Clinical background

CMV is a member of the Herpesviridae family that infects about 60% of people in the United States by age 40.1 After initial infection, CMV remains latent indefinitely and can reactivate at any time.2,3 Although CMV infections are usually asymptomatic or mild in healthy people, they are more serious in people with compromised immune systems, such as transplant recipients and people with HIV.3,4 In these patients, initial or reactivated CMV infection can cause severe disease, transplant rejection, and death.3–5

Although CMV infection can usually be treated or prevented with antiviral drugs (ie, ganciclovir/valganciclovir, cidofovir, foscarnet, letermovir, and maribavir), the virus can develop genetic mutations that confer resistance to 1 or more of these drugs.3,4 Resistance can make the drug(s) ineffective and is associated with greater morbidity and mortality.3,4 About 5% to 12% of transplant recipients treated with ganciclovir develop resistance,6 but the prevalence is higher in certain patient populations, including2,5,6

• Lung and intestinal transplant recipients
• Transplant recipients with donor-positive, recipient-negative CMV serostatus
• Patients with prolonged exposure to subtherapeutic doses of anti-CMV drugs
• Patients who are highly immunosuppressed

According to guidelines from the American Society of Transplantation Infectious Diseases Community of Practice and the Transplantation Society International CMV Consensus Group, antiviral resistance should be suspected when CMV infection is refractory to treatment.2,6 CMV infection is considered refractory when, after ≥2 weeks of appropriately dosed antiviral therapy, CMV viral load fails to decrease by >1 log10 or CMV disease fails to improve.2,6,7

According to the same guidelines, suspected antiviral resistance should be confirmed by genotypic resistance testing, which involves testing for CMV mutations that are known to confer resistance. Most resistance-conferring mutations are found in the UL54, UL56, and UL97 genes.3,4,6 Because drug targets differ, mutations in certain genes confer resistance to certain drugs (Table 1).3,4

Table 1. Genes Associated With Resistance to Anti-CMV Drugs

Quest Diagnostics offers 3 genotypic tests for CMV drug resistance that detect mutations in the UL54, UL56, and/or UL97 genes (Table 2). Detected mutations are compared to a database of known resistance-conferring mutations to predict whether the infection is resistant to each anti-CMV drug. Testing all 3 genes (test code 13947) predicts resistance for all 5 FDA-approved anti-CMV drugs, but testing fewer genes may be appropriate for certain patients, including those for whom letermovir resistance does not need to be determined (test code 13948) and those for whom only letermovir resistance needs to be determined (test code 13949).

Table 2. Available Genotypic Tests for CMV Drug Resistance

The genotypic tests offered by Quest use next-generation sequencing (NGS), which is more sensitive than traditional Sanger sequencing, potentially allowing resistance to be detected earlier.3 In particular, NGS tests can detect smaller mutant subpopulations than Sanger sequencing tests (mutation reporting threshold: 15% for Quest NGS tests vs 20%-30% for Sanger sequencing tests).3–5