Viral Resistance Analyses From the Remdesivir Phase 3 Adaptive COVID-19 Treatment Trial-1 (ACTT-1).

Autor:	Hedskog C; Gilead Sciences, Inc, Foster City, California, USA., Rodriguez L; Gilead Sciences, Inc, Foster City, California, USA., Roychoudhury P; Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington, Seattle, Washington, USA.; Fred Hutchinson Cancer Center, Seattle, Washington, USA., Huang ML; Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington, Seattle, Washington, USA., Jerome KR; Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington, Seattle, Washington, USA.; Fred Hutchinson Cancer Center, Seattle, Washington, USA., Hao L; Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington, Seattle, Washington, USA., Ireton RC; Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington, Seattle, Washington, USA., Li J; Gilead Sciences, Inc, Foster City, California, USA., Perry JK; Gilead Sciences, Inc, Foster City, California, USA., Han D; Gilead Sciences, Inc, Foster City, California, USA., Camus G; Gilead Sciences, Inc, Foster City, California, USA., Greninger AL; Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington, Seattle, Washington, USA.; Fred Hutchinson Cancer Center, Seattle, Washington, USA., Gale M Jr; Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington, Seattle, Washington, USA., Porter DP; Gilead Sciences, Inc, Foster City, California, USA.
Jazyk:	angličtina
Zdroj:	The Journal of infectious diseases [J Infect Dis] 2023 Nov 02; Vol. 228 (9), pp. 1263-1273.
DOI:	10.1093/infdis/jiad270
Abstrakt:	Background: Remdesivir is approved for treatment of coronavirus disease 2019 (COVID-19) in nonhospitalized and hospitalized adult and pediatric patients. Here we present severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resistance analyses from the phase 3 ACTT-1 randomized placebo-controlled trial conducted in adult participants hospitalized with COVID-19. Methods: Swab samples were collected at baseline and longitudinally through day 29. SARS-CoV-2 genomes were sequenced using next-generation sequencing. Phenotypic analysis was conducted directly on participant virus isolates and/or using SARS-CoV-2 subgenomic replicons expressing mutations identified in the Nsp12 target gene. Results: Among participants with both baseline and postbaseline sequencing data, emergent Nsp12 substitutions were observed in 12 of 31 (38.7%) and 12 of 30 (40.0%) participants in the remdesivir and placebo arms, respectively. No emergent Nsp12 substitutions in the remdesivir arm were observed in more than 1 participant. Phenotyping showed low to no change in susceptibility to remdesivir relative to wild-type Nsp12 reference for the substitutions tested: A16V (0.8-fold change in EC50), P323L + V792I (2.2-fold), C799F (2.5-fold), K59N (1.0-fold), and K59N + V792I (3.4-fold). Conclusions: The similar rate of emerging Nsp12 substitutions in the remdesivir and placebo arms and the minimal change in remdesivir susceptibility among tested substitutions support a high barrier to remdesivir resistance development in COVID-19 patients. Clinical Trials Registration. NCT04280705. (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
Databáze:	MEDLINE
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