Cyclosporine A or Tacrolimus for Hepatitis C Recurrence? An Old Debate

Cyclosporine A or Tacrolimus for Hepatitis C Recurrence? An Old DebateX. Forns, M. Navasa

Article first published online: 28 JUL 2011
DOI: 10.1111/j.1600-6143.2011.03511.x

Keywords:Fibrosis;hepatitis C;immunosuppression;interferon;outcomes;sustained virological response

The controversy on the efficacy and safety of cyclosporine A (CsA) versus tacrolimus (TAC) remains a long-standing debate well-known to transplant programs. It is generally accepted that TAC is a more powerful immunosuppressant than CsA, one that has fewer side effects on kidney function, blood pressure, lipid metabolism and, importantly, on so-called aesthetic effects (hirsutism, gingival hypertrophy). For these reasons, TAC is prescribed as the main calcineurin inhibitor in most liver transplant programs. The use of CsA is generally limited to cases of neurologic side effects or in some patients with diabetes mellitus. The potential influence of this calcineurin inhibitor on hepatitis C recurrence has been a matter of controversy for many years, with some articles suggesting better outcomes in patients treated with TAC versus CsA (1–3) and vice versa (4). Most reports, however, support the idea that the choice of calcineurin inhibitor does not impact the histologic severity of recurrent hepatitis C (5,6).

The study published in this issue of the American Journal of Transplantation by Irish et al. (7) reopens the debate on the type of calcineurin inhibitor most effective in HCV-infected patients. The authors analyzed data from United Network for Organ Sharing (UNOS) database for more than 8 800 HCV-infected liver transplant recipients and found poorer outcomes in terms of patient and graft survival in recipients who received CsA compared to TAC at hospital discharge. Contrary to current wisdom that “you can use either calcineurin inhibitors” their study suggests that one should use TAC. From a practical point of view, however, such a conclusion is not very relevant, since even in this study CsA was used in less than 10% of liver transplant recipients, proving that TAC is the preferred immunosuppressant for most transplant programs (at least in the United States).

The authors should be acknowledged for their efforts in analyzing such a large cohort of patients, which is obviously an important point when comparing these results with those of other studies. Although the study remains retrospective from a methodological point of view, the authors used statistical models (propensity score adjustment) to adjust for potential selection bias. Despite intentions to correct for any potential biases using this methodology, this is not always possible, particularly in the case of long-term follow-up studies. Furthermore, the analysis by Irish et al. targets immunosuppression at hospital discharge as responsible for what happens 3 years following transplantation, despite the fact that immunosuppression regimens change after discharge, particularly that of CsA. Therefore, we do not really know the real immunosuppressant used in each patient. Moreover, due to the small proportion of patients treated with CsA, it would have been relevant to exclude a center effect as a potential explanation for different survival rates among CsA- and TAC-treated patients. As one possible explanation for the difference in patient and graft survival rates between the two groups, the authors point out the significantly higher rejection and biopsy-proven rejection rates in liver transplant recipients who received CsA as their main immunosuppressant. Indeed, many studies have found that rejection and particularly the administration of corticosteroid boluses has been associated with a more aggressive course of hepatitis C recurrence.

When deciding on the choice of immunosuppressant for HCV-infected liver transplant recipients, it is also important to consider any potential effects on antiviral treatment, since CsA has recently been shown to have anti-HCV effects. Antiviral therapy, and particularly sustained virological response (SVR), is associated with improved outcomes in these patients (8,9). In this setting, the antiviral effect of CsA on hepatitis C virus replication, either in vitro or in vivo, requires further consideration. Indeed, several experiments have shown that high concentrations of CsA decrease replication of both the subgenomic replicon and the full-length virus by about four logs (10). The anti-HCV effects of CsA and its derivates (such as Debio-025 and NIM811) have been linked to their ability to interact with cyclophilins (CyPs) (10).

Despite these in vitro findings, there is still no consistent data on the differential effects of CsA versus TAC on HCV viral kinetics and viral load in HCV-infected liver transplant recipients (11,12). It has been suggested that the rate of SVR in liver transplant patients with hepatitis C recurrence who are undergoing interferon plus ribavirin therapy is higher in individuals receiving CsA compared to patients receiving TAC (9–13). Selzner et al. (13) retrospectively reviewed the rate of SVR in a cohort of 172 patients treated with interferon-based regimens and showed that CsA was an independent factor for viral clearance. Cescon et al. (11) obtained similar results analyzing a cohort of 99 treated patients. Regretfully, the study by Irish did not include data on antiviral therapy.

