August 15, 2025

Emergence of Antiviral Drug Resistance in Congenital Cytomegalovirus Infection During Treatment: An Updated Review of Literature and Case Report

Key Points

Drug resistance emerged in a newborn with severe congenital cytomegalovirus infection, necessitating combined therapy.
Two mutations (PK-M460V, PK-C592G) indicated ganciclovir resistance, while the patient responded to combination therapy.
Monitoring methods included Sanger sequencing and whole-genome sequencing to assess antiviral resistance.
This case underscores the importance of ongoing research into treatment strategies for severe congenital cytomegalovirus infections.

Abstract

Congenital cytomegalovirus (cCMV) is the most common congenital infection worldwide and a major cause of sensorineural hearing loss. A limited number of infants present with severe symptoms, including end-organ disease, developmental delay and neurologic sequelae. Infants with severe cCMV benefit from 6 months of valganciclovir (VGCV) therapy. We describe a newborn with a severe cCMV infection after primary maternal infection in the first trimester of pregnancy. Cytomegalovirus (CMV) viral load and genotype were monitored throughout infection. Prospective resistance analysis was performed by Sanger sequencing of the DNA polymerase (UL54) and protein kinase (PK; UL97) genes. Whole-genome sequencing was achieved with RNA probe-based target enrichment. Prospective resistance analysis identified 2 PK ganciclovir resistance mutations following an increase in viral load under VGCV treatment. PK-M460V and PK-C592G were found as mixed viral populations and combination foscarnet + VGCV therapy was started in response. The patient responded to treatment and viral load decreased, but did not reach undetectable levels during follow-up. A pure population of virus carrying the PK-M460V substitution was established. The patient is currently doing well with limited sequelae. Limited data exist on the prevalence and clinical consequences of drug resistance in cCMV. The case described here depicts the surveillance of viral infection and the emergence of drug resistance, which was managed by administering combination antiviral therapy. It emphasizes the need for further research into the management of severe cCMV infections and the need for monitoring antiviral drug resistance to implement adapted treatment strategies.

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