Effect of Paxlovid Treatment on Long COVID Onset: An EHR-Based Target Trial Emulation from N3C
Alexander Preiss, Abhishek Bhatia, Chengxi Zang, Leyna V Aragon, John M Baratta, Monika Baskaran, Frank Blancero, M Daniel Brannock, Robert F Chew, Ivan Diaz, Megan Fitzgerald, Elizabeth P Kelly, Andrea G Zhou, Mark G Weiner, Thomas W Carton, Fei Wang, Rainu Kaushal, Christopher G Chute, Melissa Haendel, Richard Moffitt, Emily Pfaff
doi:10.1101/2024.01.20.24301525
Preventing and treating post-acute sequelae of SARS-CoV-2 infection (PASC), commonly known as Long COVID, has become a public health priority. In this study, we examined whether treatment with Paxlovid in the acute phase of COVID-19 helps prevent the onset of PASC. We used electronic health records from the National Covid Cohort Collaborative (N3C) to define a cohort of 426,461 patients who had COVID-19 since April 1, 2022, and were eligible for Paxlovid treatment due to risk for progression to severe COVID-19. We used the target trial emulation (TTE) framework to estimate the effect of Paxlovid treatment on PASC incidence. Our primary outcome measure was a PASC computable phenotype. Secondary outcomes were the onset of novel cognitive, fatigue, and respiratory symptoms in the post-acute period. Paxlovid treatment did not have a significant effect on overall PASC incidence (relative risk [RR] = 0.99, 95% confidence interval [CI] 0.96-1.01). However, its effect varied across the cognitive (RR = 0.85, 95% CI 0.79-0.90), fatigue (RR = 0.93, 95% CI 0.89-0.96), and respiratory (RR = 0.99, 95% CI 0.95-1.02) symptom clusters, suggesting that Paxlovid treatment may help prevent post-acute cognitive and fatigue symptoms more than others.
SUPPLEMENT A -ADDITIONAL TABLES AND FIGURES sleep wake disorders, dyspnea (or shortness of breath), acute pharyngitis, hair loss, edema, fever, malaise and fatigue. 66, 67 The incident post-acute sequelae of SARS-CoV-2 (PASC) symptoms from the list above was observed during the post-acute phase (30 to 180 days after the index date), while absent during the baseline period (7 days to 3 years preceding the index date). Individuals classified as having incident PASC when he/she exhibited at least one incident PASC-related symptom during the post-acute phase. The same set of covariates as N3C were built for the adjustment analyses, including age, self-reported sex, race/ethnicity, CCI score, baseline hospitalization utilization, social-economic status and infection time. The social-economic status was quantified by the national-level area deprivation index (ADI) linked by either 9-digit zip code or geocode. The IPTW re-weighted survival analyses, including Cox proportional hazard model for the relative risk, and the Aalen-Johansen model for the cumulative incidence. Both methods considered the death to be a competing risk for the target incident outcomes. The IPTW weights were learned based on method from Zang et al. 68
Results
Table
References
Admon, Donnelly, Casey, Janz, Russell et al., Emulating a Novel Clinical Trial Using Existing Observational Data. Predicting Results of the PreVent Study, Ann Am Thorac Soc
Anschuetz, DU Study Finds History of TBI Likely Worsens Long COVID Symptoms
Bendix, Mogg, Murphy, Paxlovid may reduce the chance of long Covid. Why don't doctors prescribe it more? NBC News
Bhatia, Preiss, Xiao, Brannock, Alexander et al., Effect of Nirmatrelvir/Ritonavir (Paxlovid) on Hospitalization among Adults with COVID-19: an EHR-based Target Trial Emulation from N3C, medRxiv,
doi:10.1101/2023.05.03.23289084Boehmer, Koumans, Skillen, Kappelman, Carton et al., Racial and Ethnic Disparities in Outpatient Treatment of COVID-19 -United States, January-July 2022, MMWR Morb Mortal Wkly Rep
Bose-Brill, Hirabayashi, Pajor, Rao, Mejias et al., Pediatric Nirmatrelvir/Ritonavir Prescribing Patterns During the COVID-19 Pandemic, medRxiv,
doi:10.1101/2022.12.23.22283868Brannock, Chew, Preiss, Hadley, Redfield et al., Long COVID risk and pre-COVID vaccination in an EHR-based cohort study from the RECOVER program, Nat Commun
