various immunosuppressive regimens on post-transplant hepatitis C will continue. Overriding these discussions is the fact that hepatitis C studies must now be an important aspect of any trial of a new immunosuppressive agent or regimen. Clearly, one needs to build HCV studies into the study design such that protocol biopsies are performed and appropriate virologic data is obtained. In fact, one could argue that the impact of new agents or regimens on hepatitis C will dictate to what degree such agents or regimens are accepted for use as liver transplant immunosuppression. While post-transplant immunosuppression clearly impacts post-transplant hepatitis C severity, it cannot be emphasized enough that until we have effective therapy for post-transplant hepatitis C or even better, therapy which can prevent HCV re-infection of the allograft, we will be unlikely to impact in a major way the long-term outcomes of recipients transplanted for this disease.