Finally, it is also important to realize, that in the coming year standard treatment of chronic hepatitis C will include the protease inhibitors (PI) telaprevir and boceprevir, which have both shown a significant increase in efficacy when administered along with pegylated interferon and ribavirin. Since CsA and TAC share the same metabolic pathway than PI, significant drug-drug interactions will occur when these medications are given concomitantly, as it has been shown in patients coinfected with the HIV who underwent LT. We will need to wait and see how these interactions may affect the use of CsA and TAC.

Considering all of the arguments outlined above, we believe that TAC should be the preferred calcineurin inhibitor for use in liver transplantation as it offers a lower incidence of rejection as compared to CsA. Nonetheless, we believe that you can safely and effectively use both in HCV-infected liver transplant patients. It is likely that the tendency for disease recurrence and progression is more a reflection of an overall excess of immunosuppression than a direct effect of a specific immunosuppressive agent. The development of better in vivo and in vitro systems for evaluating the antiviral effects of various drugs, including immunosuppressive agents, will likely help in resolving this dilemma. Meanwhile, we must wait and see if large prospective studies will confirm the potential benefit of CsA on antiviral treatment outcomes and, if this is the case, whether this effect will still prevail when new antivirals are available for use in the transplant setting.

1
Lake JR. Immunosuppression and outcomes of patients transplanted for hepatitis C. J Hepatol 2006; 44: 627–629.
CrossRef,
PubMed,
Web of Science® Times Cited: 9
2
O’Grady JG, Hardy P, Burroughs AK, Elbourne D. Randomized controlled trial of tacrolimus versus microemulsified cyclosporin (TMC) in liver transplantation: Poststudy surveillance to 3 years. Am J Transplant 2007; 7: 137–141.
Direct Link:
Abstract
Full Article (HTML)
PDF(241K)
References
3
Haddad EM, McAlister VC, Renouf E, Malthaner R, Kjaer MS, Gluud LL. Cyclosporin versus tacrolimus for liver transplanted patients. Cochrane Database Syst Rev 2006; CD005161.
PubMed,
ChemPort
4
Berenguer M, Crippin J, Gish R, et al. A model to predict severe HCV-related disease following liver transplantation. Hepatology 2003; 38: 34–41.
Direct Link:
Abstract
PDF(114K)
References
5
Berenguer M, Aguilera V, Prieto M, et al. Effect of calcineurin inhibitors on survival and histologic disease severity in HCV-infected liver transplant recipients. Liver Transpl 2006; 12: 762–767.
Direct Link:
Abstract
Full Article (HTML)
PDF(132K)
References
6
Berenguer M, Aguilera V, San JF, et al. Effect of calcineurin inhibitors in the outcome of liver transplantation in hepatitis C virus-positive recipients. Transplantation 2010; 90: 1204–1209.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 1
7
Irish W, Arcona S, Bowers D, Trotter J. Cyclosporine versus tacrolimus treated liver transplant recipients with hepatitis C: Outcome analysis of the UNOS/OPTN database. Am J Transplant 2011.
Direct Link:
Abstract
Full Article (HTML)
PDF(288K)
References
8
Berenguer M, Palau A, Aguilera V, Rayon JM, Juan FS, Prieto M. Clinical benefits of antiviral therapy in patients with recurrent hepatitis C following liver transplantation. Am J Transplant 2008; 8: 679–687.
Direct Link:
Abstract
Full Article (HTML)
PDF(236K)
References
9
Carrion JA, Navasa M, Garcia-Retortillo M, et al. Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: A randomized controlled study. Gastroenterology 2007; 132: 1746–1756.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 92
10
Ciesek S, Steinmann E, Wedemeyer H, et al. Cyclosporine A inhibits hepatitis C virus nonstructural protein 2 through cyclophilin A. Hepatology 2009; 50: 1638–1645.
Direct Link:
Abstract
Full Article (HTML)
PDF(552K)
References
11
Cescon M, Grazi GL, Cucchetti A, et al. Predictors of sustained virological response after antiviral treatment for hepatitis C recurrence following liver transplantation. Liver Transpl 2009; 15: 782–789.
Direct Link:
Abstract
Full Article (HTML)
PDF(105K)
References
12
Firpi RJ, Zhu H, Morelli G, et al. Cyclosporine suppresses hepatitis C virus in vitro and increases the chance of a sustained virological response after liver transplantation. Liver Transpl 2006; 12: 51–57.
Direct Link:
Abstract
Full Article (HTML)
PDF(245K)
References
13
Selzner N, Renner EL, Selzner M, et al. Antiviral treatment of recurrent hepatitis C after liver transplantation: Predictors of response and long-term outcome. Transplantation 2009; 88: 1214–1221.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 9