CMV Resistance: Letermovir, Ganciclovir, Foscarnet, Cidofovir

Human Cytomegalovirus (CMV) infections are a major cause of morbidity and mortality among immunocompromised patients. Patient outcomes depend on effective prophylaxis and treatment with antiviral therapies, including ganciclovir, valganciclovir, foscarnet, and cidofovir. Additionally, letermovir is approved specifically for prophylactic use in hematopoietic stem cell transplant (HSCT) patients. Proper patient management requires rapid detection of resistance. Laboratory testing should be used to confirm the occurrence of drug resistance, as treatment modification based solely on clinical suspicion may result in added toxicity and increased complexity in patient management. The CMV Resistance: Letermovir, Ganciclovir, Foscarnet, Cidofovir sequencing assay is designed to detect identified mutations in the UL54, UL56 and UL97 genes of CMV. The use of genotypic sequencing offers a rapid turnaround time, a broad range of antiviral resistance information, and the ability to provide information concerning new drugs as they become available.¹

About CMV Resistance Testing
Cytomegalovirus, also known as human herpesvirus 5, is a highly ubiquitous, double-stranded DNA virus in the Betaherpesvirinae subfamily. Serological studies have demonstrated that a majority of adults in the United States have been infected with CMV.^2,3 Following primary infection, CMV establishes a lifelong latent infection, which may reactivate in both immunocompetent and immunocompromised individuals. In immunocompromised patients, primary or reactivated CMV infections can cause a range of symptoms like fever and fatigue and diseases that may include interstitial pneumonia, gastrointestinal infection, central nervous system disease, hepatitis, retinitis, and encephalitis. CMV reactivations have also been reported to occur frequently in critically ill immunocompetent patients and are associated with prolonged hospitalization or death.⁴ Due to the severity of these conditions and even life threatening outcomes, treatment of CMV diseases with antiviral drugs is common. Additionally, prophylactic treatment with antiviral drugs is used to prevent the occurrence of disease in high-risk patients. Anti-CMV drugs currently available for either treatment or prophylaxis include ganciclovir, valganciclovir (the orally administered prodrug), foscarnet, cidofovir, and letermovir. Ganciclovir targets both UL97 and UL54, while cidofovir and foscarnet target only UL54.  The newest CMV drug, Letermovir, targets subunit 2 of the viral terminase complex (UL56).  Viral UL97 phosphotransferase gene, and UL54 polymerase genotypic mutations are well documented mechanisms of resistance to these antiviral drugs.^5,6  Mutations within UL56 have been shown to confer resistance to Letermovir.⁷ Drug resistance should be suspected if quantitative CMV PCR viral load values either persist or increase, or if CMV disease presents, after several weeks of treatment with an appropriate dose.⁵

Conventional PCR followed by genotypic sequencing. Sequencing analysis provides information on selected locations in three genes involved in CMV antiviral resistance: UL54, UL56 and UL97. This test has not been cleared or approved for diagnostic use by the U.S. Food and Drug Administration.

CMV sequencing analysis provides information about selected locations in three genes, UL54, UL56, and UL97 involved in CMV antiviral resistance.