Cytomegalovirus infection and drug resistance emergence during letermovir salvage therapy in a pediatric SCID patient

Abstract

Cytomegalovirus (CMV) infection is a common complication in newborns with severe combined immunodeficiency (SCID). Prolonged antiviral treatment in immunocompromised patients increases the risk of the emergence of drug resistance. We analyzed drug resistance in a newborn with SCID who developed neonatal CMV infection. Sequencing of viral DNA polymerase (DP; UL54), protein kinase (UL97), and terminase (UL51, UL56, UL89) genes identified ganciclovir (GCV) and foscarnet (PFA) resistance mutations in blood, but not cerebrospinal fluid. After treatment was shifted to cidofovir and letermovir (LMV), a LMV resistance mutation rapidly emerged in UL56 (C325F). Eventually, a multidrug-resistant genotype was established (DP-V781I and UL56-C325F). Whole-genome sequencing of CMV in clinical blood samples showed an otherwise stable genotype. This case describes a CMV infection complicated by compartmentalization and the emergence of resistance to GCV, PFA, and LMV. It highlights the need for further investigation into alternative antiviral strategies for the prevention and treatment of CMV.

Fig. 1. Overview of clinical events, antiviral treatment, and CMV viral load (log copies/mL) in a newborn patient with SCID, in relation to the patient’s age (in days).

Samples were taken from blood (B) and cerebrospinal fluid (CSF). R resistance, PBSCT peripheral blood stem cell transplantation, DLI donor lymphocyte infusion.