A surprise to me was a recent study which identified sirolimus as a risk factor for increased mortality and graft loss in HCV-positive liver transplant patients (Liver Transpl 2012; 18: 1029-36, commentary 1003-1004).
Sirolimus mechanism of action: inhibits mammalian target of rapamycin (mTOR) which is a phosphoinositide 3-kinase which affects cell proliferation, angiogenesis, and immune function. For transplant patients, sirolimus blocks interleukin-2-induced stimulation of T lymphocytes.
Black box warnings for sirolimus: FDA warns that sirolimus can increase risk of hepatic artery thrombosis, graft loss, and death with de novo sirolimus-based treatment.
What’s different about HCV transplants? HCV reinfection occurs immediately during liver transplantation and “unlike all other indications, graft survival and patient survival have not improved” (between 1991-2001). HCV transplant survival continues to be 10-15% lower than non-HCV transplant survival. Immunosuppression allows more rapid progression of HCV; this allows ~20% of recipients to develop cirrhosis within 5 years of transplantation.
The authors of the study analyzed 26,414 patients (12,589 with hepatitis C virus) from the Scientific Registry of Transplant Recipients (SRTR) database; all recipients were >18 years. Among this database, 1685 liver transplant recipients received sirolimus; in the majority, it was administered along with a calcineurin inhibitor. A multivariate analysis of patient mortality showed the following were risk factors for increased mortality:
- recipient age
- donor age
- hepatocellular carcinoma
Tacrolimus-based immunosuppression was associated with superior survival. Whereas, the use of sirolimus was associated with increased mortality in patients with HCV, even when adjusting for confounding variables (eg. renal function, and cancer). In patients who received sirolimus at baseline, the adjusted HR for mortality at 3 years was 1.29 (p=0.0053). In non-HCV patients, the adjusted HR for the sirolimus group was 1.09 (p=0.40). Also, duration of exposure to sirolimus was directly correlated with worse outcomes. Why?
This is not clear. It is recognized that the study has several limitations. Due to the nature of the SRTR database, there is not adequate information on how sirolimus may have affected viral load, histologic progression or causes of death. Despite attempts to control for risk factors, it is possible that the sirolimus group did have higher disease severity. Nevertheless, sirolimus effects on multiple cellular functions may have deleterious consequences in certain subsets of patients.