**2.3.1 Role of immunosuppression in recurrence of hepatitis C**

Agreement exists that immunosuppression is significantly associated with the natural history of recurrent hepatitis C (Samuel et al, 2006). However, controversy still surrounds the role of each immunosuppressive agent on HCV replication and the evolution of hepatitis C on the graft.

Immunosuppression contributes greatly to the increased viral load that takes place in these patients during the immediate post-transplant months. The recipient's cellular immune response against the infected hepatocyte, and thus against the virus, is altered. It is almost absent in patients with fibrosing cholestatic hepatitis and severe disease recurrence (McCaughan 2004, Samonakis et al, 2005).

The role of the type of immunosuppressive regimen and its influence on the progression of recurrence are still unclear and there is no established ideal immunosuppression protocol.

The use of high-dose steroid boluses to treat episodes of acute rejection, , has been shown to be clearly prejudicial, as they condition an increase in viral replication, a more aggressive relapse and increased early post-transplant mortality (Samuel et al 2006, Berenguer et al, 2006a).

Some studies suggest the possible benefit of maintaining low-dose steroid regimens with progressive withdrawal during the first 6-12 months (Berenguer et al, 2006a). However, two recent meta-analyses found that steroid-free immunosuppression protocols are significantly better and provide benefits related with such factors as the acute graft hepatitis, HCV recurrence, cholesterol levels and the development of de novo diabetes mellitus (Sgourakis et al, 2009, Segev et al, 2008). Thus, the use of steroid-free immunosuppression protocols improves the management of metabolic complications.

Regarding the use of calcineurin inhibitors, numerous studies have compared the recurrence of HCV with the two drugs, cyclosporine and tracrolimus. However, the results are not completely conclusive, with most studies failing to find differences. Thus, it is not possible to recommend the use of a specific calcineurin inhibitor. There seems to be evidence that the use of cyclosporine during interferon treatment may be beneficial, and that tacrolimus seems to reduce episodes of acute rejection and the need for steroid boluses. A possible beneficial immunosuppressive regimen could be to start with tacrolimus and later substitute it with cyclosporine if antiviral treatment is considered necessary for HCV recurrence (Berenguer et al, 2007, Levy et al, 2006, O´Grady et al, 2007). For other immunosuppressive agents, such as mycophenolate, azathioprine, mTor inhibitors or anti-IL-2 receptor antibodies, no solid studies have yet been done from which to obtain conclusions. In summary, therefore, the only firm recommendation would be to avoid a state of overimmunosuppression, avoiding steroid boluses and full-dose triple or quadruple regimens. This could lead to improved results in these patients (Berenguer et al, 2006a).
