Immunosuppression, Liver Injury and Post-transplant HCV Recurrence

S. Ciesek; H. Wedemeyer


J Viral Hepat. 2012;19(1):1-8. 

In This Article

Treatment of HCV Re-infection After Transplantation

As long as no potent drugs or neutralizing antibodies are available to prevent HCV recurrence after liver transplantation, re-infection can still be treated with a combination of pegylated interferon alpha and ribavirin. However, the efficacy of this treatment is limited mainly by the poor tolerability in liver transplant recipients, and thus SVR rates are lower than in immunocompetent nontransplanted individuals.[12] Overall, SVR rates after liver transplantation for HCV genotype 1 infection are around 25–30%.[53] Furthermore, prolonged therapy seems to be required even in patients infected with the easier to treat genotypes 2 and 3 and extending antiviral therapy for more than 48 weeks might prevent virological relapse in many patients.[54,55] IL28B genotypes of both the donor and the recipient are associated with response to PEG-IFNa-based treatment after liver transplantation, and determination of the IL28b genotype may therefore be useful in clinical practice to decide which patient should receive antiviral therapy.[27] Importantly, successful treatment reduces liver-related complications in recurrent HCV infection.[56]

Even though interferon alpha can be beneficial for many patients, it has to be considered that antiviral therapy can promote rejection especially in the early phase after transplantation.[57] Thus, liver transplant recipients receiving standard antiviral therapy need to be monitored for acute cellular rejection and chronic ductopenic rejection. In addition, de novo autoimmune hepatitis may develop and immunological phenomena may even occur after treatment has been stopped. As the clinical course of HCV infection is largely influenced by co-factors, it is of particular importance in liver transplant recipients to avoid co-morbidities including ischaemic-type bile duct lesions and liver steatosis.

The use of the novel NS3/4A protease inhibitors seems to be limited in patients after liver transplantation as it has been shown that telaprevir increases tacrolimus blood levels by approximately 70-fold – precluding its use outside of clinical trials.[58] Co-administration with telaprevir also affected cyclosporine exposure and cyclosporine half-life, but to a lesser extent. No data on drug–drug interactions between calcineurin inhibitors (CNI) and boceprevir are currently available. Clinical trials are under way to determine the safety of efficacy of triple therapy of hepatitis C in liver transplant recipients. Whether combinations of PEG-IFNa with other NS3/4A protease inhibitors or with calcineurin inhibitor-free immunosuppressive regimens are feasible remains to be determined.

Currently, more than 100 novel HCV inhibitors are under preclinical and clinical investigation. These can broadly be divided in direct antiviral agents (DAA) and host factor targeting antivirals (HTA).[59] While DAAs target the virus directly and include NS3/4A protease inhibitors (first & second generation), NS5B polymerase inhibitors and NS5A inhibitors, HTAs target essential cellular factors like cyclophilin A, microRNA122 and CD81 antibodies. Disadvantages of some but not all DAA classes are that they are not effective against all HCV genotypes and that viral resistance is anticipated to become a major problem. HTAs may show broad activity across HCV genotypes and pose a higher barrier to drug resistance in comparison with DAA.[16] It is expected that some of the novel drugs will reach the market in 2015; however, none of the new anti-HCV drugs are currently being evaluated in HCV-infected liver transplant recipients. The ultimate goal will be to introduce safe interferon-free combination therapies without significant drug–drug interactions leading to cure from HCV infection within a limited time frame.


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