Nirmatrelvir Plus Ritonavir for Early COVID-19 in a Large U.S. Health System

Dryden-Peterson et al., Annals of Internal Medicine, doi:10.7326/M22-2141, Dec 2022 (preprint)

https://c19early.org/drydenpeterson.html

IPW retrospective 44,551 outpatients age 50+ in the USA, showing lower mortality and hospitalization with paxlovid treatment.

Resistance. Variants may be resistant to paxlovid1-6. Use may promote the emergence of variants that weaken host immunity and potentially contribute to long COVID7.

Confounding by contraindication. Hoertel et al. find that over 50% of patients that died had a contraindication for the use of Paxlovid8. 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 paxlovid"9.

Kidney and liver injury. Studies show significantly increased risk of acute kidney injury10 and liver injury11.

Standard of Care (SOC) for COVID-19 in the study country, the USA, is very poor with very low average efficacy for approved treatments12. Only expensive, high-profit treatments were approved. Low-cost treatments were excluded, reducing the probability of treatment—especially early—due to access and cost barriers, and eliminating complementary and synergistic benefits seen with many low-cost treatments.

This study is excluded in the after exclusion results of meta analysis: only a fraction of eligible patients received treatment and these patients may be more likely to follow other recommendations, receive additional care, and more more likely to use additional untracked treatments such as vitamin D and nasal/oral hygiene.

Important missing comments or errors? Let us know.

risk of death, 71.0% lower, RR 0.29, p = 0.006, treatment 11,797, control 32,248, propensity score weighting.

risk of death/hospitalization, 44.0% lower, RR 0.56, p < 0.001, treatment 69 of 11,797 (0.6%), control 310 of 32,248 (1.0%), NNT 266, propensity score weighting.

risk of hospitalization, 40.0% lower, RR 0.60, p = 0.001, treatment 11,797, control 32,248, propensity score weighting.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

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. 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.

8. 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.

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

10. 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.

11. 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.

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

Dryden-Peterson et al., 13 Dec 2022, retrospective, USA, peer-reviewed, 12 authors, study period 1 January, 2022 - 17 July, 2022. Contact: sldrydenpeterson@bwh.harvard.edu.

This Paper Paxlovid All

Nirmatrelvir Plus Ritonavir for Early COVID-19 in a Large U.S. Health System

MD, MSc Scott Dryden-Peterson, BS Andy Kim, MD Arthur Y Kim, ScD Ellen C Caniglia, MD, MPH, MBA Inga T Lennes, MD, MPH Rajesh Patel, RN Lindsay Gainer, RN Lisa Dutton, RN, MSN, NP-C Elizabeth Donahue, MD Rajesh T Gandhi, MD Lindsey R Baden, MD, MPH Ann E Woolley

Annals of Internal Medicine, doi:10.7326/m22-2141

Background: In the EPIC-HR (Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients) trial, nirmatrelvir plus ritonavir led to an 89% reduction in hospitalization or death among unvaccinated outpatients with early COVID-19. The clinical impact of nirmatrelvir plus ritonavir among vaccinated populations is uncertain. Objective: To assess whether nirmatrelvir plus ritonavir reduces risk for hospitalization or death among outpatients with early COVID-19 in the setting of prevalent SARS-CoV-2 immunity and immune-evasive SARS-CoV-2 lineages. Design: Population-based cohort study analyzed to emulate a clinical trial using inverse probability-weighted models to account for anticipated bias in treatment. Setting: A large health care system providing care for 1.5 million patients in Massachusetts and New Hampshire during the Omicron wave (1 January to 17 July 2022). Patients: 44 551 nonhospitalized adults (90.3% with ≥3 vaccine doses) aged 50 years or older with COVID-19 and no contraindications for nirmatrelvir plus ritonavir. Measurements: The primary outcome was a composite of hospitalization within 14 days or death within 28 days of a COVID-19 diagnosis. Results: During the study period, 12 541 (28.1%) patients were prescribed nirmatrelvir plus ritonavir, and 32 010 (71.9%) were not. Patients prescribed nirmatrelvir plus ritonavir were more likely to be older, have more comorbidities, and be vaccinated. The composite outcome of hospitalization or death occurred in 69 (0.55%) patients who were prescribed nirmatrelvir plus ritonavir and 310 (0.97%) who were not (adjusted risk ratio, 0.56 [95% CI, 0.42 to 0.75]). Recipients of nirmatrelvir plus ritonavir had lower risk for hospitalization (adjusted risk ratio, 0.60 [CI, 0.44 to 0.81]) and death (adjusted risk ratio, 0.29 [CI, 0.12 to 0.71]). Limitation: Potential residual confounding due to differential access to COVID-19 vaccines, diagnostic tests, and treatment. Conclusion: The overall risk for hospitalization or death was already low (1%) after an outpatient diagnosis of COVID-19, but nirmatrelvir plus ritonavir reduced this risk further.

Author contributions are available at Annals.org. Previous Posting: This manuscript was posted as a preprint on medRxiv on 17 June 2022. doi:10.1101/2022.06. 14.22276393

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