Effect of Oral Nirmatrelvir on Long COVID Symptoms: 4 Cases and Rationale for Systematic Studies

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Michael J. Peluso, M.D.
Khamal Anglin, M.D.
Matthew S. Durstenfeld, M.D.
Jeffrey N. Martin, M.D.
J. Daniel Kelly, M.D., Ph.D.
Priscilla Y. Hsue, M.D.
Timothy J. Henrich, M.D.
Steven G. Deeks, M.D.


Background: Efforts to understand the impact of SARS-CoV-2 variants, vaccine status, and treatment on the development and persistence of Long COVID have intensified. 

Methods: We report 4 sequential cases from a post-COVID cohort study demonstrating variability in outcomes following differentially timed nirmatrelvir therapy, received as part of clinical care. 

Results: In the first case, the participant experienced symptomatic rebound and developed Long COVID despite early initiation of antiviral therapy. In the next 2 cases, participants reported improvement in persistent COVID symptoms when nirmatrelvir was taken 25 and 60 days following initial symptom onset. In the final case, an individual with presumed Long COVID for 2 years reported substantial improvement in chronic symptoms when taking nirmatrelvir following SARS-CoV-2 re-infection. 

Conclusions: These anecdotes suggest that systematic study of antiviral therapy for Long COVID is warranted.


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Su Y, Yuan D, Chen DG, Ng RH, Wang K, Choi J, Li S, Hong S, Zhang R, Xie J, Kornilov SA, Scherler K, Pavlovitch-Bedzyk AJ, Dong S, Lausted C, Lee I, Fallen S, Dai CL, Baloni P, Smith B, Duvvuri VR, Anderson KG, Li J, Yang F, Duncombe CJ, McCulloch DJ, Rostomily C, Troisch P, Zhou J, Mackay S, DeGottardi Q, May DH, Taniguchi R, Gittelman RM, Klinger M, Snyder TM, Roper R, Wojciechowska G, Murray K, Edmark R, Evans S, Jones L, Zhou Y, Rowen L, Liu R, Chour W, Algren HA, Berrington WR, Wallick JA, Cochran RA, Micikas ME, Unit IS-SC-B, Wrin T, Petropoulos CJ, Cole HR, Fischer TD, Wei W, Hoon DSB, Price ND, Subramanian N, Hill JA, Hadlock J, Magis AT, Ribas A, Lanier LL, Boyd SD, Bluestone JA, Chu H, Hood L, Gottardo R, Greenberg PD, Davis MM, Goldman JD, Heath JR. Multiple early factors anticipate post-acute COVID-19 sequelae. Cell. 2022;185(5):881-95 e20. doi: 10.1016/j.cell.2022.01.014. PubMed PMID: 35216672; PMCID: PMC8786632.

Paxlovid EUA. Accessed May 1, 2022. Available from: https://aspr.hhs.gov/COVID-19/Therapeutics/Products/Paxlovid/Pages/emergency-use-authorization.aspx

Gupta K, Strymish J, Stack G, Charness M. Rapid relapse of symptomatic SARS-CoV-2 infection following early suppression with nirmatrelvir/ritonavir. Research Square. Preprint posted online April 26, 2022; Updated May 23, 2022.. doi: 10.21203/rs.3.rs-1588371/v1.

CDC. Post-COVID conditions. Centers for Disease Control and Prevention. Accessed April 30, 2022. Available from: https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html

Szekely Y, Lichter Y, Sadon S, Lupu L, Taieb P, Banai A, Sapir O, Granot Y, Hochstadt A, Friedman S, Laufer-Perl M, Banai S, Topilsky Y. Cardiorespiratory Abnormalities in Patients Recovering from Coronavirus Disease 2019. J Am Soc Echocardiogr. 2021;34(12):1273-84 e9. doi: 10.1016/j.echo.2021.08.022. PubMed PMID: 34508837; PMCID: PMC8425293.

Cassar MP, Tunnicliffe EM, Petousi N, Lewandowski AJ, Xie C, Mahmod M, Samat AHA, Evans RA, Brightling CE, Ho LP, Piechnik SK, Talbot NP, Holdsworth D, Ferreira VM, Neubauer S, Raman B. Symptom Persistence Despite Improvement in Cardiopulmonary Health - Insights from longitudinal CMR, CPET and lung function testing post-COVID-19. EClinicalMedicine. 2021;41:101159. doi: 10.1016/j.eclinm.2021.101159. PubMed PMID: 34693230; PMCID: PMC8527025.

Evers G, Schulze AB, Osiaevi I, Harmening K, Vollenberg R, Wiewrodt R, Pistulli R, Boentert M, Tepasse PR, Sindermann JR, Yilmaz A, Mohr M. Sustained Impairment in Cardiopulmonary Exercise Capacity Testing in Patients after COVID-19: A Single Center Experience. Can Respir J. 2022;2022:2466789. doi: 10.1155/2022/2466789. PubMed PMID: 35242250; PMCID: PMC8886771.

Hammond J, Leister-Tebbe H, Gardner A, Abreu P, Bao W, Wisemandle W, Baniecki M, Hendrick VM, Damle B, Simon-Campos A, Pypstra R, Rusnak JM, Investigators E-H. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med. 2022;386(15):1397-408. doi: 10.1056/NEJMoa2118542. PubMed PMID: 35172054; PMCID: PMC8908851.

