Immunosuppression, Liver Injury and Post-transplant HCV Recurrence

S. Ciesek; H. Wedemeyer

Disclosures

J Viral Hepat. 2012;19(1):1-8. 

In This Article

Immunosuppression and Graft Hepatitis C

As HCV re-infection cannot be prevented and curative treatment is unsuccessful in the majority of cases, the question arises whether there are ways to optimize post-transplant management, most notably the immunosuppressive regimen used, to minimize the risk of transplant hepatitis and graft loss. Advances in the development of novel immunosuppressive drugs have resulted in an improved clinical outcome after transplantation and transformed liver transplantation into a routine clinical procedure with overall reasonable long-term results. However, individualization of immunosuppressive therapy owing to the underlying disease is still a major goal to enhance graft survival especially in HCV-positive individuals. Furthermore, it has been suggested that the type of immunosuppressive therapy might be responsible for the worse outcome of HCV-positive individuals after liver transplantation observed in recent years.[60]

Calcineurin inhibitors form the backbone of immunosuppression in the majority of liver transplant recipients. The discovery of CNI in the early 1970s and the FDA approval of cyclosporine A (CsA) in 1983 were major milestones for the immunosuppressive management of transplant recipients and increased 1-year graft survival rates from 24% in the late 70s to up to 60% in the 80s.[61] Two CNIs, tacrolimus (Tac) and CsA, are currently approved for immunosuppression after liver transplantation. There is a large experience with both compounds and some differences in efficacy and the side effect profile became evident over the years. Therapy with Tac is associated with a higher incidence of post-transplant diabetes mellitus, while CsA treatment leads more frequently to dyslipidaemia, hypertension, hirsutism and gingival hyperplasia.[62] Tacrolimus treatment may also cause more often hearing impairments, which is a common phenomenon in liver-transplanted patients.[63] Tac is about 100 times more potent than CsA and exerts its action by binding to the FK binding protein 12 (FKBP12), while CsA binds to cyclophilins (e.g. cyclophilin A). Importantly, both of these complexes inhibit calcineurin, a pivotal enzyme in T-cell receptor signalling and activation, which dephosphorylates the transcription factor NF-AT (nuclear factor activating T cell). NF-AT regulates the activity of genes coding for IL-2 and other cytokines in T cells[62] and thus inhibition of calcineurin prevents T-cell activation. Effects on other immune cells have also been noted, e.g. the function of regulatory T cells may be altered by both CsA and Tac.[64]

Cyclophilin A, the target protein of CsA, is not only involved in T-cell activation but also serves HCV as an essential host factor for viral replication.[65] For this reason, CsA very efficiently suppresses HCV RNA replication in vitro. In contrast, treatment with Tac has no effect on HCV RNA levels.[66] This observation has led to the clinical development of non immunosuppressive CsA analogues for the treatment of HCV infection. The cyclophilin A inhibitor alisporivir is currently the most advanced HTA in development, phase II studies have shown good efficacy and very low rates of viral resistance[52,67] and phase III studies for the treatment of chronic hepatitis C patients are ongoing. While alisporivir seems promising in the nontransplant population, the antiviral effect of CsA did not lower HCV viremia in patients after liver transplantation[68] or in a humanized mouse model.[69] Even though, some earlier studies suggested that immunosuppression with cyclosporine might be associated with a better histological outcome of graft hepatitis C.[70] However, the far majority of several subsequent studies did not identify major differences between CsA and Tac in the outcome of HCV infection after liver transplantation as nicely summarized by Berenguer et al. already in 2007.[71] Conversely, a recent retrospective study with more than 8000 HCV-positive liver-transplanted individuals showed that patient death, graft failure, failure owing to recurrent disease and acute cellular rejection were slightly enhanced in the CsA-treated group in comparison with the Tac group.[72] These results may cast doubt on the targeted long-term administration of CsA to HCV-infected liver transplant recipients. However, as part of strategies to avoid HCV re-infection, it might be helpful to employ a CsA-based immunosuppressive regimen in the early phase after transplantation as CsA has a clear additive antiviral effect in vitro.[73] Moreover, some studies suggested that immunosuppression with CsA enhances SVR rates in liver transplant patients treated with interferon alpha and ribavirin.[53,74] Finally, CsA may have advantages concerning drug–drug interactions if novel HCV protease inhibitors are explored as CsA drug levels were less affected than Tac levels when co-administered with telaprevir.[58]

Besides the question of the optimal CNI for HCV-positive liver transplant recipients, the use of steroids after transplantation of HCV patients has been a matter of debate for several years. While it is widely accepted that steroids should be avoided in individuals with HBV infection after liver transplantation, conflicting data have been published for hepatitis C. Clearly, repeated administration of high doses of corticosteroids to treat rejection is associated with more rapid fibrosis progression and poor long-term outcome of graft hepatitis C.[75] Several studies confirmed that there is a strong correlation between steroid bolus therapies of acute rejection episodes and severe recurrence of hepatitis C.[76–78] Moreover, an interim analysis of the American HCV-3 study showed that a steroid-free immunosuppression regime was superior to steroid containing regimes regarding fibrosis progression which is in line with European experience demonstrating that immunosuppression without steroids reduces bacterial infections and improves histological short-term evolution of HCV recurrence.[79] Besides the immunosuppressive effects of glucocorticoids, a recent in vitro study has revealed a direct stimulation of HCV infection by steroids. This was mediated through an upregulation of SR-BI and occludin, two crucial HCV entry factors, suggesting a novel direct mechanism of steroid-dependent exacerbation of HCV infection after liver transplantation.[66] Taken together, it is widely accepted that immunosuppressive regimens after liver transplantation for hepatitis C should avoid steroid boli therapies, if possible. Overall, immunosuppression without steroids is safe after liver transplantation and has been shown to reduce infectious and metabolic complications. However, low-dose corticosteroids may not necessarily have to be avoided in HCV infection after liver transplantation. If steroids are used, slow rather than rapid tapering should be preferred.[80]

The impact of other immunosuppressive agents including mycophenolate mofetil, azathioprine or interleukin-2 inhibitors on HCV recurrence remains controversial. For all of these drugs, conflicting studies have been published indicating both positive and negative effects on the course of HCV re-infection after transplantation. However, large high-quality prospective studies with a long-term follow-up are lacking. Thus, no recommendation can be given at this stage for preferential usage or avoidance of any of these compounds in the context of graft hepatitis C.

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