Association of nirmatrelvir for acute SARS‐CoV‐2 infection with subsequent Long COVID symptoms in an observational cohort study
Matthew S Durstenfeld, Michael J Peluso, Feng Lin, Noah D Peyser, Carmen Isasi, Thomas W Carton, Timothy J Henrich, Steven G Deeks, Jeffrey E Olgin, Mark J Pletcher, Alexis L Beatty, Gregory M Marcus, Priscilla Y Hsue
Journal of Medical Virology, doi:10.1002/jmv.29333
Oral nirmatrelvir/ritonavir is approved as treatment for acute COVID-19, but the effect of treatment during acute infection on risk of Long COVID is unknown. We hypothesized that nirmatrelvir treatment during acute SARS-CoV-2 infection reduces risk of developing Long COVID and rebound after treatment is associated with Long COVID. We conducted an observational cohort study within the Covid Citizen Science (CCS) study, an online cohort study with over 100 000 participants. We included vaccinated, nonhospitalized, nonpregnant individuals who reported their first SARS-CoV-2 positive test March-August 2022. Oral nirmatrelvir/ritonavir treatment was ascertained during acute SARS-CoV-2 infection. Patient-reported Long COVID symptoms, symptom rebound and test-positivity rebound were asked on subsequent surveys at least 3 months after SARS-CoV-2 infection. A total of 4684 individuals met the eligibility criteria, of whom 988 (21.1%) were treated and 3696 (78.9%) were untreated; 353/988 (35.7%) treated and 1258/3696 (34.0%) untreated responded to the Long COVID survey (n = 1611). Among 1611 participants, median
The other authors report no conflicts of interest.
DATA AVAILABILITY STATEMENT The data that support the findings of this study are available from the corresponding author upon reasonable request. Data are available by application to the COVID Citizen Science leadership committee. Data may be requested by emailing covid19@eurekaplatform.org.
SUPPORTING INFORMATION Additional supporting information can be found online in the Supporting Information section at the end of this article.
References
Antar, Yu, Demko, Long COVID brain fog and muscle pain are associated with longer time to clearance of SARS-CoV-2 RNA from the upper respiratory tract during acute infection, Front Immunol,
doi:10.3389/fimmu.2023.1147549Apple, Oddi, Peluso, Risk factors and abnormal cerebrospinal fluid associate with cognitive symptoms after mild COVID-19, Ann Clin Transl Neurol
Bajema, Berry, Streja, Effectiveness of COVID-19 treatment with nirmatrelvir-ritonavir or molnupiravir among U.S. veterans: target trial emulation studies with one-month and sixmonth outcomes, Ann Intern Med
Beatty, Peyser, Butcher, The COVID-19 citizen science study: protocol for a longitudinal digital health cohort study, JMIR Res Protoc
Congdon, Narrowe, Yone, Nirmatrelvir/ritonavir and risk of long COVID symptoms: a retrospective cohort study, Sci Rep
Dryden-Peterson, Kim, Kim, Nirmatrelvir plus ritonavir for early COVID-19 in a large U.S. health system: a population-based cohort study, Ann Intern Med
Durstenfeld, Peluso, Kaveti, Reduced Exercise Capacity, Chronotropic incompetence, and early systemic inflammation in cardiopulmonary phenotype long coronavirus disease 2019, J Infect Dis,
doi:10.1093/infdis/jiad131Durstenfeld, Peluso, Peyser, Factors associated with long COVID symptoms in an online cohort study, Open Forum Infect Dis
Edelstein, Boucau, Uddin, SARS-CoV-2 virologic rebound with nirmatrelvir-ritonavir therapy: an observational study, Ann Intern Med,
doi:10.7326/M23-1756Geng, Bonilla, Shafer, Miglis, Yang, The use of nirmatrelvir-ritonavir in a case of breakthrough long COVID, Explor Res Hypothesis Med,
doi:10.14218/ERHM.2022.00045Hammond, Leister-Tebbe, Gardner, Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19, N Engl J Med
