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Cytomegalovirus (CMV) Genotype 

Test codes: 13947, 13948, 13949

  • Cytomegalovirus (CMV) Genotype (UL97 / UL54 / UL56)
  • Cytomegalovirus (CMV) Genotype (UL97 / UL54)
  • Cytomegalovirus (CMV) Genotype (UL56)

Currently, 5 FDA-approved anti-CMV drugs are available for treatment or prophylaxis of CMV infection. These include valganciclovir,1 cidofovir,2 foscarnet,3 maribavir,4 and letermovir.5

CMV genotyping detects mutations in specific viral genes that are associated with drug resistance to anti-CMV drugs. Mutations in the UL97 phosphotransferase gene confer resistance to ganciclovir6,7 and maribavir.8 Mutations in the UL54 polymerase gene also confer resistance to ganciclovir, as well as to cidofovir and foscarnet.6, 7 Mutations in the UL56 gene, a part of the viral terminase complex, confer resistance to letermovir.6,9,10

The CMV genotyping test should be considered for patients with CMV infections that are refractory to treatment. Several indicators of therapeutic refractoriness have been proposed, including an increase in CMV DNA viral load of 0.5 to 1 log after 2 weeks of adequate treatment or a decrease of <1 log in CMV DNA viral load after several weeks of treatment.11-13

Yes, professional societies have published the following guidelines for using CMV genotyping:

  • Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7)12
  • The Third International Consensus Guidelines on the Management in Solid Organ Transplantation11
  • American Society for Transplantation and Cellular Therapy Series: #4 - Cytomegalovirus treatment and management of resistant or refractory infections after hematopoietic cell transplantation13

Compared to Sanger sequencing, NGS can detect resistance mutations at a lower threshold (<15%), while demonstrating excellent agreement with Sanger sequencing for mutations that are present above the limit of detection (~25%) for Sanger sequencing.14-16 Therefore, NGS may detect emerging resistance mutations sooner than Sanger sequencing.14

CMV resistance is predicted based on the presence of mutations in the UL97, UL54, and UL56 genes; clinical significance of these mutations has been established in the scientific literature through recombinant phenotyping (marker transfer).6,7,17

The patient report includes mutations detected in 15% or more of the viral species. One limitation is that not all CMV mutations have been subjected to recombinant phenotyping and their clinical impact on drug resistance is undetermined. A second limitation is that some mutations may be present below the 15% reporting threshold, but the clinical significance of these minority mutations is not known.

Example report with no resistance predicted

Cytomegalovirus (CMV) Genotype (UL97 / UL54 / UL56)

Ganciclovir Resistance Not Predicted

Maribavir Resistance Not Predicted

Foscarnet Resistance Not Predicted

Cidofovir Resistance Not Predicted

Letermovir Resistance Not Predicted

 

Mutations detected

UL97 Kinase Mutations: None

UL54 Polymerase Mutations: None

UL56 Terminase Mutations: None

 

Example Report With Resistance predicted

Cytomegalovirus (CMV) Genotype (UL97 / UL54 / UL56)

Ganciclovir Resistance Predicted

Maribavir Resistance Not Predicted

Foscarnet Resistance Predicted

Cidofovir Resistance Predicted

Letermovir Resistance Not Predicted

 

Mutations Detected

UL97 Kinase Mutations: M460V, A594V

UL54 Polymerase Mutations: D588N

UL56 Terminase Mutations: None

No. The test code 13947 includes UL97, UL54, and UL56 genotyping. However, test code 13948 includes UL97 and UL54 genotyping, and test code 13949 includes only UL56 genotyping for patients who have only been treated with letermovir.

References

  1. FDA Label for VALCYTE. https://ndclist.com/ndc/0004-0038/label
  2. FDA Label for CIDOFOVIR DIHYDRATE. https://ndclist.com/ndc/23155-216/label
  3. FDA Label for FOSCARNET SODIUM. https://ndclist.com/ndc/0143-9192/label
  4. FDA Label for LIVTENCITY (maribavir). https://ndclist.com/ndc/64764-800/label
  5. FDA Label for PREVYMIS (letermovir). https://ndclist.com/ndc/0006-3075/label
  6. Chou S. Advances in the genotypic diagnosis of cytomegalovirus antiviral drug resistance. Antiviral Res. 2020;176:104711. doi: 10.1016/j.antiviral.2020.104711.
  7. Lurain NS, Chou S. Antiviral drug resistance of human cytomegalovirus. Clin Microbiol Rev. 2010;23(4):689-712. doi: 10.1128/CMR.00009-10.
  8. Chou S, Song K, Wu J, Bo T, Crumpacker C. Drug resistance mutations and associated phenotypes detected in clinical trials of maribavir for treatment of cytomegalovirus infection. J Infect Dis. 2022;226(4):576-584. doi: 10.1093/infdis/jiaa462.
  9. Komatsu TE, Hodowanec AC, Colberg-Poley AM, et al. In-depth genomic analyses identified novel letermovir resistance-associated substitutions in the cytomegalovirus UL56 and UL89 gene products. Antiviral Res. 2019;169:104549. doi: 10.1016/j.antiviral.2019.104549.
  10. Strizki JM, Diamond TL, Teal VL, et al. Cytomegalovirus antiviral resistance among participants in the phase 3 trial of letermovir vs valganciclovir prophylaxis in kidney transplant recipients. J Infect Dis. 2024;jiae287. doi: 10.1093/infdis/jiae287.
  11. Kotton CN, Kumar D, Caliendo AM, et al. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018;102(6):900-931. doi: 10.1097/TP.0000000000002191.
  12. Ljungman P, de la Camara R, Robin C, et al. Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis. 2019;19(8):e260-e272. doi: 10.1016/S1473-3099(19)30107-0.
  13. Yong MK, Shigle TL, Kim YJ, et al. American Society for Transplantation and Cellular Therapy Series: #4 - Cytomegalovirus treatment and management of resistant or refractory infections after hematopoietic cell transplantation. Transplant Cell Ther. 2021;27(12):957-967. doi: 10.1016/j.jtct.2021.09.010.
  14. Garrigue I, Moulinas R, Recordon-Pinson P, et al. Contribution of next generation sequencing to early detection of cytomegalovirus UL97 emerging mutants and viral subpopulations analysis in kidney transplant recipients. J Clin Virol. 2016;80:74-81. doi: 10.1016/j.jcv.2016.04.017.
  15. Grgic I, Gorenec L. Human Cytomegalovirus (HCMV) Genetic Diversity, Drug Resistance Testing and Prevalence of the Resistance Mutations: A Literature Review. Trop Med Infect Dis. 2024;9(2). doi: 10.3390/tropicalmed9020049.
  16. von Bredow B, Caldera JR, Cerón S, et al. Clinical next-generation sequencing assay combining full-length gene amplification and shotgun sequencing for the detection of CMV drug resistance mutations. J Clin Virol. 2023;165:105520. doi: 10.1016/j.jcv.2023.105520.
  17. Chou S. Recombinant phenotyping of cytomegalovirus UL97 kinase sequence variants for ganciclovir resistance. Antimicrob Agents Chemother. 2010;54(6):2371-2378. doi: 10.1128/AAC.00186-10.

 

 

This FAQ is provided for informational purposes only and is not intended as medical advice. A physician’s test selection and interpretation, diagnosis, and patient management decisions should be based on the physician’s education, clinical expertise, and assessment of the patient.

 

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