CMV Resistance: Maribavir, 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 maribavir, letermovir, cidofovir, ganciclovir, valganciclovir and foscarnet. 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: Maribavir, 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
| Assay | UL | Gene |
| *NEW* CMV Resistance: Maribavir, Letermovir, Ganciclovir, Foscarnet, Cidofovir | 54, 56 and 97 | Terminase, Polymerase and Phosphotransferase |
| *NEW* CMV Resistance: Maribavir, Ganciclovir, Foscarnet, Cidofovir | 54 and 97 | Polymerase and Phosphotransferase |
| CMV Resistance: Letermovir | 56 only | Terminase |
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, letermovir, and maribavir (Livtencity™). Maribavir targets UL97, and ganciclovir targets both UL97 and UL54. Cidofovir and foscarnet target UL54 alone. Letermovir, targets subunit 2 of the viral terminase complex, known as UL56. Viral UL97 phosphotransferase gene, and UL54 polymerase genotypic mutations are well documented mechanisms of resistance to these antiviral drugs.5,6,9 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.
SpecificityCMV sequencing analysis provides information about selected locations in three genes, UL54, UL56, and UL97 involved in CMV antiviral resistance.
2-4 business days from receipt of specimen.
| Specimen Type | Test Code | CPT Code | NY Approved | Volume | Assay Range | Special Instructions |
|---|---|---|---|---|---|---|
| plasma | 33125 | 87910 x 3 | Yes | 2 mL (min. 1000 IU/mL) |
Mutations in the UL54, UL56 and UL97 genes will be reported as Resistant/None Detected. Interpretation of gene mutations and association with antiviral resistance, including maribavir, ganciclovir, foscarnet, and cidofovir and letermovir will be provided with the report. See CMV Resistance Mutations for more information. |
|
Ship Monday through Friday. Friday shipments must be labeled for Saturday delivery. All specimens must be labeled with patient's name and collection date. A Eurofins Viracor test requisition form must accompany each specimen. Multiple tests can be run on one specimen. Ship specimens FedEx Priority Overnight® to: Eurofins Viracor, 18000 W 99th St. Ste, #10, Lenexa, KS 66219.
Causes for RejectionCMV DNA concentrations too low to allow antiviral resistance testing (see above for minimum volume and viral load), whole blood frozen, specimens beyond their acceptable length of time from collection as listed in the specimen handling, or specimen types other than those listed.
Specimens are approved for testing in New York only when indicated in the Specimen Information field above. The CPT codes provided are based on Eurofins Viracor's interpretation of the American Medical Association's Current Procedural Terminology (CPT) codes and are provided for informational purposes only. CPT coding is the sole responsibility of the billing party. Questions regarding coding should be addressed to your local Medicare carrier. Eurofins Viracor assumes no responsibility for billing errors due to reliance on the CPT codes illustrated in this material.
References1. Kotton, C. N., Kumar, D., Caliendo, A. M., Åsberg, A., Chou, S., Danziger-Isakov, L., & Humar, A. (2013). Updated International Consensus Guidelines on the Management of Cytomegalovirus in Solid-Organ Transplantation. Transplantation Journal, 96(4), 333-360. doi:10.1097/tp.0b013e31829df29d
2. Bate SL, Dollard SC, Cannon MJ. Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988-2004. Clin Infect Dis. 2010 Jun 1;50(11):1439-47.
3. Staras SA, Dollard SC, Radford KW, Flanders WD, Pass RF, Cannon MJ. Seroprevalence of cytomegalovirus infection in the United States, 1988-94. Clin Infect Dis. 2006 Nov 1;43(9):1143-51.
4. Limaye A, Kirby K, Rubenfeld G, et al. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA. 2008;300(4):413-22.
5. Lurain NS, Chou S. Antiviral drug resistance of human cytomegalovirus. Clin Microbiol Rev. 2010 Oct;23(4):689-712.
6. Hakki M, Chou S. The biology of cytomegalovirus drug resistance. Curr Opin Infect Dis. 2011 Dec;24(6):605-11.
7. Chou, S. (2015, October 01). Rapid In Vitro Evolution of Human Cytomegalovirus UL56 Mutations That Confer Letermovir Resistance. Retrieved March 12, 2018 from http://aac.asm.org/content/59/10/6588.full
8. Francisco, M. M. (2017, December 21). Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation | NEJM. Retrieved March 12, 2018, from http://www.nejm.org/doi/full/10.1056/NEJMoa1706640
9. Chou, S. (2020, Jan 09) Advances in the genotypic diagnosis of cytomegalovirus antiviral drug. Antiviral Resistance. Retrieved November 1, 2021 from https://doi.org/10.1016/j.antiviral.2020.104711.