Management of Recurrent Hepatitis C Following Liver Transplantation: Immunosuppression

Immunosuppressive regimens initiated at the time of liver transplantation, as well as methods of treating acute cellular rejection during the post-transplant course, appear to have a significant role in the development of liver disease associated with HCV recurrence. Consequently, several strategies have emerged with the goal of minimizing the negative impact of high-dose or pulse corticosteroids. Some data have suggested that a treatment approach characterized by slow tapering of corticosteroids following transplantation may be asso­ciated with a reduced severity of recurrent HCV and fibrosis progression, in contrast to more rapid or abrupt decreases in corticosteroid doses. It is not clear that avoiding corticosteroids entirely may result in improved long-term outcomes; however, a recent meta-analysis noted a potential decrease in the risk of recurrent HCV based upon histologic parameters in addition to a decrease in the risk of CMV infection.

The use of highly specific monoclonal antibody therapy has recently been introduced as an alternative approach to corticosteroids in liver transplant recipients with HCV. The interleukin (IL)-2 receptor antagonists, daclizumab (Zenapax, Hoffman-La Roche; human­ized) and basiliximab (Simulect, Novartis; chimeric), are monoclonal antibodies that avidly bind to the alpha subunit (CD25) of the IL-2 receptor, leading to inhibi­tion of activated T lymphocytes. Both daclizumab and basiliximab have been used successfully in patients with HCV as induction immunosuppressive agents in steroid- free regimens. In these clinical trials, the incidence of allograft rejection in steroid-free arms was decreased or not significantly different compared to regimens that included steroids. Although these agents are viable alternatives in transplant recipients with HCV, studies thus far have not demonstrated any significant benefit with regard to HCV recurrence, fibrosis progression, or survival after 1-2 years of follow-up. suhagra 100

Cyclosporine (CSA) is a widely used immunosup- pressive agent that may have a direct inhibitory effect on HCV replication. CSA, as well as CSA analogues without immunosuppressive properties such as NIM811 and DEBIO-25, have demonstrated in vitro activity against HCV via inhibition of cyclophilins, which are cellular proteins involved in HCV nonstructural protein binding and viral replication within the host. Ret­rospective data have suggested increased SVR rates in patients undergoing antiviral therapy with PegIFN and RBV who receive CSA-based immunosuppression.

Although lower serum HCV RNA levels were described in patients undergoing antiviral therapy who converted to a CSA-based regimen, a recent prospective, random­ized, pilot study did not reveal a significant difference in SVR compared to those who received tacrolimus (TAC). Additional data have not demonstrated a significant dif­ference in long-term outcomes between CSA and TAC, including endpoints such as patient or graft survival and incidence of rejection. Whether the use of CSA in liver transplant recipients with HCV will have long-term ben­efit or whether conversion of immunosuppression to a CSA-based regimen during antiviral therapy is warranted will require further prospective investigation.
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