Hansen, Makkar, Sahner, Paxlovid (nirmatrelvir/ ritonavir) effectiveness against hospitalization and death in N3C: a target trial emulation study, medRxiv,
doi:10.1101/2023.05.26.23290602Hernán, Robins, Using big data to emulate a target trial when a randomized trial is not available, Am J Epidemiol
Najjar-Debbiny, Gronich, Weber, Effectiveness of paxlovid in reducing severe COVID-19 and mortality in high risk patients, Clin Infect Dis
Natarajan, Zlitni, Brooks, Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA suggest prolonged gastrointestinal infection, Med
Patel, Dani, Khadke, Incidence of symptoms associated with post-acute sequelae of SARS-CoV-2 infection in nonhospitalized vaccinated patients receiving Nirmatrelvir-Ritonavir, medRxiv,
doi:10.1101/2023.04.05.23288196Peluso, Anglin, Durstenfeld, Effect of oral nirmatrelvir on Long COVID symptoms: 4 cases and rationale for systematic studies, Pathogens and Immunity
Peluso, Deeks, Mustapic, SARS-CoV-2 and mitochondrial proteins in neural-derived exosomes of COVID-19, Ann Neurol
Peluso, Ryder, Flavell, Multimodal molecular imaging reveals tissue-based T cell activation and viral RNA persistence for up to 2 years following COVID-19, medRxiv,
doi:10.1101/2023.07.27.23293177Qi, Wang, Nirmatrelvir-ritonavir therapy and COVID-19 vaccination improve clinical outcomes of SARS-CoV-2 omicron variant infection, J Med Virol,
doi:10.1002/jmv.28497Ranganath, Horo, Challener, Rebound phenomenon after nirmatrelvir/ritonavir treatment of coronavirus disease 2019 (COVID-19) in high-risk persons, Clin Infect Dis
Shah, Joyce, Plumb, Paxlovid associated with decreased hospitalization rate among adults with COVID-19 -United States, April-September 2022, Am J Transplant (AJT)
Soriano, Murthy, Marshall, Relan, Diaz, A clinical case definition of post-COVID-19 condition by a Delphi consensus, The Lancet Infectious Diseases
Stein, Ramelli, Grazioli, SARS-CoV-2 infection and persistence in the human body and brain at autopsy, Nature
Su, Yuan, Chen, Multiple early factors anticipate postacute COVID-19 sequelae, Cell
Swank, Senussi, Manickas-Hill, Persistent circulating SARS-CoV-2 spike is associated with post-acute COVID-19 sequelae, Clin Infect Dis,
doi:10.1093/cid/ciac722Uhm, Ahn, Hyun, Patterns of viral clearance in the natural course of asymptomatic COVID-19: comparison with symptomatic non-severe COVID-19, Int J Infect Dis
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
Von Elm, Altman, Egger, Pocock, Gøtzsche et al., The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies, Ann Intern Med
Wai, Chan, Cheung, Association of molnupiravir and Nirmatrelvir-Ritonavir with preventable mortality, hospital admissions and related avoidable healthcare system cost among high-risk patients with mild to moderate COVID-19, Lancet Reg Health West Pac
Wang, Zhao, Liu, Chen, Feng, Early administration of paxlovid reduces the viral elimination time in patients infected with SARS-CoV-2 omicron variants, J Med Virol
Watanabe, Iwagami, Yasuhara, Takagi, Kuno, Protective effect of COVID-19 vaccination against long COVID syndrome: a systematic review and meta-analysis, Vaccine
Wong, Au, Lau, Lau, Cowling et al., Real-world effectiveness of early molnupiravir or nirmatrelvirritonavir in hospitalised patients with COVID-19 without supplemental oxygen requirement on admission during Hong Kong's omicron BA.2 wave: a retrospective cohort study, Lancet Infect Dis
Wong, Yip, Lai, Wong, Hui et al., Incidence of viral rebound after treatment with nirmatrelvir-ritonavir and molnupiravir, JAMA Network Open
Xie, Choi, Al-Aly, Association of treatment with nirmatrelvir and the risk of post-COVID-19 condition, JAMA Int Med
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