Antiviral resistance testing for DNA viruses in immunocompromised patients: Mechanisms, clinical utility, and limitations

Immunocompromised patients, including transplant recipients, individuals receiving chemotherapy or chronic immunosuppression, and those with primary or acquired immunodeficiency, are at increased risk for severe viral infections and treatment failure due to antiviral drug resistance (ADR). In these populations, prolonged viral replication under antiviral pressure promotes the emergence of resistance-associated mutations (RAMs). ADR testing using phenotypic and genotypic approaches can support effective clinical management, particularly for clinically actionable double-stranded DNA viruses such as cytomegalovirus and herpes simplex virus. Genotypic testing offers faster turnaround time (TAT) and improved scalability but is limited to known resistance mutations. Phenotypic testing enables functional assessment of antiviral susceptibility but is labor-intensive and less widely available. This review summarizes available evidence on antiviral resistance mechanisms and testing for double-stranded DNA viruses, emphasizing both their clinical utility and current limitations.