SARS-CoV-2 RNA and Nucleocapsid Antigen Are Blood Biomarkers Associated With Severe Disease Outcomes That Improve in Response to Remdesivir
Authors: Singh Kanal , Rubenstein Kevin , Callier Viviane , Shaw-Saliba Katy , Rupert Adam , Dewar Robin , Laverdure Sylvain , Highbarger Helene , Lallemand Perrine , Huang Meei-Li , Jerome Keith R , Sampoleo Reigran , Mills Margaret G , Greninger Alexander L , Juneja Kavita , Porter Danielle , Benson Constance A , Dempsey Walla , El Sahly Hana M , Focht Chris , Jilg Nikolaus , Paules Catharine I , Rapaka Rekha R , Uyeki Timothy M , Clifford Lane H , Beigel John , Dodd Lori E ,   the Adaptive COVID-19 Treatment Trial (ACTT-1) Study Group Members, Mehta Aneesh K , Rouphael Nadine G , Traenkner Jessica J , Cantos Valeria D , Alaaeddine Ghina , Zingman Barry S , Grossberg Robert , Riska Paul F , Hohmann Elizabeth , Torres-Soto Mariam , Jilg Nikolaus , Chu Helen Y , Wald Anna , Green Margaret , Luetkemeyer Annie , Crouch Pierre-Cedric B , Jang Hannah , Kline Susan , Billings Joanne , Noren Brooke , de Castilla Diego Lopez , Van Winkle Jason W , Riedo Francis X , Finberg Robert W , Wang Jennifer P , Wessolossky Mireya , Dierberg Kerry , Eckhardt Benjamin , Neumann Henry J , Tapson Victor , Grein Jonathan , Sutterwala Fayyaz , Hsieh Lanny , Amin Alpesh N , Patterson Thomas F , Javeri Heta , Vu Trung , Paredes Roger , Mateu Lourdes , Sweeney Daniel A , Benson Constance A , Ali Farhana , Short William R , Tebas Pablo , Torgersen Jessie , Touloumi Giota , Gioukari Vicky , Lye David Chien , Ong Sean W X , Ohmagari Norio , Mikami Ayako , Fätkenheuer Gerd , Malin Jakob J , Koehler Philipp , Kalil Andre C , Larson LuAnn , Hewlett Angela , Kortepeter Mark G , Creech C Buddy , Thomsen Isaac , Rice Todd W , Taiwo Babafemi , Krueger Karen , Cohen Stuart H , Thompson George R , Wolfe Cameron , Walter Emmanuel B , Frank Maria , Young Heather , Falsey Ann R , Branche Angela R , Goepfert Paul , Erdmann Nathaniel , Yang Otto O , Ahn Jenny , Goodman Anna , Merrick Blair , Novak Richard M , Wendrow Andrea , Arguinchona Henry , Arguinchona Christa , George Sarah L , Tennant Janice , Atmar Robert L , El Sahly Hana M , Whitaker Jennifer , Price D Ashley , Duncan Christopher J A , Metallidis Simeon , Chrysanthidis Theofilos , McLellan F , Oh Myoung-don , Park Wan Beom , Kim Eu Suk , Jung Jongtak , Ortiz Justin R , Kotloff Karen L , Angus Brian , Germain Seymour Jack David , Hynes Noreen A , Sauer Lauren M , Ahuja Neera , Nadeau Kari , Jackson Patrick E H , Bell Taison D , Antoniadou Anastasia , Protopapas Konstantinos , Davey Richard T , Voell Jocelyn D , Muñoz Jose , Roldan Montserrat , Kalomenidis Ioannis , Zakynthinos Spyros G , Paules Catharine I , McGill Fiona , Minton Jane , Koulouris Nikolaos , Barmparessou Zafeiria , Swiatlo Edwin , Widmer Kyle , Huprikar Nikhil , Ganesan Anuradha , Ruiz-Palacios Guillermo M , de León Alfredo Ponce , Rajme Sandra , Pineda Justino Regalado , Martinez-Orozco José Arturo , Holodniy Mark , Chary Aarthi , Wolf Timo , Stephan Christoph , Wasmuth Jan-Christian , Boesecke Christoph , Llewelyn Martin , Philips Barbara , Colombo Christopher J , Colombo Rhonda E , Lindholm David A , Mende Katrin , Lee Tida , Lalani Tahaniyat , Maves Ryan C , Utz Gregory C , Lundgren Jens , Helleberg Marie , Gerstoft Jan , Benfield Thomas , Jensen Tomas , Lindegaard Birgitte , Weise Lothar , Knudsen Lene , Johansen Isik , Madsen Lone W , Østergaard Lars , Stærke Nina , Nielsen Henrik , Burgess Timothy H , Green Michelle , Makowski Mat , Ferreira Jennifer L , Wierzbicki Michael R , Bonnett Tyler , Gettinger Nikki , Engel Theresa , Wang Jing , Beigel John H , Tomashek Kay M , Nayak Seema , Dodd Lori E , Dempsey Walla , Nomicos Effie , Lee Marina , Wolff Peter , Pikaart-Tautges Rhonda , Elsafy Mohamed , Jurao Robert , Koo Hyung , Proschan Michael , Follmann Dean , Lane H Clifford 
Published: April 2024

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 &gt;245 pg/mL vs 1.04 (95% CI, .76–1.42) for levels &lt;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).