@article{47e92e67abd54016a1b3cad2444ad4cf,
title = "Letermovir resistance analysis in a clinical trial of cytomegalovirus prophylaxis for hematopoietic stem cell transplant recipients",
abstract = "Background: Letermovir (LET), a cytomegalovirus (CMV) deoxyribonucleic acid (DNA) terminase inhibitor, was recently approved for prophylaxis of CMV infection in adult CMV-seropositive recipients of allogeneic hematopoietic stem cell transplantation. Cytomegalovirus genotyping was performed to identify LET-resistance-associated variants (RAVs) among subjects in a Phase 3 trial. Methods. The CMV UL56 and UL89 genes, encoding subunits of CMV DNA terminase, were sequenced from plasma collected from subjects with clinically significant CMV infection (CS-CMVi). Novel variants were evaluated by recombinant phenotyping to assess their potential to confer resistance to LET. Results. Genotyping was successful for 50 of 79 LET subjects with CS-CMVi. Resistance-associated variants (encoding pUL56 V236M and C325W) were detected independently in subjects 1 and 3 who experienced CS-CMVi while receiving LET prophylaxis, and 2 other variants (encoding pUL56 E237G and R369T) were detected >3 weeks after subjects 2 and 3, respectively, had discontinued LET prophylaxis and received preemptive therapy with ganciclovir. Conclusions. The detected incidence of CMV resistance among subjects who received LET as prophylaxis in this Phase 3 trial was low. The LET RAVs that were detected mapped to the CMV UL56 gene at positions associated with reduced susceptibility to LET based on resistance selections in cell culture.",
keywords = "Antiviral drug resistance, Cytomegalovirus, Letermovir, Prophylaxis, RAV",
author = "Douglas, {Cameron M.} and Richard Barnard and Daniel Holder and Randi Leavitt and Diane Levitan and Maureen Maguire and David Nickle and Valerie Teal and Hong Wan and {van Alewijk}, {Dirk C.J.G.} and {van Doorn}, {Leen Jan} and Sunwen Chou and Julie Strizki",
note = "Funding Information: Potential conflicts of interest. C. M. D., R. B., D. H., R. L., D. L., M. M., D. N., V. T., H. W., and J. S. are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., (Kenilworth, NJ) and may own stock/stock options in Merck & Co., Inc., (Kenilworth, NJ). L.-J. v. D. reports a financial relationship with DDL Diagnostic Laboratory, outside the submitted work. S. C. reports a Cooperative Research & Development Agreement from Merck & Co., Inc.; a grant from the National Institutes of Health; and a Cooperative Research and Development Agreement from Shire, a Takeda company, outside the submitted work. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Funding Information: Financial support. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., (Kenilworth, NJ) and National Institutes of Health Grant AI116635 (to S. C.) and supported by use of Department of Veterans Affairs facilities and resources for recombinant phenotyping. Publisher Copyright: {\textcopyright} The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.",
year = "2020",
month = mar,
day = "16",
doi = "10.1093/infdis/jiz577",
language = "English (US)",
volume = "221",
pages = "1117--1126",
journal = "Journal of Infectious Diseases",
issn = "0022-1899",
publisher = "Oxford University Press",
number = "7",
}