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 H. Beigel, Lori E. Dodd, the Adaptive COVID-19 Treatment Trial (ACTT-1) Study Group Members, Aneesh K. Mehta, Nadine Rouphael, Jessica Traenkner, Valeria D Cantos, Ghina Alaaeddine, Barry S. Zingman, Robert Grossberg, Paul Riska, Elizabeth Hohmann, Mariam Torres-Soto, Nikolaus Jilg, Helen Y. Chu, Anna Wald, Margaret Green, Annie Luetkemeyer, Pierre-Cedric B. Crouch, Hannah Jang, Susan Kline, Joanne Billings, Brooke Noren, Diego López de Castilla, Jason W. Van Winkle, Francis X. Riedo, Robert W. Finberg, Jennifer Wang, Mireya Wessolossky, Kerry Dierberg, Benjamin Eckhardt, Henry Neumann, Victor F. Tapson, Jonathan Grein, Fayyaz S. Sutterwala, Lanny Hsieh, Alpesh Amin, Thomas F. Patterson, Heta Javeri, Trung Vu, Roger Paredes, Lourdes Mateu, Daniel A Sweeney, Constance A Benson, Farhana Ali, William R. Short, Pablo Tebas, Jessie Torgersen, Giota Touloumi, Vicky Gioukari, David Chien Lye, Sean Wei Xiang Ong, Norio Ohmagari, Ayako Mikami, Gerd Fätkenheuer, Jakob J Malin, Philipp Koehler, André C. Kalil, LuAnn Larson, Angela Hewlett, Mark G. Kortepeter, C. Buddy Creech, Isaac Thomsen, Todd W. Rice, Babafemi Taiwo, Karen Krueger, Stuart H. Cohen, George R. Thompson, Cameron R. Wolfe, Emmanuel B. Walter, Maria G. Frank, Heather A. Young, Ann R. Falsey, Angela R Branche, Paul Goepfert
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).