1. Development and Dynamics of Cytomegalovirus UL97 Ganciclovir Resistance Mutations in Transplant Recipients Detected by Next-Generation Sequencing
- Author
-
Henrik Sengeløv, Hans H. Hirsch, Mette Jørgensen, Isabelle Paula Lodding, Søren Schwartz Sørensen, Jens D Lundgren, Allan Rasmussen, Michael Perch, Klaudia Naegele, Finn Gustafsson, Marc Bennedbæk, and Nikolai Kirkby
- Subjects
Ganciclovir ,medicine.medical_treatment ,viruses ,Cytomegalovirus ,Hematopoietic stem cell transplantation ,Viral quasispecies ,medicine.disease_cause ,Solid organ transplantation ,medicine ,Major Article ,Clinical significance ,Prospective cohort study ,cytomegalovirus ,solid organ transplantation ,business.industry ,virus diseases ,Valganciclovir ,Ganciclovir resistance ,Virology ,Transplantation ,Infectious Diseases ,AcademicSubjects/MED00290 ,Oncology ,ganciclovir resistance ,hematopoietic stem cell transplantation ,Next-generation sequencing ,next-generation sequencing ,business ,medicine.drug - Abstract
Background (Val)ganciclovir resistance mutations in CMV UL97 (UL97-GCV-R) complicate anti-CMV therapy in recipients of solid organ and hematopoietic stem cell transplants, but comprehensive data on prevalence, emergence, and outcome are scarce. Methods Using next-generation sequencing (NGS; Illumina MiSeq platform), we analyzed UL97-GCV-R in patients with available plasma samples and refractory CMV replication/DNAemia (n = 87) containing viral loads ≥910 IU/mL. Twenty-one patients with CMV DNAemia resolving under antiviral therapy were analyzed as controls. Detected mutations were considered induced and of potential clinical significance if they increased by ≥10% compared with the first detected frequency or if they had a maximum frequency ≥25%. Results Nineteen of 87 (21.8%) with refractory CMV replication had ≥1 UL97-GCV-R detected by NGS, in comparison to 0/21 of the controls (P = .02). One-third of the recipients had 2 or more induced UL97-GCV-R mutations. The most frequently induced mutations affected codons 595 (42% [8/19]), 594 (32% [6/19]), and 603 (32% [6/19]). C592G was present in all episodes of both cases and controls at frequencies Conclusions UL97-GCV-R is common among transplant patients with refractory CMV replication. Early testing by NGS allows for identification of major mutations at codons 595, 594, and 603 and excludes a major role of C592G in ganciclovir resistance. Large prospective studies on UL97-GCV-R are warranted.
- Published
- 2021