Hepatitis C pathogenesis and outcomes after liver transplantation: Probing microRNA expression for new insights

Hepatitis C virus (HCV)–related liver disease is now the largest single indication for liver transplantation worldwide, and a growing disease burden is predicted over coming years. However, infection of the allograft is essentially universal, and it is often associated with accelerated disease progression, with recurrent cirrhosis occurring in approximately 30% of recipients within 5 years of transplantation. Transplantation for this indication is thus associated with reduced allograft and recipient survival, and this renders its outcomes inferior to those for transplantation performed for many other etiologies. A number of clinical risk factors, including increased levels of immunosuppression, increased donor age, posttransplant cytomegalovirus infections, and high levels of HCV viremia after transplantation, have been associated with more rapid disease progression. However, particularly in an age of increasing donor shortages, many of these factors are unmodifiable. Despite the significant pathology associated with HCV recurrence after liver transplantation, outcomes can be highly variable, and the decision to proceed to antiviral therapy in an individual patient remains a difficult clinical challenge. Combination therapy with interferon-a (IFN-a) and ribavirin after liver transplantation is associated with response rates of generally less than 30% and entails the risk of inducing allograft rejection. In addition, toxicity-related dropout rates are high. In the longer term the development of IFN-free direct antiviral agent regimens may lead to significant improvements in our ability to treat this patient group. However, the availability of protease inhibitor therapy as an adjunct to IFN-based treatment presents not inconsiderable challenges, as evidenced by recent data indicating substantial morbidity in the treatment of individuals with decompensated liver disease before transplantation, and also because of issues of significant drug interactions with calcineurin inhibitors after transplantation. In this setting, 2 significant issues have attracted much interest with respect to basic laboratory investigation within this field. First, the mechanisms underlying the accelerated recurrence of liver disease associated with HCV recurrence after transplantation remain poorly understood. Extensive research effort has thus been expended in gaining insights into these mechanisms, not only to inform future work into therapies to modify outcomes, but also to develop biomarkers predicting the development of aggressive fibrosis. The latter would be a major advance in guiding clinical decision making regarding the commencement of antiviral therapy. Second, the histopathological diagnosis of acute cellular rejection in the presence of recurrent HCV remains problematic: this is of critical importance because of the potential for increased immunosuppression to exacerbate HCV-related disease progression. Therefore, the development of biomarkers indicating the presence of acute cellular rejection in individuals with HCV recurrence has been an important experimental focus.