SARS-CoV-2 RNA and Nucleocapsid Antigen Are Blood Biomarkers Associated With Severe Disease Outcomes That Improve in Response to Remdesivir

Kanal Singh; Kevin Rubenstein; Viviane Callier; Katy Shaw-Saliba; Adam Rupert; Robin Dewar; Sylvain Laverdure; Helene Highbarger; Perrine Lallemand; Meei-Li Huang; Keith R Jerome; Reigran Sampoleo; Margaret G Mills; Alexander L Greninger; Kavita Juneja; Danielle Porter; Constance A Benson; Walla Dempsey; Hana M El Sahly; Chris Focht; Nikolaus Jilg; Catharine I Paules; Rekha R Rapaka; Timothy M Uyeki; H Clifford Lane; John Beigel; Lori E Dodd; Adaptive COVID-19 Treatment Trial (ACTT-1) Study Group Members

doi:10.1093/infdis/jiae198

SARS-CoV-2 RNA and Nucleocapsid Antigen Are Blood Biomarkers Associated With Severe Disease Outcomes That Improve in Response to Remdesivir

Kanal Singh, Kevin Rubenstein, Viviane Callier, Katy Shaw-Saliba, Adam Rupert, Robin Dewar, Sylvain Laverdure, Helene Highbarger, Perrine Lallemand, Meei-Li Huang, Keith R Jerome, Reigran Sampoleo, Margaret G Mills, Alexander L Greninger, Kavita Juneja, Danielle Porter, Constance A Benson, Walla Dempsey, Hana M El Sahly, Chris FochtNikolaus Jilg, Catharine I Paules, Rekha R Rapaka, Timothy M Uyeki, H Clifford Lane, John Beigel, Lori E Dodd, Adaptive COVID-19 Treatment Trial (ACTT-1) Study Group Members

Department of Infectious Diseases

10 Citations (Scopus)

Abstract

BACKGROUND: Although antivirals remain important for the treatment COVID-19, methods to assess treatment efficacy are lacking. Here, we investigated the impact of remdesivir on viral dynamics and their contribution to understanding antiviral efficacy in the multicenter Adaptive COVID-19 Treatment Trial 1, which randomized patients to remdesivir or placebo.

METHODS: Longitudinal specimens collected during hospitalization from a substudy of 642 patients with COVID-19 were measured for viral RNA (upper respiratory tract and plasma), viral nucleocapsid antigen (serum), and host immunologic markers. Associations with clinical outcomes and response to therapy were assessed.

RESULTS: Higher baseline plasma viral loads were associated with poorer clinical outcomes, and decreases in viral RNA and antigen in blood but not the upper respiratory tract correlated with enhanced benefit from remdesivir. The treatment effect of remdesivir was most pronounced in patients with elevated baseline nucleocapsid antigen levels: the recovery rate ratio was 1.95 (95% CI, 1.40-2.71) for levels >245 pg/mL vs 1.04 (95% CI, .76-1.42) for levels <245 pg/mL. Remdesivir also accelerated the rate of viral RNA and antigen clearance in blood, and patients whose blood levels decreased were more likely to recover and survive.

CONCLUSIONS: Reductions in SARS-CoV-2 RNA and antigen levels in blood correlated with clinical benefit from antiviral therapy.

CLINICAL TRIAL REGISTRATION: NCT04280705 (ClinicalTrials.gov).

Original language	English
Journal	The Journal of infectious diseases
Volume	230
Issue number	3
Pages (from-to)	624-634
Number of pages	11
ISSN	0022-1899
DOIs	https://doi.org/10.1093/infdis/jiae198
Publication status	Published - 23 Sept 2024

Keywords

Humans
Adenosine Monophosphate/analogs & derivatives
Alanine/analogs & derivatives
SARS-CoV-2/immunology
Antiviral Agents/therapeutic use
COVID-19 Drug Treatment
RNA, Viral/blood
COVID-19/blood
Male
Female
Biomarkers/blood
Middle Aged
Viral Load
Treatment Outcome
Adult
Coronavirus Nucleocapsid Proteins/immunology
Aged
Antigens, Viral/blood
clinical trial
antiviral efficacy
remdesivir
COVID-19
SARS-CoV-2

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10.1093/infdis/jiae198

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Singh, K., Rubenstein, K., Callier, V., Shaw-Saliba, K., Rupert, A., Dewar, R., Laverdure, S., Highbarger, H., Lallemand, P., Huang, M.-L., Jerome, K. R., Sampoleo, R., Mills, M. G., Greninger, A. L., Juneja, K., Porter, D., Benson, C. A., Dempsey, W., El Sahly, H. M., ... Adaptive COVID-19 Treatment Trial (ACTT-1) Study Group Members (2024). SARS-CoV-2 RNA and Nucleocapsid Antigen Are Blood Biomarkers Associated With Severe Disease Outcomes That Improve in Response to Remdesivir. The Journal of infectious diseases, 230(3), 624-634. https://doi.org/10.1093/infdis/jiae198

