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Abstract

Objectives: Cytomegalovirus infection and disease remain an issue in solid-organ transplant. Universal prophylaxis is more cost-effective than a preemptive strategy and is associated with significantly less cytomegalovirus resistance after kidney transplant, especially in cytomegalovirus-seropositive donors and cytomegalovirus-seronegative recipients. Materials and Methods: Registry data and metaanalyses have shown that mammalian target of rapamycin inhibitors (sirolimus-and everolimus-based immunosuppression) are associated with significantly less cytomegalovirus events in de novo kidney transplant patients than in patients who are treated with calcineurin inhibitors plus mycophenolate-based immunosuppression. Results: Recent pooled analyses of 3 randomized controlled trials in de novo kidney transplant patients, where immunosuppression was based on cyclosporine with either mycophenolate or everolimus, showed that patients who received everolimus had significantly less cytomegalovirus events (cytomegalovirus viremia, cytomegalovirus infection/disease) than those who received mycophenolate, with or without cytomegalovirus as prophylaxis. An even more recent prospective randomized controlled study on de novo kidney transplant patients with no anticytomegalovirus prophylaxis demonstrated that everolimus-based immunosuppression plus low-dose tacrolimus was associated with significantly less cytomegalovirus infection than standard-dose tacrolimus plus mycophenolate. Conclusions: The potential benefits are not fully known of such a therapeutic strategy to limit the longterm indirect effects mediated by cytomegalovirus infections.

Real-World Treatment Patterns of Antiviral Prophylaxis for Cytomegalovirus Among Adult Kidney Transplant Recipients: A Linked USRDS-Medicare Database Study

“…The use of certain T-cell depleting agents (ATG, alemtuzumab) (13,15,16) and high doses of immunosuppressive agents have been shown to be associated with increases in the risk of CMV (7). Additionally, younger age (17,18), African American race, use of mammalian target of rapamycin inhibitors (19)(20)(21)(22)(23)(24), and PRA ≥80% (25) are associated with decreased risk of CMV infection, and hence, decreased need for CMV prophylaxis. There is some evidence that basiliximab is negatively associated with CMV infection and the need for prophylaxis (17,26).…”

The Host Cell ViroCheckpoint: Identification and Pharmacologic Targeting of Novel Mechanistic Determinants of Coronavirus-Mediated Hijacked Cell States

“…For instance, the MAPK inhibitor trametinib, one of the top ViroTreat hits for SARS-CoV, was shown to inhibit MERS-CoV replication in vitro (5,20), as well as influenza A virus both in vitro and in vivo (67). Similarly, everolimus, an mTOR inhibitor identified by ViroTreat, has also been shown to inhibit MERS-CoV (5,20) and cytomegalovirus(68) replication in vitro, as well as to reduce incidence of cytomegalovirus infections following kidney transplant (69). Among tyrosine kinase inhibitors identified by ViroTreat, dasatinib was previously described to inhibit MERS-CoV (5,19) and HIV-1 (70) replication in vitro; while erlotinib was shown to inhibit dengue(71), hepatitis C(72) and ebola (73) replication.…”

Prevention and Management of CMV Infections after Liver Transplantation: Current Practice in German Transplant Centers

“…Everolimus, an mTOR inhibitor, downregulates cap-dependent translation from messenger RNA into proteins, which is triggered through activation of the phosphatidylinositol 3-kinase-Akt-mTOR pathway. As CMV uses the same pathways for replication, everolimus has additional virostatic effects on CMV at early stages of infection [69,70]. Therefore, the choice of immunosuppressive agents might be an adjunctive to antiviral strategies to modify the development of CMV-related complications.…”

“…There are several large meta-analyses showing that the use of mTOR inhibitors reduces CMV replication by 2-to > 3-fold vs. MMF in various types of solid organ transplantation [70,[72][73][74], and a switch from MMF to mTOR inhibitor as an additive therapy to tacrolimus improves the CMV infection-free survival [75]. Similarly, mTOR inhibitor-based immunosuppression reduces viral replication by 2.3-to 2.5-fold [76] and mTOR-containing immunosuppressive regimes reduced the incidence of CMV infection in kidney transplant patients in comparison to CNI-based immunosuppression [77].…”