Development and dynamics of cytomegalovirus UL97 ganciclovir resistance mutations in transplant recipients detected by next-generation sequencing
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Development and dynamics of cytomegalovirus UL97 ganciclovir resistance mutations in transplant recipients detected by next-generation sequencing. / Lodding, Isabelle P.; Jørgensen, Mette; Bennedbæk, Marc; Kirkby, Nikolai; Naegele, Klaudia; Gustafsson, Finn; Perch, Michael; Rasmussen, Allan; Sengeløv, Henrik; Sørensen, Søren S.; Hirsch, Hans H.; Lundgren, Jens D.
I: Open Forum Infectious Diseases, Bind 8, Nr. 10, ofab462, 2021.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Development and dynamics of cytomegalovirus UL97 ganciclovir resistance mutations in transplant recipients detected by next-generation sequencing
AU - Lodding, Isabelle P.
AU - Jørgensen, Mette
AU - Bennedbæk, Marc
AU - Kirkby, Nikolai
AU - Naegele, Klaudia
AU - Gustafsson, Finn
AU - Perch, Michael
AU - Rasmussen, Allan
AU - Sengeløv, Henrik
AU - Sørensen, Søren S.
AU - Hirsch, Hans H.
AU - Lundgren, Jens D.
N1 - Publisher Copyright: © The Author(s) 2021.
PY - 2021
Y1 - 2021
N2 - 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 <15%, but never induced. UL97-GCV-R tended to be more frequent in donor/recipient CMV immunoglobulin G mismatch or following failure to complete primary prophylaxis, and many developed invasive CMV disease. 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.
AB - 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 <15%, but never induced. UL97-GCV-R tended to be more frequent in donor/recipient CMV immunoglobulin G mismatch or following failure to complete primary prophylaxis, and many developed invasive CMV disease. 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.
KW - Cytomegalovirus
KW - Ganciclovir resistance
KW - Hematopoietic stem cell transplantation
KW - Next-generation sequencing
KW - Solid organ transplantation
U2 - 10.1093/ofid/ofab462
DO - 10.1093/ofid/ofab462
M3 - Journal article
C2 - 34660835
AN - SCOPUS:85118938715
VL - 8
JO - Open Forum Infectious Diseases
JF - Open Forum Infectious Diseases
SN - 2328-8957
IS - 10
M1 - ofab462
ER -
ID: 286313664