Real-world effectiveness of early nirmatrelvir/ritonavir initiation after COVID-19 diagnosis in outpatient setting against severe illness, hospitalization, death, and long COVID in N3C
Year: 2026
Type: article
Study design: Observational Study
Abstract: Background COVID-19 has placed a monumental burden on the health care system globally. Although no longer a public health emergency, there is still a pressing need for effective treatments that prevent adverse outcomes associated with this disease. Nirmatrelvir/ritonavir (NMV-R) is a promising and potentially effective antiviral, which until recently was under emergency use authorization. Our objective was to evaluate the real-world effectiveness of NMV-R in preventing severe illness, hospitalization, death and long-COVID in a large nationwide cohort of outpatients with COVID-19. Methods Population-based retrospective cohort study of patients with a SARS-CoV-2 positive test or diagnosis (index) date between December 2021 and February 2023 within the National COVID Cohort Collaborative (N3C), with at least one risk factor for severe COVID-19, no evidence of contraindicated medical conditions or medication use, and no hospital or emergency department visit or death within 24 hours of eligibility. We emulated a sequence of target trials beginning on each of the first five days of diagnosis with COVID-19. We identified 921,034 eligible person-trials (each representing a patient’s eligibility at a given diagnosis day across sequential emulated trials), of which 77,449 were initiators and 846,585 were non-initiators of NMV-R treatment. NMV-R Initiators were matched to non-initiators in each trial. The marginal hazard ratio between initiators and non-initiators was estimated for four acute outcomes: severe illness, hospitalization or death, hospitalization, and death; and the post-COVID condition or long COVID. Results Of 921,034 eligible “person-trials”, 74,449 were initiators and 846,585 were non-initiators of NMV-R treatment. Pooled across trials, the hazard for severe illness (HR: 0.76, 95% CI: 0.71 to 0.81), hospitalization or death (HR: 0.50, 95% CI: 0.44 to 0.57), hospitalization (sdHR: 0.52, 95% CI: 0.46 to 0.60), death (HR: 0.33, 95% CI: 0.21 to 0.51), and long-COVID (sdHR: 0.85, 95% CI: 0.77 to 0.95) were significantly lower among NMV-R initiators compared to non-initiators. Results further indicated larger associations between NMV-R and reduced risk of both acute and post-acute outcomes with early versus delayed NMV-R treatment initiation, and among unvaccinated versus vaccinated patient subgroups. Conclusions NMV-R is overall effective at preventing the risk of severe acute outcomes including hospitalization and death, as well as long COVID. Results were robust across multiple sensitivity considerations. Clinical trial number Not applicable.
Source: BMC Infectious Diseases
Authors: Steve R. Makkar, Kristen Hansen, Arjun S. Yadaw, Therese Tripler, David Sahner, Josh Fessel, Nathan Hotaling, Hythem Sidky, On behalf of the N3C, Kenneth R. Gersing, Mariam Deacy, Rebecca Erwin-Cohen, Samuel Bozzette, Valery Gordon, Christopher Chute, Adam B. Wilcox, Adam M. Lee, Alexis Graves, Alfred Jerrod Anzalone, Amin Manna, Andrew T. Girvin, Benjamin Amor, Katie Rebecca Bradwell, Mark M. Bissell, Michael G. Kurilla, Shawn T. O’Neil, Amit Saha, Amy Olex, Andrea Zhou, Andrew E. Williams, Andrew M. Southerland, Anita Walden, Anjali Sharathkumar, Benjamin Bates, Brian Hendricks, Brijesh Patel, G. Caleb Alexander, Carolyn T. Bramante, Cavin Ward-Caviness, Charisse Madlock-Brown, Christine Suver, Christopher Dillon, Chunlei Wu, Clare Schmitt, Joni L. Rutter, Cliff Takemoto, Dan Housman, Davera Gabriel, Harold P. Lehmann, Richard L. Zhu, Stephanie S. Hong, Xiaohan Tanner Zhang, David A. Eichmann, Diego Mazzotti, Donald E. Brown, Eilis Boudreau, Elaine L. Hill, Emily Carlson Marti, Emily R. Pfaff, Kellie M. Walters, Evan French, Farrukh M. Koraishy, Randeep Jawa, Federico Mariona, Fred Prior, George Sokos, Greg Martin, Heidi Spratt, Hemalkumar B. Mehta, J. W. Awori Hayanga, Lee Pyles, Lesley Cottrell, Jami Pincavitch, Jaylyn Clark, Jeremy Richard Harper, Jessica Yasmine Islam, Jin Ge, Joel Gagnier, Johanna J. Loomba, John B. Buse, Jomol Mathew, Julie A. McMurry, Justin Guinney, Justin Starren, Karen Crowley, Ken Wilkins, Kenrick Cato, Kimberly Murray, Kristin Kostka, Lavance Northington, Lili M. Portilla, Marshall Clark, Mary Emmett, Matvey B. Palchuk, Melissa A. Haendel, Meredith Adams, Umit Topaloglu, Meredith Temple-O’Connor, Michele Morris, Nasia Safdar, Nicole Garbarini, Noha Sharafeldin, Ofer Sadan, Patricia A. Francis, Penny Wung Burgoon, Philip R. O. Payne, Rena C. Patel, Richard A. Moffitt, Rishikesan Kamaleswaran, Robert Hurley, Robert T. Miller, Saiju Pyarajan, Sam G. Michael, Sandeep K. Mallipattu, Satyanarayana Vedula, Scott Chapman, Soko Setoguchi, Steven G. Johnson, Tellen D. Bennett, Tiffany J. Callahan, Vignesh Subbian, Warren A. Kibbe, Wenndy Hernandez, Will Beasley, William Cooper, William Hillegass
Institutions: National Institutes of Health, National Center for Advancing Translational Sciences, Johns Hopkins University, University of Washington, University of North Carolina at Chapel Hill, University of Iowa, University of Nebraska Medical Center, Atrium Health Wake Forest Baptist, Wake Forest University, University of Virginia, Tufts Medical Center, Tufts Clinical and Translational Science Institute, Oregon Health & Science University, Rutgers, The State University of New Jersey, West Virginia University, University of Minnesota, Environmental Protection Agency, University of Tennessee Health Science Center, Sage Bionetworks, Virginia Commonwealth University, Scripps Research Institute, Office of the Director, St. Jude Children's Research Hospital, University of Kansas, University of Kansas Medical Center, Portland VA Medical Center, University of Rochester Medicine, University of Rochester, Stony Brook Medicine, Beaumont Hospital, Dearborn, University of Arkansas for Medical Sciences, West Virginia University at Parkersburg, Emory University, The University of Texas Medical Branch at Galveston, Regenstrief Institute, Moffitt Cancer Center, University of California, San Francisco, University of Wisconsin–Madison, University of Colorado Anschutz, Tempus Labs (United States), Lurie Children's Hospital, Brown University, National Institute of Diabetes and Digestive and Kidney Diseases, University of Pennsylvania, The University of Texas Health Science Center at Houston, University of Oxford, University of Alabama at Birmingham, Charleston Area Medical Center, Vanderbilt University Medical Center, Wake Forest University Health Sciences, University of Pittsburgh, William S. Middleton Memorial Veterans Hospital, National Institute of Environmental Health Sciences, National Institute of Allergy and Infectious Diseases, Washington University in St. Louis, TriNetX (United States), VA Boston Healthcare System, University of Maryland Medical Center, Columbia University Irving Medical Center, University of Arizona, National Cancer Institute, University of Oklahoma, Stony Brook University, University of Mississippi
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,090
OpenAlex ID: W7203779271
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