Singh, K, Rubenstein, K, Callier, V, Shaw-Saliba, K, Rupert, A, Dewar, R, Laverdure, S, Highbarger, H, Lallemand, P, Huang, M-L, Jerome, KR, Sampoleo, R, Mills, MG, Greninger, AL, Juneja, K, Porter, D, Benson, CA, Dempsey, W, El Sahly, HM, Focht, C, Jilg, N, Paules, CI, Rapaka, RR, Uyeki, TM, Clifford Lane, H, Beigel, J, Dodd, LE & Adaptive COVID-19 Treatment Trial (ACTT-1) Study Group Members 2024, 'SARS-CoV-2 RNA and Nucleocapsid Antigen Are Blood Biomarkers Associated With Severe Disease Outcomes That Improve in Response to Remdesivir', The Journal of infectious diseases, vol. 230, no. 3, pp. 624-634. https://doi.org/10.1093/infdis/jiae198

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title = "SARS-CoV-2 RNA and Nucleocapsid Antigen Are Blood Biomarkers Associated With Severe Disease Outcomes That Improve in Response to Remdesivir",

abstract = "BACKGROUND: Although antivirals remain important for the treatment COVID-19, methods to assess treatment efficacy are lacking. Here, we investigated the impact of remdesivir on viral dynamics and their contribution to understanding antiviral efficacy in the multicenter Adaptive COVID-19 Treatment Trial 1, which randomized patients to remdesivir or placebo.METHODS: Longitudinal specimens collected during hospitalization from a substudy of 642 patients with COVID-19 were measured for viral RNA (upper respiratory tract and plasma), viral nucleocapsid antigen (serum), and host immunologic markers. Associations with clinical outcomes and response to therapy were assessed.RESULTS: Higher baseline plasma viral loads were associated with poorer clinical outcomes, and decreases in viral RNA and antigen in blood but not the upper respiratory tract correlated with enhanced benefit from remdesivir. The treatment effect of remdesivir was most pronounced in patients with elevated baseline nucleocapsid antigen levels: the recovery rate ratio was 1.95 (95\% CI, 1.40-2.71) for levels >245 pg/mL vs 1.04 (95\% CI, .76-1.42) for levels <245 pg/mL. Remdesivir also accelerated the rate of viral RNA and antigen clearance in blood, and patients whose blood levels decreased were more likely to recover and survive.CONCLUSIONS: Reductions in SARS-CoV-2 RNA and antigen levels in blood correlated with clinical benefit from antiviral therapy.CLINICAL TRIAL REGISTRATION: NCT04280705 (ClinicalTrials.gov).",

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author = "Kanal Singh and Kevin Rubenstein and Viviane Callier and Katy Shaw-Saliba and Adam Rupert and Robin Dewar and Sylvain Laverdure and Helene Highbarger and Perrine Lallemand and Meei-Li Huang and Jerome, \{Keith R\} and Reigran Sampoleo and Mills, \{Margaret G\} and Greninger, \{Alexander L\} and Kavita Juneja and Danielle Porter and Benson, \{Constance A\} and Walla Dempsey and \{El Sahly\}, \{Hana M\} and Chris Focht and Nikolaus Jilg and Paules, \{Catharine I\} and Rapaka, \{Rekha R\} and Uyeki, \{Timothy M\} and \{Clifford Lane\}, H and John Beigel and Dodd, \{Lori E\} and Lundgren, \{Jens D.\} and \{Adaptive COVID-19 Treatment Trial (ACTT-1) Study Group Members\}",

note = "Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.",

year = "2024",

month = sep,

day = "23",

doi = "10.1093/infdis/jiae198",

language = "English",

volume = "230",

pages = "624--634",

journal = "The Journal of infectious diseases",

issn = "0022-1899",

publisher = "Oxford University Press",

number = "3",

}

TY - JOUR

T1 - SARS-CoV-2 RNA and Nucleocapsid Antigen Are Blood Biomarkers Associated With Severe Disease Outcomes That Improve in Response to Remdesivir

AU - Singh, Kanal

AU - Rubenstein, Kevin

AU - Callier, Viviane

AU - Shaw-Saliba, Katy

AU - Rupert, Adam

AU - Dewar, Robin

AU - Laverdure, Sylvain

AU - Highbarger, Helene

AU - Lallemand, Perrine

AU - Huang, Meei-Li

AU - Jerome, Keith R

AU - Sampoleo, Reigran

AU - Mills, Margaret G

AU - Greninger, Alexander L

AU - Juneja, Kavita

AU - Porter, Danielle

AU - Benson, Constance A

AU - Dempsey, Walla

AU - El Sahly, Hana M

AU - Focht, Chris

AU - Jilg, Nikolaus

AU - Paules, Catharine I

AU - Rapaka, Rekha R

AU - Uyeki, Timothy M

AU - Clifford Lane, H

AU - Beigel, John

AU - Dodd, Lori E

AU - Adaptive COVID-19 Treatment Trial (ACTT-1) Study Group Members

A2 - Lundgren, Jens D.