Gaebler C, Wang Z, Lorenzi JCC, Muecksch F, Finkin S, Tokuyama M, Cho A, Jankovic M, Schaefer-Babajew D, Oliveira TY, Cipolla M, Viant C, Barnes CO, Bram Y, Breton G, Hagglof T, Mendoza P, Hurley A, Turroja M, Gordon K, Millard KG, Ramos V, Schmidt F, Weisblum Y, Jha D, Tankelevich M, Martinez-Delgado G, Yee J, Patel R, Dizon J, Unson-O’Brien C, Shimeliovich I, Robbiani DF, Zhao Z, Gazumyan A, Schwartz RE, Hatziioannou T, Bjorkman PJ, Mehandru S, Bieniasz PD, Caskey M, Nussenzweig MC. Evolution of antibody immunity to SARS-CoV-2. Nature. 2021;591(7851):639-44. doi: 10.1038/s41586-021-03207-w. PubMed PMID: 33461210; PMCID: PMC8221082.

Chertow D, Stein S, Ramelli S, Grazioli A, Chung J-Y, Singh M, Yinda CK, Winkler C, Dickey J, Ylaya K, Ko SH, Platt A, Burbelo P, Quezado M, Pittaluga S, Purcell M, Munster V, Belinky F, Ramos-Benitez M, Boritz E, Herr D, Rabin J, Saharia K, Madathil R, Tabatabai A, Soherwardi S, McCurdy M, Peterson K, Cohen J, de Wit E, Vannella K, Hewitt S, Kleiner D. SARS-CoV-2 infection and persistence throughout the human body and brain. Research Square. Preprint posted online December 10, 2021. doi: 10.21203/rs.3.rs-1139035/v1. [In Review]

Natarajan A, Zlitni S, Brooks EF, Vance SE, Dahlen A, Hedlin H, Park RM, Han A, Schmidtke DT, Verma R, Jacobson KB, Parsonnet J, Bonilla HF, Singh U, Pinsky BA, Andrews JR, Jagannathan P, Bhatt AS. Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA suggest prolonged gastrointestinal infection. Med (N Y). 2022;0(0). doi: 10.1016/j.medj.2022.04.001. PubMed PMID: 35434682; PMCID: PMC9005383.

Geng LN, Bonilla HF, Shafer RW, Miglis MG, Yang PC. Case Report of Breakthrough Long COVID and the Use of Nirmatrelvir-Ritonavir. Research Square. Preprint posted online March 15, 2022. doi: 10.21203/rs.3.rs-1443341/v1.

Peluso MJ, Deeks SG, Mustapic M, Kapogiannis D, Henrich TJ, Lu S, Goldberg SA, Hoh R, Chen JY, Martinez EO, Kelly JD, Martin JN, Goetzl EJ. SARS-CoV-2 and Mitochondrial Proteins in Neural-Derived Exosomes of COVID-19. Ann Neurol. 2022;91(6):772-81. doi: 10.1002/ana.26350. PubMed PMID: 35285072; PMCID: PMC9082480.

Antonelli M, Penfold RS, Merino J, Sudre CH, Molteni E, Berry S, Canas LS, Graham MS, Klaser K, Modat M, Murray B, Kerfoot E, Chen L, Deng J, Osterdahl MF, Cheetham NJ, Drew DA, Nguyen LH, Pujol JC, Hu C, Selvachandran S, Polidori L, May A, Wolf J, Chan AT, Hammers A, Duncan EL, Spector TD, Ourselin S, Steves CJ. Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study. Lancet Infect Dis. 2022;22(1):43-55. doi: 10.1016/S1473-3099(21)00460-6. PubMed PMID: 34480857; PMCID: PMC8409907

Groff D, Sun A, Ssentongo AE, Ba DM, Parsons N, Poudel GR, Lekoubou A, Oh JS, Ericson JE, Ssentongo P, Chinchilli VM. Short-term and Long-term Rates of Postacute Sequelae of SARS-CoV-2 Infection: A Systematic Review. JAMA Netw Open. 2021;4(10):e2128568. doi: 10.1001/jamanetworkopen.2021.28568. PubMed PMID: 34643720; PMCID: PMC8515212.

Tran V-T, Perrodeau E, Saldanha J, Pane I, Ravaud P. Efficacy of COVID-19 vaccination on the symptoms of patients with long COVID: a target trial emulation using data from the ComPaRe e-cohort in France. Research Square. Preprint posted online February 17, 2022. doi: 10.21203/rs.3.rs-1350429/v1.

Peluso MJ, Lu S, Tang AF, Durstenfeld MS, Ho HE, Goldberg SA, Forman CA, Munter SE, Hoh R, Tai V, Chenna A, Yee BC, Winslow JW, Petropoulos CJ, Greenhouse B, Hunt PW, Hsue PY, Martin JN, Daniel Kelly J, Glidden DV, Deeks SG, Henrich TJ. Markers of Immune Activation and Inflammation in Individuals With Postacute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 Infection. J Infect Dis. 2021;224(11):1839-48. doi: 10.1093/infdis/jiab490. PubMed PMID: 34677601; PMCID: PMC8643408.

Phetsouphanh C, Darley DR, Wilson DB, Howe A, Munier CML, Patel SK, Juno JA, Burrell LM, Kent SJ, Dore GJ, Kelleher AD, Matthews GV. Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection. Nat Immunol. 2022;23(2):210-6. doi: 10.1038/s41590-021-01113-x. PubMed PMID: 35027728.

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