Management of Cytomegalovirus Infections in the Era of the Novel Antiviral Players, Letermovir and Maribavir

Abstract

Cytomegalovirus (CMV) infections may increase morbidity and mortality in immunocompromised patients. Until recently, standard antiviral drugs against CMV were limited to viral DNA polymerase inhibitors (val)ganciclovir, foscarnet and cidofovir with a risk for cross-resistance. These drugs may also cause serious side effects. This narrative review provides an update on new antiviral agents that were approved for the prevention and treatment of CMV infections in transplant recipients. Letermovir was approved in 2017 for CMV prophylaxis in CMV-seropositive adults who received an allogeneic hematopoietic stem cell transplant. Maribavir followed four years later, with an indication in the treatment of adult and pediatric transplant patients with refractory/resistant CMV disease. The target of letermovir is the CMV terminase complex (constituted of pUL56, pUL89 and pUL51 subunits). Letermovir prevents the cleavage of viral DNA and its packaging into capsids. Maribavir is a pUL97 kinase inhibitor, which interferes with the assembly of capsids and the egress of virions from the nucleus. Both drugs have activity against most CMV strains resistant to standard drugs and exhibit favorable safety profiles. However, high-level resistance mutations may arise more rapidly in the UL56 gene under letermovir than low-grade resistance mutations. Some mutations emerging in the UL97 gene under maribavir can be cross-resistant with ganciclovir. Thus, letermovir and maribavir now extend the drug arsenal available for the management of CMV infections and their respective niches are currently defined.

Keywords: antiviral drugs; cytomegalovirus; drug resistance; immunocompromised patients; letermovir; maribavir.

Figure 1

Chemical structures of the different DNA polymerase inhibitors, letermovir and maribavir. Concentrations of antivirals that reduce cytomegalovirus growth by 50% (EC₅₀) are also indicated.

Figure 2

Strategies used for the prevention of CMV infection in solid organ transplant (SOT) and hematopoietic stem cell (HSC) recipients. Universal prophylaxis is based on the administration of antivirals (blue line) to all at-risk patients for 3 or 6 months after transplantation (Tx). During pre-emptive therapy (PET), the antiviral (blue triangle) is administered when the viral load (determined in blood every week for 3 or 6 months) is higher than a defined threshold (red circle) and stopped when the viral is below the threshold (white circle). D⁺/R⁻, donor positive/recipient negative for CMV; R⁺, recipient positive for CMV. Adapted from Limaye et al. [5].

Figure 3

Confirmed cytomegalovirus resistance mutations to DNA polymerase inhibitors. Panel (A) shows a representation of the pUL97 kinase with its conserved regions (grey boxes) and the localization of amino acid substitutions conferring resistance to ganciclovir (vertical bars). The ATP-binding site, the phosphate transfer (P-transfer) domain, the nucleoside-binding site (NBS) and some regions conserved among the protein kinase family (i.e., I, II, III, VIB, VII, VIII and IX) are indicated above the boxes. The shaded area corresponds to the codon 590–603 region where different amino acid deletions were identified (i.e., deletions 591–594; 591–607; 595; 595–603; 600 and 601–603). Panel (B) shows a representation of pUL54 DNA polymerase with its conserved regions (grey boxes) and the localization of amino acids associated with resistance to ganciclovir (GCV^R), foscarnet (FOS^R) and/or cidofovir (CDV^R) (colored bars). The Roman numbers (I to VII) and δ-region C correspond to conserved regions in the polymerase domain. Exo I, Exo II and Exo III are conserved motifs in the exonuclease domain.

Figure 4

Novel targets for anti-cytomegalovirus inhibitors. During CMV replication, the viral DNA synthesis proceeds by a rolling circle mechanism. This process involves the viral pUL54 DNA polymerase (pol), which is the target of ganciclovir-triphosphate (GCV-TP), cidofovir-diphosphate (CDV-DP) and foscarnet (FOS). The viral terminase complex formed by the pUL56, pUL89 and pUL51 subunits is involved in the cleavage of DNA concatemers at Pac site and their packaging into capsids. Letermovir (LMV) is an inhibitor of the viral terminase complex and more specifically of the pUL56 subunit. On the other hand, pUL97 kinase is involved in the phosphorylation of several viral and host proteins. pUL97 kinase also participates in the disruption of the nuclear lamina and in the nuclear egress of virions. Maribavir (MBV) is a selective inhibitor of the pUL97 kinase activity.

Figure 5

Confirmed amino acid changes associated with resistance to letermovir detected in CMV laboratory strains and clinical specimens. Panel (A) shows amino acid substitutions in the pUL56 subunit associated with letermovir resistance (vertical bars). Grey boxes represent the conserved regions of pUL56, which are numbered I to XII. Hatched boxes represent the two variable regions, which are labeled as VRI and VRII. Panel (B) shows amino acid substitutions in the pUL89 subunit conferring resistance to letermovir (vertical bars). Grey boxes represent the conserved regions in pUL89, which are numbered I to XII. Panel (C) shows amino acid substitutions in pUL51 subunit conferring letermovir resistance (vertical bars). In all panels, vertical bars show amino acid substitutions associated with letermovir resistance identified in laboratory strains (black) and clinical specimens (red).

Figure 6

Confirmed amino acid changes associated with resistance to maribavir detected in CMV laboratory strains and clinical specimens. Panel (A) shows amino acid substitutions in the pUL97 kinase conferring CMV resistance to maribavir (vertical bars in blue) or to maribavir/ganciclovir (vertical bars in green). Grey boxes represent the ATP-binding site, the phosphate transfer (P-transfer) domain, the nucleoside-binding site (NBS) and some regions conserved among the protein kinase family (i.e., I, II, III, VIB, VII, VIII and IX). Panel (B) shows amino acid substitutions in the pUL27 associated with resistance to maribavir (vertical bars in black). The hatched box represents codons 301–311 deletion that confers maribavir resistance. Grey boxes represent the conserved regions in pUL27, which are numbered I to IV.