Regarding the calcineurin inhibitors (CNI), most of the studies suggest that there is no significant difference between tacrolimus and cyclosporine with respect to their impact on histologically diagnosed HCV recurrence and graft or patient survival (Iacob 2007, Berenguer 2007). Cyclosporine has a strong in vitro suppressive effect on HCV replication (Watashi 2003). Several clinical although relatively small studies suggested a higher sustained virologic response (SVR) in HCV LT patients receiving cyclosporine and interferon therapy.
The cornerstone of immunosuppressive agents, the corticosteroids, slowly tapered off over a long time, may prevent progression to severe forms of recurrent disease (Iacob 2007, Brillanti 2002). In contrast, the boluses of methylprednisolone (MP) used for acute rejection episodes were deleterious to the HCV-related graft survival. Outcome of HCV-positive patients who received multiple pulses of MP is significantly worse than that in patients with a single pulse therapy (Bahra 2005). High levels of viremia can determine an HCV-cytopathic mechanism involved in the allograft injury. Currently, steroid-free immunosuppression regimens are preferred in HCV recipients. Actual data for mycophenolate mofetil (MMF), a morpholino ester prodrug of mycophenolic acid (MPA), favor its use in recurrent hepatitis C. MPA is a selective, noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase (IMPD), a key enzyme in the biosynthetic pathway of the guanine nucleotides. It is also a potent inhibitor of both B and T cell proliferation. MMF in combination with CNI taper showed a positive effect on fibrosis progression, graft inflammation and ALT levels (Lake 2009, Iacob 2007). Less data are available for azathioprine, but its inclusion in the maintenance regimen was associated with survival advantage.
The potential antifibrotic and antiviral benefit of mTOR (mammalian target of rapamycin) inhibitors after LT in HCV positive patients awaits further investigation in prospective randomized controlled trials. Sirolimus, a macrolide isolated from Streptomyces hygroscopius reduces TGF-? and procollagen, inhibits hepatic stellate cell proliferation and may have an inhibitory action on HCV replication through phosphorylation of signal transducers and activators of transcription (STAT-1) (Matsumoto 2009).