Risk of Post-COVID Conditions among adolescents and adults who received nirmatrelvir-ritonavir for acute COVID-19: a retrospective cohort study

Dalton et al., medRxiv, doi:10.1101/2025.05.30.25327809, May 2025

https://c19early.org/dalton2.html

Retrospective 291,433 paxlovid recipients matched 1:2 to 582,866 untreated COVID-19 outpatients in the USA reporting a modest reduction in long COVID in the primary model for patients 50+. Analysis requiring a positive laboratory test or ICD-10 diagnosis, removing prescription-only cases solely in the treated arm and thereby eliminating asymmetric misclassification, shows overall HR 1.01 and benefit only for adults ≥65. As paxlovid’s antiviral mechanism is not age-dependent, the age-restricted benefit may reflect residual healthy-user bias whereby healthier, more proactive seniors are more inclined and able to seek treatment, as often seen in other studies. These more health-conscious patients are also more likely to take other steps to reduce risk along with other non-prescription treatments.

Resistance. Variants may be resistant to paxlovid1-7. Use may promote the emergence of variants that weaken host immunity and potentially contribute to long COVID8.

Confounding by contraindication. Hoertel et al. find that over 50% of patients that died had a contraindication for the use of Paxlovid9. 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 paxlovid10.

Kidney and liver injury. Studies show significantly increased risk of acute kidney injury11 and liver injury12.

Standard of Care (SOC) for COVID-19 in the study country, the USA, is very poor with very low average efficacy for approved treatments13. Only expensive, high-profit treatments were approved for early treatment. Low-cost treatments were excluded, reducing the probability of early treatment due to access and cost barriers, and eliminating complementary and synergistic benefits seen with many low-cost treatments.

Important missing comments or errors? Let us know.

risk of PASC, 1.0% higher, RR 1.01, p = 0.048, adjusted per study, all patients, 1+ PCC, positive test or ICD-10 diagnosis.

risk of PASC, 8.0% higher, RR 1.08, p = 0.04, adjusted per study, 12-17, 1+ PCC, positive test or ICD-10 diagnosis.

risk of PASC, 5.0% higher, RR 1.05, p < 0.001, adjusted per study, 18-49, 1+ PCC, positive test or ICD-10 diagnosis.

risk of PASC, 2.0% higher, RR 1.02, p = 0.008, adjusted per study, 50-64, 1+ PCC, positive test or ICD-10 diagnosis.

risk of PASC, 8.0% lower, RR 0.92, p < 0.001, adjusted per study, 65+, 1+ PCC, positive test or ICD-10 diagnosis.

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1. Zhou et al., Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system, Science Advances, doi:10.1126/sciadv.add7197.science.org, doi.org.

2. Moghadasi et al., Rapid resistance profiling of SARS-CoV-2 protease inhibitors, npj Antimicrobials and Resistance, doi:10.1038/s44259-023-00009-0.nature.com, doi.org.

3. Jochmans et al., The Substitutions L50F, E166A, and L167F in SARS-CoV-2 3CLpro Are Selected by a Protease Inhibitor In Vitro and Confer Resistance To Nirmatrelvir, mBio, doi:10.1128/mbio.02815-22.asm.org, doi.org.

4. Lopez et al., SARS-CoV-2 Resistance to Small Molecule Inhibitors, Current Clinical Microbiology Reports, doi:10.1007/s40588-024-00229-6.springer.com, doi.org.

5. Zvornicanin et al., Molecular Mechanisms of Drug Resistance and Compensation in SARS-CoV-2 Main Protease: The Interplay Between E166 and L50, bioRxiv, doi:10.1101/2025.01.24.634813.biorxiv.org, doi.org.

6. Vukovikj et al., Impact of SARS-CoV-2 variant mutations on susceptibility to monoclonal antibodies and antiviral drugs: a non-systematic review, April 2022 to October 2024, Eurosurveillance, doi:10.2807/1560-7917.ES.2025.30.10.2400252.eurosurveillance.org, doi.org.

