Real-world effectiveness of Paxlovid in protecting Long COVID for outpatient adult patients: A target trial emulation study from the RECOVER Initiative
et al., PLOS Global Public Health, doi:10.1371/journal.pgph.0005771, Oct 2026
This study contains inconsistencies / errors pending response from the authors - 21,672 eligible patients are unaccounted for in Figure 1, there are more high-risk patients aged ≥65 in Figure 3 than the total number of patients ≥65 in Table 1, vaccination categories sum to >100%, there are contradictory enrollment cutoff dates (Feb 1 vs. Feb 28, 2023), Table 1’s ‘sickle cell disease or thalassemia’ appears mislabeled, and the Figure 2 caption swaps panels B and C.
Substantial residual frailty/healthy-user confounding and incomplete exclusion for contraindications (4.7%) may inflate the reported reductions in post-acute mortality, incident dementia, and malnutrition. A 5-day antiviral lowering incident dementia within 6 months by a quarter is suggestive of healthy-user or frailty bias.
Resistance. Variants may be resistant to paxlovid1-9. Use may promote the emergence of variants that weaken host immunity and potentially contribute to long COVID10. Confounding by contraindication. Hoertel et al. find that over 50% of patients that died had a contraindication for the use of Paxlovid11. Retrospective studies that do not exclude contraindicated patients may significantly overestimate efficacy. Black box warning. The FDA notes that severe, life-threatening, and/or fatal adverse reactions due to drug interactions have been reported in patients treated with paxlovid12. Kidney and liver injury. Studies show significantly increased risk of acute kidney injury13 and liver injury14,15. Viral rebound. Studies show significantly increased risk of replication-competent viral rebound16-18.
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Zang et al., 28 Oct 2026, retrospective, USA, peer-reviewed, 16 authors, study period 1 March, 2022 - 28 February, 2023.
Contact: few2001@med.cornell.edu, recoverehrinformatics@med.cornell.edu.
Abstract:
RESEARCH ARTICLE
Real-world effectiveness of Paxlovid in protecting Long COVID for outpatient adult patients: A target trial emulation study from the RECOVER Initiative
Chengxi Zang 1 , Haoyang Li 1 , Dhruv Khullar 1 , Yongkang Zhang 1 , Stephenson Strobel 1 , Yong Chen 2 , Marc A. Sala 3 , Payal Bharat Patel 4 , Alejandro P. Comellas 5 , Andrew Wylam 6 , Mark Weiner 1 , Chris B. Forrest 7 , Thomas Carton 8 , Fei Wang 1 * , Rainu Kaushal 1 , on behalf of the RECOVER Consortium ¶
1 Department of Population Health Sciences, Weill Cornell Medicine, New York, New York, United States of America, 2 Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America, 3 Division of Pulmonary and Critical Care, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America, 4 Department of Neurology, University of Washington School of Medicine, Seattle, Washington, United States of America, 5 Division of Pulmonary, Critical Care and Occupational Medicine, University of Iowa, Iowa City, Iowa, United States of America, 6 Patient representative for Long COVID patients with the National Institutes of Health's RECOVER Initiative, Bethesda, Maryland, United States of America, 7 Applied Clinical Research Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America, 8 Louisiana Public Health Institute, New Orleans, Louisiana, United States of America
¶ Membership of the RECOVER Consortium is provided in the Acknowledgments.
[* few2001@med.cornell.edu](mailto:few2001@med.cornell.edu)
Abstract
Paxlovid (nirmatrelvir/ritonavir) has been approved for use in patients who are at high risk for severe acute COVID-19 illness. Evidence regarding whether acute use of Paxlovid protects against Post-Acute Sequelae of SARS-CoV-2 infection (PASC), or Long COVID, is mixed in high-risk patients and lacking in low-risk patients. With a target trial emulation framework, we evaluated the association of Paxlovid treatment within 5 days of SARS-CoV-2 infection with incident Long COVID and hospitalization or death from any cause in the post-acute period (30-180 days after infection) using electronic health records from the Patient-Centered Clinical Research Networks (PCORnet) RECOVER repository. The study population included 497,499 SARSCoV-2 positive patients between March 1, 2022, to February 28, 2023. For those who had at least 1 risk factor for severe COVID-19 illness, 159,659 were treated with at least one dose of Paxlovid within 5 days since infection and 272,048 were not treated with Paxlovid or other COVID-19 treatments during the acute infection period. Compared with the non-treated group, Paxlovid treatment was associated with reduced risk of Long COVID with a Hazard Ratio (HR) of 0.88 (95% CI, 0.87 to 0.89) and absolute risk reduction of 2.99 events per 100 persons (95% CI, 2.65 to 3.32). For those without documented risk factors, the associations (HR, 1.03, 95% CI 0.95 to
Citation: Zang C, Li H, Khullar D, Zhang Y, Strobel S, Chen Y, et al. (2026) Real-world effectiveness of Paxlovid in protecting Long COVID for outpatient adult patients: A target trial emulation study from the RECOVER Initiative. PLOS Glob Public Health 6(10): e0005771. https://doi.org/10.1371/journal. pgph.0005771
Editor: Julia Robinson, PLOS: Public Library of Science, UNITED STATES OF..
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"abstract": "<jats:p>Paxlovid (nirmatrelvir/ritonavir) has been approved for use in patients who are at high risk for severe acute COVID-19 illness. Evidence regarding whether acute use of Paxlovid protects against Post-Acute Sequelae of SARS-CoV-2 infection (PASC), or Long COVID, is mixed in high-risk patients and lacking in low-risk patients. With a target trial emulation framework, we evaluated the association of Paxlovid treatment within 5 days of SARS-CoV-2 infection with incident Long COVID and hospitalization or death from any cause in the post-acute period (30–180 days after infection) using electronic health records from the Patient-Centered Clinical Research Networks (PCORnet) RECOVER repository. The study population included 497,499 SARS-CoV-2 positive patients between March 1, 2022, to February 28, 2023. For those who had at least 1 risk factor for severe COVID-19 illness, 159,659 were treated with at least one dose of Paxlovid within 5 days since infection and 272,048 were not treated with Paxlovid or other COVID-19 treatments during the acute infection period. Compared with the non-treated group, Paxlovid treatment was associated with reduced risk of Long COVID with a Hazard Ratio (HR) of 0.88 (95% CI, 0.87 to 0.89) and absolute risk reduction of 2.99 events per 100 persons (95% CI, 2.65 to 3.32). For those without documented risk factors, the associations (HR, 1.03, 95% CI 0.95 to 1.11; risk increase 0.80 events per 100 persons, 95% CI -0.84 to 2.45) were inconclusive. High-risk, nonhospitalized adult patients with COVID-19 who were treated with Paxlovid within 5 days of SARS-CoV-2 infection had a lower risk of Long COVID and all-cause hospitalization or death in the post-acute period. However, Long COVID risk reduction with Paxlovid was not observed in low-risk patients.</jats:p>",
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