Cytomegalovirus antiviral resistance: characterization of results from clinical specimens

Abstract

Background: Cytomegalovirus (CMV) infections are a major cause of disease among immunocompromised patients. Prolonged antiviral therapy is often necessary to prevent or treat CMV disease, and may lead to development of antiviral resistance (AVR). Timely identification of viral mutations conferring resistance is essential for effective patient management.

Methods: Amplification by polymerase chain reaction followed by bi-directional nucleotide sequencing was performed for relevant regions of the CMV UL97 and UL54 genes. Results from 570 samples submitted to a commercial reference laboratory for testing were reviewed and characterized with respect to the frequency of mutations detected, association with viral load (VL), and consistency of results in a subset of patients with multiple samples. Only AVR mutations confirmed by marker transfer experiments were included in the analysis.

Results: AVR mutations were identified in 176 (30.9%) of the 570 samples evaluated. A total of 17 different UL97 mutations and 29 different UL54 mutations were detected. A single mutation per sample was most commonly observed, although 61 samples (10.7%) had >1 mutation, with 40 samples (7.0%) having mutations in both UL97 and UL54 genes. The VL of samples with AVR mutations ranged from 2.03-7.15 log10 copies/mL, and the VL did not differ significantly from samples without AVR mutations. A subset of patients (N = 85) had >1 sample tested, and 48.2% of these patients returned the same result for each sample analyzed, while the remainder had a different results.

Conclusions: Genomic mutations conferring resistance in CMV to antiviral drugs were commonly identified in samples submitted from clinical patients to a reference laboratory for AVR testing. Mutations were identified over the full range of VLs and no correlation was identified between VL and the presence of AVR mutations. In patients with multiple samples submitted for analysis, approximately half of the patients had samples with variable results when the initial result was compared to subsequent results.

Keywords: UL54; UL97; antiviral; clinical; cytomegalovirus; resistance.