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.
Hepatitis C virus (HCV) infects an estimated 170 million people worldwide and is the single most common indication for orthotopic liver transplantation (OLT) in Europe and the United States [1,2]. Indeed, end stage liver disease from hepatitis C is the indication for liver transplantation in approximately 40% of liver transplant candidates. Although up to 40% of patients who develop acute HCV infection may spontaneously clear infection; in contrast, after liver transplantation HCV reinfection post-transplant is universal [3-6]. An estimated 20% of liver transplant recipients with chronic HCV infection develop cirrhosis 4-5 years post-liver transplant [6,7]. The accelerated course of hepatitis C may be due age of the donor liver, gender, and viral properties, as well as immunosuppression [3,5,7-9].
2. Hepatitis C Replication and Calcineurin Inhibitors HCV is a hepatotropic member of the flaviviridae family. The virus is transmitted parenterally and rarely through vertical and sexual transmission [
The lack of a robust animal model hindered the development of therapy against HCV, but the creation of the HCV replicon model overcame many of these limitations. HCV attaches to the host cell surface by utilizing at least four receptors, CD81, scavenger receptor class B type I (SR-BI), claudin-1 (CLDN1), and occludin (OCLN) [
Prior to the approval of cyclosporine (CsA) in the United States in 1983, survival rates for liver transplant recipients were less than 50%. Steroids and azathioprine were the mainstay of therapy to prevent rejection. The development of calcineurin inhibitors (CNIs) revolutionized transplant medicine and after the introduction of cyclosporine survival rates increased to more than 70%. Currently most patients undergoing OLT will receive either one of two such immunosuppressants, either tacrolimus (Tac) or (CsA) [1,9]. Calcineurin (CN) is a calcium-dependent serine/threonine phosphatase that promotes T cell activation, by the expression of several cytokine genes, the most important interleukin-2 (IL-2), but also interleukin-4 (IL-4). Cyclosporine A was first isolated from the fungus Tolypocladium inflatum and has powerful immunosuppressive effects. Cyclosporins are cyclic peptides that have broad spectrum of biological activity. CsA binds to cyclophilin (Cyp) to form a binary complex that binds CN and inhibits its activity. Tacrolimus (Tac) is an immunosuppressant that attaches to FK binding proteins which then decreases calcineurin activity ultimately leading to immunosupression [
Cyclosporine or tacrolimus are the most commonly used CNI’s used after liver transplantation. The different molecular processes and properties leading to calcineurin inhibition may thus provide a theoretical basis for which each CNI may interact with viral components. Furthermore, the difference between Tac and CsA potency has influenced how they were used in the past. Indeed, Tac was previously preferred in patients with HCV infection due to its higher potency, thus further limiting the use of steroids [
Studies suggest that CsA inhibits HCV viral replication and increases endogenous interferon. In vitro data using the HCV subgenomic replicon system demonstrate an inhibitory effect of CsA on HCV protein expression and replication [8-11]. Cyclophilins interact with the NS5 protein complex. For example cyclophilin B interacts with the NS5B polymerase to directly stimulate RNA binding activity. By binding to cyclophilins, CsA may disrupt the CypB-NS5 complex formation and thus HCV replication in vitro [
Due the central role IFN-α plays in the control of HCV infection and the ability of HCV to suppress IFN-α production, it has been hypothesized that CsA may have an effect on IFN expression. Indeed, some authors have demonstrated that HCV replication was suppressed by CsA with associated elevated levels of endogenous IFN-α. More specifically, Liu and colleagues report that CsA treatment of HCV JFH-1-infected Huh7 hepatocytes restored endogenous levels of IFN-α and also enhanced its expression but others found no evidence that either CsA or Tac interferes with IFN-α-induced gene expression or antiviral activity [5,15]. In addition to effects of viral replication, CsA decreases the activation of intrahepatic fibroblasts induced by IL-4, thus reducing fibrosis in recurrent HCV [
By binding to host proteins, CsA is thought to mediate its antiviral effects. Other investigators further report that CypA is the isoform that serves as the essential cofactor for HCV replication and that the interaction of cyclophilins with NS5A seems to be the most critical [
Identifying the optimal immunosuppressive regimen is critical because recurrent HCV is a significant problem after liver transplant and treatment of post-transplant chronic HCV patients is plagued by lower rates of SVR (about 20%), side effects and the potential for increased graft loss with use of alpha interferon (IFN) [5,15]. Thus, there remains potential for development of novel therapy for HCV for post-liver transplant recipients.
Initial comparisons by Wiesner, et al. suggest that longterm outcome was superior for Tac-based therapy in patients infected with HCV when compared to a regimen based on CsA [12,19] (
administered. The CsA arm, on the other hand, received greater doses of steroids. Thus, the observed differences may not have been related to the type of CN-inhibitor, but rather due to drug dose, higher steroid doses in the CsA arms, and/or overall levels of immunosuppression [6,12]. Other early studies not primarily designed to compare HCV recurrence rates between CsA and Tac, such as those reported by Ghobrial et al. and a systematic review, however, suggested cyclosporine was associated with lower rates of HCV recurrence and better responses rates to antiviral therapy [20,21] (
The approved protease inhibitors for genotype 1 patients in the US and Europe, telaprevir and boceprevir, used in combination with peginterferon and ribavirin have substantially improved sustained viral response rates in the nontransplant population. These agents significantly increase tacrolimus and cyclosporine levels and ongoing clinical trials will study pharmacokinetics, drug interactions, and efficacy. DEBIO-025 is a cyclophilin under development without immunosuppressant properties but has in vitro and in vivo anti-HCV properties [
Although in vitro data suggest the should be a benefit of cyclosporine over tacrolimus in hepatitis C liver transplant recipients, clinical studies have not shown that hepatitis C recurrence is significantly lower in recipients treated with cyclosporine. Furthermore, the development of DAA’s has changed the efficacy and side effect profile of treatment and the impact of these new classes of agents and interaction with CNI’s needs further study. Thus, cyclosporine can not be routinely recommended for hepatitis C recipients. Another exciting class of agents are cyclophilin inhibitors, and if proven to be safe and effective, CsA-derivatives may prove to be an important part of the regimen for liver transplant recipients infected with HCV.