Clinical development of letermovir and maribavir: Overview of human cytomegalovirus drug resistance

The prevention and treatment of human cytomegalovirus (HCMV) infections is based on the use of antiviral agents that currently target the viral DNA polymerase and that may cause serious side effects. The search for novel inhibitors against HCMV infection led to the discovery of new molecular targets, the viral terminase complex and the viral pUL97 kinase. The most advanced compounds consist of letermovir (LMV) and maribavir (MBV). LMV inhibits the cleavage of viral DNA and its packaging into capsids by targeting the HCMV terminase complex. LMV is safe and well tolerated and exhibits pharmacokinetic properties that allow once daily dosing. LMV showed efficacy in a phase III prophylaxis study in hematopoietic stem cell transplant (HSCT) recipients seropositive for HCMV. LMV was recently approved under the trade name Prevymis (TM) for prophylaxis of HCMV infection in adult seropositive recipients of an allogeneic HSCT. Amino acid substitutions conferring resistance to LMV selected in vitro map primarily to the pUL56 and rarely to the pUL89 and pUL51 subunits of the HCMV terminase complex. MBV is an inhibitor of the viral pUL97 kinase activity and interferes with the morphogenesis and nuclear egress of nascent viral particles. MBV is safe and well tolerated and has an excellent oral bioavailability. MBV was effective for the treatment of HCMV infections (including those that are refractory or drug resistant) in transplant recipients in two phase II studies and is further evaluated in two phase III trials. Mutations conferring resistance to MBV map to the UL97 gene and can cause cross-resistance to ganciclovir. MBV-resistant mutations also emerged in the UL27 gene in vitro and could compensate for the inhibition of pUL97 kinase activity by MBV. Thus, LMV and probably MBV will broaden the armamentarium of antiviral drugs available for the prevention and treatment of HCMV infections.