N1 - Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.

PY - 2024/9/23

Y1 - 2024/9/23

N2 - BACKGROUND: Although antivirals remain important for the treatment COVID-19, methods to assess treatment efficacy are lacking. Here, we investigated the impact of remdesivir on viral dynamics and their contribution to understanding antiviral efficacy in the multicenter Adaptive COVID-19 Treatment Trial 1, which randomized patients to remdesivir or placebo.METHODS: Longitudinal specimens collected during hospitalization from a substudy of 642 patients with COVID-19 were measured for viral RNA (upper respiratory tract and plasma), viral nucleocapsid antigen (serum), and host immunologic markers. Associations with clinical outcomes and response to therapy were assessed.RESULTS: Higher baseline plasma viral loads were associated with poorer clinical outcomes, and decreases in viral RNA and antigen in blood but not the upper respiratory tract correlated with enhanced benefit from remdesivir. The treatment effect of remdesivir was most pronounced in patients with elevated baseline nucleocapsid antigen levels: the recovery rate ratio was 1.95 (95% CI, 1.40-2.71) for levels >245 pg/mL vs 1.04 (95% CI, .76-1.42) for levels <245 pg/mL. Remdesivir also accelerated the rate of viral RNA and antigen clearance in blood, and patients whose blood levels decreased were more likely to recover and survive.CONCLUSIONS: Reductions in SARS-CoV-2 RNA and antigen levels in blood correlated with clinical benefit from antiviral therapy.CLINICAL TRIAL REGISTRATION: NCT04280705 (ClinicalTrials.gov).

AB - BACKGROUND: Although antivirals remain important for the treatment COVID-19, methods to assess treatment efficacy are lacking. Here, we investigated the impact of remdesivir on viral dynamics and their contribution to understanding antiviral efficacy in the multicenter Adaptive COVID-19 Treatment Trial 1, which randomized patients to remdesivir or placebo.METHODS: Longitudinal specimens collected during hospitalization from a substudy of 642 patients with COVID-19 were measured for viral RNA (upper respiratory tract and plasma), viral nucleocapsid antigen (serum), and host immunologic markers. Associations with clinical outcomes and response to therapy were assessed.RESULTS: Higher baseline plasma viral loads were associated with poorer clinical outcomes, and decreases in viral RNA and antigen in blood but not the upper respiratory tract correlated with enhanced benefit from remdesivir. The treatment effect of remdesivir was most pronounced in patients with elevated baseline nucleocapsid antigen levels: the recovery rate ratio was 1.95 (95% CI, 1.40-2.71) for levels >245 pg/mL vs 1.04 (95% CI, .76-1.42) for levels <245 pg/mL. Remdesivir also accelerated the rate of viral RNA and antigen clearance in blood, and patients whose blood levels decreased were more likely to recover and survive.CONCLUSIONS: Reductions in SARS-CoV-2 RNA and antigen levels in blood correlated with clinical benefit from antiviral therapy.CLINICAL TRIAL REGISTRATION: NCT04280705 (ClinicalTrials.gov).

KW - Humans

KW - Adenosine Monophosphate/analogs & derivatives

KW - Alanine/analogs & derivatives

KW - SARS-CoV-2/immunology

KW - Antiviral Agents/therapeutic use

KW - COVID-19 Drug Treatment

KW - RNA, Viral/blood

KW - COVID-19/blood

KW - Male

KW - Female

KW - Biomarkers/blood

KW - Middle Aged

KW - Viral Load

KW - Treatment Outcome

KW - Adult

KW - Coronavirus Nucleocapsid Proteins/immunology

KW - Aged

KW - Antigens, Viral/blood

KW - clinical trial

KW - antiviral efficacy

KW - remdesivir

KW - COVID-19

KW - SARS-CoV-2

UR - https://www.scopus.com/pages/publications/85204819223

U2 - 10.1093/infdis/jiae198

DO - 10.1093/infdis/jiae198

M3 - Journal article

C2 - 38657001

SN - 0022-1899

VL - 230

SP - 624

EP - 634

JO - The Journal of infectious diseases

JF - The Journal of infectious diseases

IS - 3

ER -

SARS-CoV-2 RNA and Nucleocapsid Antigen Are Blood Biomarkers Associated With Severe Disease Outcomes That Improve in Response to Remdesivir

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Keywords

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