Burden, Long, Collaborators, Wulf Hanson, Abbafati et al., Estimated Global Proportions of Individuals With Persistent Fatigue, Cognitive, and Respiratory Symptom Clusters Following Symptomatic COVID-19 in 2020 and 2021, JAMA
Burgner, Crawford, Goeman, Gray, Hsu, COVID-19 in children. II: Pathogenesis, disease spectrum and management, J Paediatr Child Health
Chatterjee, Bhattacharya, Nag, Dhama, Chakraborty, A Detailed Overview of SARS-CoV-2 Omicron: Its Sub-Variants, Mutations and Pathophysiology, Clinical Characteristics, Immunological Landscape, Immune Escape, and Therapies, Viruses,
doi:10.3390/v15010167Cohen, Jaudon, Schurman, Kava, Vogel et al., Impact of extended-course oral nirmatrelvir/ritonavir (Paxlovid) in established Long COVID: Case series and research considerations, Res Sq,
doi:10.21203/rs.3.rs-3359429/v1Congdon, Narrowe, Yone, Gunn, Deng et al., Nirmatrelvir/ritonavir and risk of long COVID symptoms: A retrospective cohort study,
doi:10.21203/rs.3.rs-3231786/v1Consulting, What We Heard: Engagement Report on the Working Definition for Long COVID
Crosskey, Mcintee, Preiss, Brannock, Yoo et al., Reengineering a machine learning phenotype to adapt to the changing COVID-19 landscape: A study from the N3C and RECOVER consortia, bioRxiv,
doi:10.1101/2023.12.08.23299718Dickerman, García-Albéniz, Logan, Denaxas, Hernán, Avoidable flaws in observational analyses: an application to statins and cancer, Nat Med
Dryden-Peterson, Kim, Kim, Caniglia, Lennes et al., Nirmatrelvir Plus Ritonavir for Early COVID-19 in a Large U.S. Health System : A Population-Based Cohort Study, Ann Intern Med
Durstenfeld, Peluso, Lin, Peyser, Isasi et al., Association of nirmatrelvir for acute SARS-CoV-2 infection with subsequent Long COVID symptoms in an observational cohort study, J Med Virol
Fernández-De-Las-Peñas, Palacios-Ceña, Gómez-Mayordomo, Florencio, Cuadrado et al., Prevalence of post-COVID-19 symptoms in hospitalized and non-hospitalized COVID-19 survivors: A systematic review and meta-analysis, Eur J Intern Med
Geng, Bonilla, Shafer, Miglis, Yang, The use of nirmatrelvir-ritonavir in a case of breakthrough long COVID, Explor Res Hypothesis Med
Gupta, Wang, Hayek, Chan, Mathews et al., Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19, JAMA Intern Med
Haendel, Chute, Bennett, Eichmann, Guinney et al., The National COVID Cohort Collaborative (N3C): Rationale, design, infrastructure, and deployment, J Am Med Inform Assoc
Hammond, Leister-Tebbe, Gardner, Abreu, Wisemandle, Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19, N Engl J Med
Hernán, Leaf, Target Trial Emulation: A Framework for Causal Inference From Observational Data, JAMA
Hernán, Robins, Using Big Data to Emulate a Target Trial When a Randomized Trial Is Not Available, Am J Epidemiol
Hill, Mehta, Sharma, Mane, Singh et al., Risk factors associated with post-acute sequelae of SARS-CoV-2: an N3C and NIH RECOVER study, BMC Public Health
Hripcsak, Duke, Shah, Reich, Huser et al., Observational Health Data Sciences and Informatics (OHDSI): Opportunities for Observational Researchers, Stud Health Technol Inform
Imai, King, Stuart, Misunderstandings between experimentalists and observationalists about causal inference, J R Stat Soc Ser A Stat Soc
Iwasaki, Putrino, Why we need a deeper understanding of the pathophysiology of long COVID, Lancet Infect Dis
Klein, Hardesty, Vieira, Farmakiotis, Use of anti-spike monoclonal antibodies in kidney transplant recipients with COVID-19: Efficacy, ethnic and racial disparities, Am J Transplant
Lin, Fadel, Huang, Milinovich, Sacha et al., Nirmatrelvir or Molnupiravir Use and Severe Outcomes From Omicron Infections, JAMA Netw Open
Lin, Glynn, Singer, Murphy, Lii et al., Out-of-system Care and Recording of Patient Characteristics Critical for Comparative Effectiveness Research, Epidemiology
Malden, Hong, Lewin, Hospitalization and Emergency Department Encounters for COVID-19 After Paxlovid Treatment -California
