Letermovir Resistance Analysis in a Clinical Trial of Cytomegalovirus Prophylaxis for Hematopoietic Stem Cell Transplant Recipients.

Autor:	Douglas CM; Infectious Disease Research, Merck & Co., Inc., Kenilworth, New Jersey, USA., Barnard R; Infectious Disease Research, Merck & Co., Inc., Kenilworth, New Jersey, USA., Holder D; Biostatistics and Research Decision Sciences, Merck & Co., Inc., Kenilworth, New Jersey, USA., Leavitt R; Clinical Research, Merck & Co., Inc., Kenilworth, New Jersey, USA., Levitan D; Translational Molecular Biomarkers, Merck & Co., Inc., Kenilworth, New Jersey, USA., Maguire M; Translational Molecular Biomarkers, Merck & Co., Inc., Kenilworth, New Jersey, USA., Nickle D; Pharmacogenomics and Genetics, Merck & Co., Inc., Kenilworth, New Jersey, USA., Teal V; Biostatistics and Research Decision Sciences, Merck & Co., Inc., Kenilworth, New Jersey, USA., Wan H; Biostatistics and Research Decision Sciences, Merck & Co., Inc., Kenilworth, New Jersey, USA., van Alewijk DCJG; DDL Diagnostics Laboratory, Rijswijk, the Netherlands., van Doorn LJ; DDL Diagnostics Laboratory, Rijswijk, the Netherlands., Chou S; Department of Veterans Affairs Medical Center, Oregon Health and Science University, Portland, Oregon, USA., Strizki J; Infectious Disease Research, Merck & Co., Inc., Kenilworth, New Jersey, USA.
Jazyk:	angličtina
Zdroj:	The Journal of infectious diseases [J Infect Dis] 2020 Mar 16; Vol. 221 (7), pp. 1117-1126.
DOI:	10.1093/infdis/jiz577
Abstrakt:	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. (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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