Lower incidence of cytomegalovirus infection with everolimus versus mycophenolate mofetil inde novocardiac transplant recipients: a randomized, multicenter study

Abstract

Cytomegalovirus (CMV) is a major cause of infectious complications following cardiac transplantation, severely affecting short- and long-term outcomes. A 12-month, multicenter, randomized, open-label study in de novo cardiac transplant patients was undertaken to compare the efficacy, renal function, and safety of everolimus plus reduced cyclosporine versus mycophenolate mofetil (MMF) plus standard cyclosporine (ClinicalTrials.gov NCT00150046). CMV-specific data was prospectively collected on infections, laboratory evidence, CMV syndrome, and CMV disease. In total, 176 patients were randomized (everolimus 92; MMF 84). Use of CMV prophylaxis was similar between groups (everolimus 20.8%; MMF 24.0%). Patients in the everolimus arm had a significantly lower incidence of any CMV event (8.8% versus 32.5% with MMF, P<0.001), CMV infection as an adverse event (4.4% versus 16.9%, P=0.011), laboratory evidence of CMV (antigenemia 7.7% versus 27.7%, P<0.001; polymerase chain reaction assay 2.2% versus 12.0%, P=0.015), and CMV syndrome (1.1% versus 8.4%, P=0.028). In the donor (D)+/recipient (R)+and D-/R+ subgroups, even after adjusting for use of prophylaxis, the CMV event rate remained significantly lower with everolimus than with MMF (P=0.0015 and P=0.0381, respectively). In conclusion, de novo cardiac transplant recipients experienced lower rates of CMV infection, CMV syndrome, or organ involvement on an everolimus-based immunosuppressant regimen compared with MMF.

Mechanistic target of rapamycin inhibitors in solid organ transplantation

“…mTORi may present antiviral properties [82,83 && ,84] as reduction of cytomegalovirus (CMV) incidence with mTORi regimens was consistently reported, whatever the antiviral treatment used [85][86][87]. In fact, statistical significance was only reached for recipients with CMV-positive status before transplantation [88]; lower incidence of BK virus (BKV) infection has been inconsistently reported [66, 88,89].…”

Antiviral Drug Resistance of Human Cytomegalovirus

“…Several recent studies have reported that the immunosuppressive agents sirolimus (rapamycin) and its derivative everolimus are associated with a significantly reduced incidence of HCMV infections in both solid organ transplant recipients (64,93,196) and allogeneic hematopoietic stem cell recipients (145). A switch to sirolimus has also been reported to be associated with reduced viral loads in patients infected with GCV-resistant HCMV strains (160).…”

“…In vitro exposure of infected cells to rapamycin results in transient or incomplete inhibition of virus infection (55,105,117), but no specific antiviral target has been identified. It is assumed that there is an indirect effect through inhibition of host cell proliferation and signaling pathways (105,117,196). Drugs that have both immunosuppressive and anti-HCMV activity could be therapeutically advantageous in transplant recipients.…”

The CECARI Study: Everolimus (Certican®) Initiation and Calcineurin Inhibitor Withdrawal in Maintenance Heart Transplant Recipients with Renal Insufficiency: A Multicenter, Randomized Trial

“…Third, everolimus interferes with the phosphatidylinositol 3-kinase pathway, a critical step for viral signaling and replication. There is convincing evidence indicating a reduced rate of cytomegalovirus (CMV) infection in everolimus-treated heart transplant recipients [13–15]. Fourth, everolimus exhibits antiproliferative activity.…”