Current and Emerging Antiviral Agents in the Prevention and Treatment of Cytomegalovirus in Pediatric Transplant Recipients

Abstract

Despite current prophylaxis regimens, cytomegalovirus (CMV) is common in hematopoietic cell transplantation (HCT) and solid organ transplantation (SOT) and remains a significant cause of morbidity and mortality. Newer antiviral medications are reshaping the landscape for prevention and treatment of CMV DNAemia, infection, and disease. Letermovir is approved for CMV prevention in adult HCT patients and is attractive due to the absence of marrow suppression seen with ganciclovir/valganciclovir. Letermovir should not be routinely used for CMV treatment due to its low threshold for resistance. Maribavir is approved for the treatment of refractory or resistant CMV disease in HCT and SOT recipients ≥12 years of age, though it has no current role in CMV prevention. More research is needed to fully elucidate the roles, efficacy, and safety of these newer agents in prevention and treatment of CMV in pediatric transplant recipients.

Keywords: antiviral; cytomegalovirus; pediatric; resistance; transplantation.

Figure 1.

Mechanisms of activity of anti-CMV antivirals. Ganciclovir (GCV) is a nucleoside analog that requires initial phosphorylation by the viral protein kinase encoded by UL97. It is subsequently di- and tri-phosphorylated by host cellular kinases. Ganciclovir triphosphate inhibits CMV DNA polymerase (UL54) activity and also serves as substrate for the enzyme, substituting for deoxyguanosine triphosphate (dGTP) during chain elongation, slowing viral DNA synthesis. Cidofovir (CDV) is not a substrate for UL97 but is di- and tri-phosphorylated by host kinases, as with GCV monophosphate, and serves as competitive inhibitor of DNA polymerase. Foscarnet (FOS) is a noncompetitive inhibitor of CMV DNA polymerase, blocking the pyrophosphate binding site and preventing cleavage of deoxynucleotide triphosphates. Maribavir (MBV) is a potent inhibitor of the UL97 kinase, which is involved in phosphorylation of a number of viral proteins, leading to inhibition of multiple stages of CMV DNA replication, viral encapsulation, and nuclear egress. Letermovir (LET) inhibits the CMV DNA terminase complex by binding to its pUL56 subunit. The enzymatic targets are also the main sites of resistance for each drug: GCV–UL97 > UL54; CDV–UL54; FOS–UL54; MBV–UL97; LET–UL56 > UL89. Figure was made using Biorender. Abbreviations: CDV, cidofovir; CMV, cytomegalovirus; FOS foscarnet; GCV, ganciclovir; LET, letermovir; MBV, maribavir; NUC, nucleotide.