Initial enthusiasm for the use of mTOR inhibitors in liver transplantation was tempered when the FDA issued a black box warning for de novo sirolimus use in liver transplantation http://www.selleckchem.com/products/Abiraterone.html after two studies reported hepatic artery thrombosis (HAT) [38, 44]. In 2009, the FDA issued a second black box warning, after a trial that compared conversion from CNIs to sirolimus versus continued CNI use showed that the number of deaths (3.8% (15/393) versus 1.4% (3/214)) was higher in the conversion group, although this was not significant. In addition, the rates of premature study discontinuation, overall adverse events (specifically infections), and biopsy-proven acute liver graft rejection at 12 months were all significantly higher in the conversion group compared to the group continuing with CNIs [38].

Unfortunately, it was not until recently that the complete data that led to these warnings were published [45] allowing them to be properly scrutinized [46]. Notwithstanding the warnings, the Scientific Registry of Transplant Recipients (SRTR) indicates that between 1999 and 2008 in the US, sirolimus and everolimus were used in 8.8% and 0.2% of liver transplant recipients, respectively, as maintenance therapy from the period of discharge to 1 year after transplantation [47]. Given the large amount of data available on the use of mTOR inhibitors in liver transplantation and the controversy surrounding the black box warnings, we have revisited the use of mTOR inhibitors in liver transplantation.

To this end, we searched the literature from 2001 to 2012 to determine whether the clinical evidence supports a role for this class of immunosuppression with respect to efficacy, safety, and the ability to address unmet clinical needs. 2. Methods 2.1. Identification of Published Clinical Data regarding the Use of mTOR Inhibitors in Liver Transplantation We searched the bibliographic AV-951 database, PubMed, for studies published from January 2001 to April 2012. The following search criteria were used in the PubMed search: ��everolimus liver transplantation�� OR ��sirolimus liver transplantation�� OR ��everolimus liver transplant�� OR ��sirolimus liver transplant.�� Prospective or retrospective clinical studies and reviews of single transplantation centers were considered. We only included studies that met the following criteria: (1) focus on adult liver transplant recipients receiving immunosuppression with mTOR inhibitors, (2) publication in English, and (3) a patient sample size of at least n = 7 in the mTOR inhibitor treatment group. The studies identified were not subjected to a systematic review but are summarized and discussed based on the combined clinical experience of the authors.