Mccarthy, Paxlovid as a potential treatment for long COVID, Expert Opin Pharmacother
Morgan, Teal, Reddy, Ford, Ashton, Measurement in Veterans Affairs Health Services Research: veterans as a special population, Health Serv Res
Munblit, Hara, Akrami, Perego, Olliaro et al., Long COVID: aiming for a consensus, Lancet Respir Med
Munz, Why should veterans diagnosed with mesothelioma seek legal help? Mesothelioma Center -Vital Services for Cancer Patients & Families
Najjar-Debbiny, Gronich, Weber, Khoury, Amar et al., Effectiveness of Paxlovid in Reducing Severe Coronavirus Disease 2019 and Mortality in High-Risk Patients, Clin Infect Dis
Peluso, Anglin, Durstenfeld, Martin, Kelly et al., Effect of Oral Nirmatrelvir on Long COVID Symptoms: 4 Cases and Rationale for Systematic Studies, Pathog Immun
Perez Giraldo, Ali, Kang, Patel, Budhiraja et al., Neurologic Manifestations of Long COVID Differ Based on Acute COVID-19 Severity, Ann Neurol
Petito, García-Albéniz, Logan, Howlader, Mariotto et al., Estimates of Overall Survival in Patients With Cancer Receiving Different Treatment Regimens: Emulating Hypothetical Target Trials in the Surveillance, Epidemiology, and End Results (SEER)-Medicare Linked Database, JAMA Netw Open
Pfaff, Girvin, Bennett, Bhatia, Brooks et al., Identifying who has long COVID in the USA: a machine learning approach using N3C data, Lancet Digit Health
Pfaff, Girvin, Gabriel, Kostka, Morris et al., Synergies between centralized and federated approaches to data quality: a report from the national COVID cohort collaborative, J Am Med Inform Assoc
Schneider, Peltz, Li, Bahorik, Gardner et al., Traumatic Brain Injury and Long-Term Risk of Stroke Among US Military Veterans, Stroke
Soriano, Murthy, Marshall, Relan, Diaz, WHO Clinical Case Definition Working Group on Post-COVID-19 Condition. A clinical case definition of post-COVID-19 condition by a Delphi consensus, Lancet Infect Dis
Stuart, Matching methods for causal inference: A review and a look forward, Stat Sci
Van Walraven, Bennett, Forster, Administrative database research infrequently used validated diagnostic or procedural codes, J Clin Epidemiol
Visvabharathy, Orban, Koralnik, Case report: Treatment of long COVID with a SARS-CoV-2 antiviral and IL-6 blockade in a patient with rheumatoid arthritis and SARS-CoV-2 antigen persistence, Front Med
Wang, Shaw, Mathelier, Kimmel, French, Evaluating Risk-Prediction Models Using Data from Electronic Health Records, Ann Appl Stat
Wells, Chagin, Nowacki, Kattan, Strategies for handling missing data in electronic health record derived data, EGEMS
Wen, Chen, Tang, Wang, Zhou et al., Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19：a meta-analysis, Ann Med
Wiltz, Feehan, Molinari, Ladva, Truman et al., Racial and Ethnic Disparities in Receipt of Medications for Treatment of COVID-19 -United States, March 2020-August 2021, MMWR Morb Mortal Wkly Rep
Wu, Kumar, Moore, Hall, Vysniauskaite et al., Disparities in COVID-19 Monoclonal Antibody Delivery: a Retrospective Cohort Study, J Gen Intern Med
Xie, Bowe, Al-Aly, Burdens of post-acute sequelae of COVID-19 by severity of acute infection, demographics and health status, Nat Commun
Xie, Choi, Al-Aly, Association of Treatment With Nirmatrelvir and the Risk of Post-COVID-19 Condition, JAMA Intern Med
Yip, Lui, Lai, Wong, Tse et al., Impact of the Use of Oral Antiviral Agents on the Risk of Hospitalization in Community Coronavirus Disease 2019 Patients (COVID-19), Clin Infect Dis
Zang, Zhang, Xu, Bian, Morozyuk et al., Data-driven analysis to understand long COVID using electronic health records from the RECOVER initiative, Nat Commun
Zang, Zhang, Xu, Zhang, Fouladvand et al., High-throughput target trial emulation for Alzheimer's disease drug repurposing with real-world data, Nat Commun
Zhang, Zang, Xu, Zhang, Xu et al., Data-driven identification of post-acute SARS-CoV-2 infection subphenotypes, Nat Med
Zheng, Ma, Wang, Cheng, Zhou et al., Efficacy and safety of Paxlovid for COVID-19:a meta-analysis, J. Infect
