Abstract
The thrombopoietin receptor agonist eltrombopag was successfully used against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to immunomodulatory and antiviral drugs. These effects were ascribed to the effects of eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV replication in human fibroblasts and adult mesenchymal stem cells infected with six different virus strains and drug-resistant clinical isolates. Eltrombopag also synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. Time-of-addition experiments suggested that eltrombopag interfered with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and the addition of Fe3+ prevented the anti-HCMV effects, indicating that it inhibits HCMV replication via iron chelation. This may be of particular interest for the treatment of cytopenias after hematopoietic stem cell transplantation, as HCMV reactivation is a major reason for transplantation failure. Since therapeutic eltrombopag concentrations are effective against drug-resistant viruses, and synergistically increase the effects of ganciclovir, eltrombopag is also a drug-repurposing candidate for the treatment of therapy-refractory HCMV disease.
Highlights
Eltrombopag is a thrombopoietin receptor agonist that is used for the treatment of thrombocytopenia, including hepatitis C virus-associated thrombocytopenia [1,2,3]
A case report described the use of eltrombopag in an immunocompetent patient who suffered from human cytomegalovirus (HCMV)-associated thrombocytopenia [17]
We found that eltrombopag exerts anti-HCMV effects via iron chelation
Summary
Eltrombopag is a thrombopoietin receptor ( known as c-Mpl or MPL) agonist that is used for the treatment of thrombocytopenia, including hepatitis C virus-associated thrombocytopenia [1,2,3]. Its use has been suggested for the treatment of cytopenias after hematopoietic stem cell transplantations and case reports support its safety and efficacy [4,5,6,7,8,9]. Anti-HCMV drugs, including ganciclovir, cidofovir, and foscarnet, are available, but their use is associated with severe side effects [13]. The use of ganciclovir (and its prodrug valganciclovir), the mainstay treatment for cytomegalovirus disease, is associated with severe hematological side effects, including thrombocytopenia [14,15,16]. A case report described the use of eltrombopag in an immunocompetent patient who suffered from human cytomegalovirus (HCMV)-associated thrombocytopenia [17]. Immunosuppressive treatment for thrombocytopenia (prednisone, intravenous immunoglobulin, dapsone), in combination with antiviral therapy (ganciclovir/valganciclovir, HCMV hyperimmune globulin), only resulted in a temporary platelet response with subsequent relapse. We found that eltrombopag exerts anti-HCMV effects via iron chelation
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