Drug-resistant cytomegalovirus: clinical implications of specific mutations

Cytomegalovirus (CMV) infection can be refractory to antiviral treatment. Although refractoriness can be due impaired host immunity, it can also be due to viral mutations that confer antiviral drug resistance. This article provides a succinct review of mutations in CMV genes that confer drug resistance, and offer guidance on clinical management.

Recent advances in medical and research technology have confirmed traditional mutations and identified novel ones that confer resistance to current antiviral drugs. Resistance to ganciclovir is commonly predicted by mutations in UL97, which encode for viral kinase that catalyzes its phosphorylation. Mutations in UL54, which encode for CMV DNA polymerase, confer resistance (or cross-resistance) to ganciclovir, cidofovir and/or foscarnet. Resistance to letermovir, the new drug approved for CMV prophylaxis in allogeneic hematopoietic stem cell transplant recipients, has emerged and mapped most commonly to mutations in UL56 and less commonly UL51 and UL89, the gene complex that encode for viral terminase.

Mutations in CMV genes can be selected during antiviral drug exposure, and manifests phenotypically as nonresponsive drug-resistant disease. Knowledge of specific mutations informs clinicians in selecting appropriate antivirals for managing transplant patients with CMV disease.