Steroids in recurrent hepatitis C following liver transplantation: Pitfall or panacea?
Authors: Robert S. Brown
Journal: Journal of Hepatology (2007)

Of all the issues and dilemmas in liver transplantation at the current time, perhaps none is more vexing than the problem of post-transplant recurrent hepatitis C and graft loss. Thus, strategies to minimize recurrent hepatitis C (HCV) as well as to predict or ameliorate its course have been of intense interest among transplant physicians and surgeons. Advanced donor age, donor steatosis, prolonged graft ischemia time, and biliary complications have all been postulated as risk factors for more rapid fibrosis following liver transplantation [[1]Verna E.C. Brown Jr., R.S. Hepatitis C virus and liver transplantation.Clin Liver Dis. 2006; 10: 919-940Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar]. The impact of different immunosuppressive regimens on severity of HCV recurrence has been controversial. Data on the different calcineurin inhibitors as well as mycophenolate mofetil have been contradictory [2Jain 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 (137) Google Scholar, 3Wiesner R. Rabkin J. Klintmalm G. McDiarmid S. Langnas A. Punch J. et al.A randomized double-blind comparative study of mycophenolate mofetil and azathioprine in combination with cyclosporine and corticosteroids in primary liver transplant recipients.Liver Transpl. 2001; 7: 442-450Crossref PubMed Scopus (228) Google Scholar, 4Terrault N.A. Hepatitis C virus and liver transplantation.Semin Gastrointest Dis. 2000; 11: 96-114PubMed Google Scholar, 5Martin P. Busuttil R.W. Goldstein R.M. Crippin J.S. Klintmalm G.B. Fitzsimmons W.E. et al.Impact of tacrolimus versus cyclosporine in hepatitis C virus-infected liver transplant recipients on recurrent hepatitis: a prospective, randomized trial.Liver Transpl. 2004; 10: 1258-1262Crossref PubMed Scopus (115) Google Scholar]. In contrast, steroids, including both the total steroid dose and, most markedly, steroid bolus treatment for rejection, have historically been almost uniformly associated with worse HCV outcomes. Bolus steroid treatment in the NIDDK liver transplantation database was associated with increased mortality risk in HCV positive but not HCV negative patients [6Charlton M. Seaberg E. Wiesner R. Everhart J. Zetterman R. Lake J. et al.Predictors of patient and graft survival following liver transplantation for hepatitis C.Hepatology. 1998; 28: 823-830Crossref PubMed Scopus (515) Google Scholar, 7Charlton 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 Surg. 1999; 5: S107-S114Crossref PubMed Scopus (22) Google Scholar]. These findings led to a desire to minimize or eliminate steroid treatment, in particular high dose steroids. A proliferation of studies, many uncontrolled, with steroid-free regimens or rapid steroid tapers reported favorable results [8Llado 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, 9Eason J.D. Nair S. Cohen A.J. Blazek J.L. Loss Jr., G.E. Steroid-free liver transplantation using rabbit antithymocyte globulin and early tacrolimus monotherapy.Transplantation. 2003; 75: 1396-1399Crossref PubMed Scopus (160) Google Scholar, 10Everson G.T. Trouillot T. Wachs M. Bak T. Steinberg T. Kam I. et al.Early steroid withdrawal in liver transplantation is safe and beneficial.Liver Transpl Surg. 1999; 5: S48-S57PubMed Google Scholar, 11Belli L.S. Alberti A.B. Vangeli M. Airoldi A. Pinzello G. Tapering off steroids three months after liver transplantation is not detrimental for hepatitis C virus disease recurrence.Liver Transpl. 2003; 9: 201-202Crossref PubMed Scopus (20) Google Scholar]. However, a growing body of data suggests that hepatitis C outcomes post-transplant worsened during an era in which steroid minimization and immunosuppressive minimization strategies developed and graft survival for other transplant indications improved [[12]Berenguer M. Ferrell L. Watson J. Prieto M. Kim M. Rayon M. et al.HCV-related fibrosis progression following liver transplantation: increase in recent years.J Hepatol. 2000; 32: 673-684Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar]. Though some of this may be a cohort effect and related to different viral species, prior failed interferon treatment, older donor age and other factors, it has led some experts to rethink their immunosuppressive philosophy. This new paradigm postulates that rapid changes in the immunosuppressive milieu lead to worse hepatitis C outcomes possibly by inducing viral replication during the period of intense immunosuppression followed by immune reconstitution with a destruction of HCV infected hepatocytes [[1]Verna E.C. Brown Jr., R.S. Hepatitis C virus and liver transplantation.Clin Liver Dis. 2006; 10: 919-940Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar]. Two retrospective cohort studies supported this theory reporting improved outcomes in terms of recurrent hepatitis C with slower steroid tapers compared to historical controls with more rapid steroid tapers [13Brillanti S. Vivarelli M. De Ruvo N. Aden A.A. Camaggi V. D’Errico A. et al.Slowly tapering off steroids protects the graft against hepatitis C recurrence after liver transplantation.Liver Transpl. 2002; 8: 884-888Crossref PubMed Scopus (124) Google Scholar, 14Berenguer M. Aguilera V. Prieto M. San Juan F. Rayon J.M. Benlloch S. et al.Significant improvement in the outcome of HCV-infected transplant recipients by avoiding rapid steroid tapering and potent induction immunosuppression.J Hepatol. 