7. Deschenes et al., Functional and structural characterization of treatment-emergent nirmatrelvir resistance mutations at low frequencies in the main protease (Mpro) reveals a unique evolutionary route for SARS-CoV-2 to gain resistance, The Journal of Infectious Diseases, doi:10.1093/infdis/jiaf294.oup.com, doi.org.

8. Thomas et al., Nirmatrelvir-Resistant Mutations in SARS-CoV-2 Mpro Enhance Host Immune Evasion via Cleavage of NF-κB Essential Modulator, bioRxiv, doi:10.1101/2024.10.18.619137.biorxiv.org, doi.org.

9. Hoertel et al., Prevalence of Contraindications to Nirmatrelvir-Ritonavir Among Hospitalized Patients With COVID-19 at Risk for Progression to Severe Disease, JAMA Network Open, doi:10.1001/jamanetworkopen.2022.42140.jamanetwork.com, doi.org.

10. FDA, Fact sheet for healthcare providers: emergency use authorization for paxlovid, www.fda.gov/media/155050/download.fda.gov.

11. Kamo et al., Association of Antiviral Drugs for the Treatment of COVID-19 With Acute Renal Failure, In Vivo, doi:10.21873/invivo.13637.iiarjournals.org, doi.org.

12. Wang et al., Development and validation of a nomogram to assess the occurrence of liver dysfunction in patients with COVID-19 pneumonia in the ICU, BMC Infectious Diseases, doi:10.1186/s12879-025-10684-1.biomedcentral.com, doi.org.

13. c19early.org, c19early.org/soc/usa.html.c19early.org/soc/usa.html.

Dalton et al., 31 May 2025, retrospective, USA, preprint, 9 authors, study period 1 April, 2022 - 31 December, 2022. Contact: adalton@cdc.gov.

This Paper Paxlovid All

Risk of Post-COVID Conditions among adolescents and adults who received nirmatrelvir-ritonavir for acute COVID-19: a retrospective cohort study

PhD Alexandra F Dalton, Sarah Baca, PhD Julia Raykin, PhD Cria O Gregory, PhD Tegan K Boehmer, MD, MPH Emilia H Koumans, MD, MPH Priti R Patel, MD, MPH Pragna Patel, Sharon Saydeh

doi:10.1101/2025.05.30.25327809

Introduction: Post-COVID Conditions (PCC) potentially affect millions of people, but it is unclear whether treating acute COVID-19 with nirmatrelvir-ritonavir may reduce the risk of PCC. Methods: Retrospective cohort study using real-world, closed claims data to assess the relationship between nirmatrelvir-ritonavir and PCC by age group (12-17, 18-49, 50-64, ≥65 years). Eligible patients had a COVID-19 index date (positive laboratory test, ICD-10 diagnosis code, or nirmatrelvir-ritonavir prescription) from April 1 -August 31, 2022, in the outpatient, telehealth, or emergency department setting, and had a higher risk of severe COVID-19 based on age (≥50 years) or underlying risk factors. Treated patients (i.e., received a nirmatrelvir-ritonavir prescription within +/-5 days of index date) were matched 1:2 on age, sex, month of index date, and HHS region with untreated patients. PCC was defined by the presence of ≥1 of 45 new-onset symptoms or conditions recorded ≥60 days after index date. Results: 291,433 treated patients were matched to 582,866 untreated patients. Treatment with nirmatrelvirritonavir reduced PCC risk in adults 50-64 years (aHR 0.93, 95%CI 0.92-0.95) and ≥65 years (aHR 0.88, 95% CI 0.87-0.90). Treatment had minimal effect among high-risk adults 18-49 years (aHR 0.98, 95% CI 0.97-0.99), and no effect among high-risk adolescents 12-17 years (aHR 1.06, 95% CI 0.66-1.13). Conclusion: Results using real-world data suggest a protective relationship between nirmatrelvir-ritonavir during acute illness and PCC risk among older adults, but not among adolescents. Consideration may be given to outpatient treatment of mild to moderate COVID-19 with nirmatrelvir-ritonavir to reduce the risk of severe disease and PCC.

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