Sirolimus Conversion May Suppress Viral Replication in Hepatitis C Virus-Positive Renal Transplant Candidates

Abstract

Objectives: Hepatitis C virus in renal transplant recipients is an independent risk factor for sickness and death. It has been shown that one might limit hepatitis C virus progression in liver transplant recipients with sirolimus-based immunosuppression. The mammalian target of rapamycin is an influential molecule for the anti-hepatitis C virus action of interferon. We report our experience with sirolimus conversion in hepatitis C virus-positive patients with chronic allograft nephropathy regarding hepatic and hematologic effects that might affect its future use. Materials and Methods: Twenty-five patients who had received renal transplants with anti-hepatitis C virus-positive and normal liver function were enrolled. Ten patients had allograft dysfunction because of cyclosporine nephrotoxicity. Sirolimus was initiated at 2 mg/d and adjusted to 6 to 8 ng/mL. Cyclosporine was gradually tapered and then stopped; 15 patients were used as a control group. Sirolimus-related hepatitis was defined as a rise in liver transferases or alkaline phosphatase or bilirubin over twice the upper limit of normal. Viral replication was defined as elevated liver enzymes and increasing viral load and/or biopsy-proven hepatitis C virus active hepatitis. Results: After conversion, there was a reduction of hemoglobin and hematocrit. In 1 patient, the immunosuppressive regimen was changed back to cyclosporine owing to anemia and hepatotoxicity leading to prompt return of hematocrit and liver enzymes to their original values. One of 10 antihepatitis C virus-positive patients (10.0%) developed sirolimus-associated hepatotoxicity, compared with 2 patients in the control group (13%). Sirolimus patients showed a significant decrease in the HCV PCR levels from 700 000 to 400 000 IU/mL; P < .001, compared to 680 000 to 660 000 IU/mL in cyclosporine patients; P = NS, with comparable levels of transaminases Conclusions: Our data suggest that sirolimus has the potential to suppress viral replication in hepatitis C virus-positive renal transplant candidates.

Host cell mTORC1 is required for HCV RNA replication

“…To this end, rapamycin and everolimus may be attractive agents as part of an immunosuppressive regimen for this special patient group. Rapamycin has been seen as an attractive immunosuppressant as it reduces the risk of significant hepatic fibrosis after OLT in HCV-positive patients31 and suppresses viral replication in vivo after solid organ transplantation,25 but the molecular reason for these observations had not been identified yet. Our data show for the first time that mTOR inhibitors directly inhibit important steps in the HCV replication cycle.…”

“…In addition, Asthana et al 24 observed in a retrospective analysis of 141 patients that de novo rapamycin-based immunosuppression leads to slower progression of fibrosis. In an interventional open-label prospective study, renal transplanted patients with HIV and HCV benefited from rapamycin monotherapy in comparison to treatment with CsA 25. Moreover, rapamycin treatment significantly suppressed viral replication in HCV-positive renal transplanted patients compared with patients receiving CsA 25.…”

“…In an interventional open-label prospective study, renal transplanted patients with HIV and HCV benefited from rapamycin monotherapy in comparison to treatment with CsA 25. Moreover, rapamycin treatment significantly suppressed viral replication in HCV-positive renal transplanted patients compared with patients receiving CsA 25. However, little is known about the relation between mTOR-mediated signalling and HCV RNA replication from a molecular point of view.…”

Optimizing the clinical utility of sirolimus‐based immunosuppression for kidney transplantation

“…Case studies also suggest that conversion to sirolimus may lessen cutaneous warts caused by the human papillomavirus . Conversion to sirolimus may also suppress viral replication in hepatitis C virus‐positive renal transplant patients …”

Effect of conversion from calcineurin inhibitors to everolimus on hepatitis C viremia in adult kidney transplant recipients

“…Moreover, most clinical trials exclude HCV-positive patients. To the best of our knowledge, only one non-randomized study 14 can be found in the literature concerning the use of mTOR inhibitors as potential drugs for reducing HCV viral load in renal transplantation patients, justifying the importance of the present study.…”