2006; 44: 717-722Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar]. This data had never been validated prospectively. In this issue of the Journal, Vivarelli et al. performed a randomized, prospective trial comparing a rapid steroid taper with discontinuation of steroids at three months to a slow taper with indefinite low-dose steroids, both in conjunction with tacrolimus [[15]Vivarelli M. Burra P. La Barba G. Canova D. Senzolo M. Cucchetti A. et al.Influence of steroids on HCV recurrence after liver transplantation: A prospective study.J Hepatol. 2007; 47: 793-798Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar]. Though the authors find no overall difference in overall survival or death from recurrent hepatitis C, they did find a statistically significant lower rate of advanced fibrosis in the slow steroid taper arm (group B). They conclude that a slower steroid taper is advantageous in hepatitis C infected individuals undergoing transplantation. The difference in fibrosis progression between the two groups is striking and the study was carefully performed with protocol liver biopsies in both groups. However, there are several caveats that one must make before we accept this paradigm and utilize indefinite corticosteroid therapy in going forward. First, the sample size in this study was quite small. This normally presents a power issue, which would not affect the small alpha error in this study. However, the very high rate of advanced fibrosis in patients in group A (rapid steroid taper) of 42% makes one wonder whether this is a random chance occurrence. It is certainly one of the highest rates of fibrosis progression reported in the literature and one or two fewer patients with advanced fibrosis in group A would have substantially altered the results. The progression of fibrosis between year 1 and year 2 is very similar in the two groups, which may be due to stabilization of disease, small sample size, or the fact that both groups are on stable immunosuppression. Consequently, there is no data in the paper to support ongoing steroid use after year 1 which might limit long-term complications of steroid therapy. The second issue that I have with the data is the fact that rejection episodes requiring steroid boluses were more frequent in group B patients (slow steroid taper) and yet the frequency of advanced fibrosis was not more common in this group. The adverse impact of steroid bolus therapy on hepatitis C outcome has been established in multiple trials and the authors provide no explanation or hypothesis for why the steroid boluses were not associated with worse recurrent HCV. Why there would be more rejection in this group also deserves explanation. The steroid doses appeared to be the same for the first month when the rejection episodes occurred and group B received more steroids after month 1. Perhaps the only patients with severe recurrence in group B were those that got steroid boluses and the remainder of the patients did well; but this deserves further inquiry. It is also possible that this reflects investigator bias due to the unblinded nature of the study or random chance due to the sample size. The third issue is that the protocol had patients receiving monotherapy with tacrolimus very early on in the rapid taper group. It is possible that with this low level of immunosuppression that an element of chronic rejection played a role in the rapid fibrosis in group A. There is a clear interplay between hepatitis C and rejection in HCV patients. Whether mycophenolate mofetil as part of a triple drug regimen with a slow taper might have improved outcomes remains an open question. Finally, if the rate of advanced fibrosis is so markedly different, it is unexpected to have identical mortality from recurrent hepatitis C in the two groups. Perhaps differences in outcome will be seen as the length of follow-up increases. However, the mortality in patients with recurrent graft cirrhosis from HCV is high [[16]Berenguer M. Prieto M. Rayon J.M. Mora J. Pastor M. Ortiz V. et al.Natural history of clinically compensated hepatitis C virus-related graft cirrhosis after liver transplantation.Hepatology. 2000; 32: 852-858Crossref PubMed Scopus (498) Google Scholar] and the lack of a survival difference or retransplant rate in the two groups with a relatively long follow-up makes one wonder whether there was some degree of confounding in their results. Despite these limitations, I do believe that rapid changes in immune milieu are adverse to hepatitis C outcomes. Both steroid boluses for mild episodes of acute rejection as well as very rapid tapering of immunosuppressive agents are likely to be deleterious and should be avoided. At our center we have adopted a “low and slow” approach to steroid tapers and use modulation or mild intensification of baseline immunosuppression rather than bolus steroid treatment for mild rejection episodes. I commend the authors for taking the first steps toward prospectively validating that hypothesis. Despite that, the ideal immunosuppressive strategy for HCV patients undergoing transplant remains elusive. Whether complete avoidance of steroids is equivalent to slow steroid tapers or not, the duration of steroid therapy that best balances the clear long-term metabolic and bone-related risks with possible histologic benefit, and the optimal use of other immunosuppressive agents (e.g., antibody induction, mycophenolate mofetil, rapamycin) as part of these regimens remains uncertain. Larger multicenter, prospective trials, perhaps with triple immunosuppressive regimens, are certainly needed to further improve our outcomes in recurrent HCV. Until then, for steroid therapy, it seems the best guidance is “proceed with caution”.