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COVID-19 hospitalization risk after outpatient nirmatrelvir/ritonavir use, January to August 2022, North Carolina

Henderson et al., Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkae042

Feb 2024

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EHR retrospective 44, 671 patients with 4,948 receiving paxlovid, showing lower hospitalization with treatment.

Confounding by treatment propensity. This study analyzes a population where only a fraction of eligible patients received the treatment. Patients receiving treatment may be more likely to follow other recommendations, more likely to receive additional care, and more likely to use additional treatments that are not tracked in the data (e.g., nasal/oral hygiene1,2, vitamin D3, etc.) — either because the physician recommending paxlovid also recommended them, or because the patient seeking out paxlovid is more likely to be familiar with the efficacy of additional treatments and more likely to take the time to use them. Malden et al. confirm significant bias in the use of paxlovid, showing that treated patients are more likely to be from affluent neighborhoods, be more health-conscious, and have better access to care. Therefore, these kind of studies may overestimate the efficacy of treatments.

Resistance. Variants may be resistant to paxlovid5-7. 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 paxlovid"10.

AKI. Kamo et al. show significantly increased risk of acute kidney injury.

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 hospitalization, 84.0% lower, HR 0.16, p = 0.002, treatment 4,948, control 39,723.

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

1. c19early.org, c19early.org/p.c19early.org/p.

2. c19early.org (B), c19early.org/ph.c19early.org/ph.

3. c19early.org (C), c19early.org/d.c19early.org/d.

4. Malden et al., Predictors of nirmatrelvir–ritonavir receipt among COVID-19 patients in a large US health system, Scientific Reports, doi:10.1038/s41598-024-57633-7.nature.com, doi.org.

5. 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.

6. 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.

7. 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.

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.

Henderson et al., 21 Feb 2024, retrospective, USA, peer-reviewed, 11 authors, study period January 2022 - August 2022.

This Paper Paxlovid All

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We evaluated ' 'the association of nirmatrelvir/ritonavir therapy with time to hospitalization by estimating ' 'adjusted HRs and assessed the impact of nirmatrelvir/ritonavir on predicted COVID-19 ' 'hospitalizations using machine-learning methods.\n' ' \n' ' \n' ' Results\n' ' Among 44\u200a671 patients, 4948 (11%) received ' 'nirmatrelvir/ritonavir, and 201 (0.4%) were hospitalized within 28\u2005days of COVID-19 ' 'diagnosis. Nirmatrelvir/ritonavir recipients were more likely to be older, white, vaccinated, ' 'have comorbidities and reside in areas with higher average socioeconomic status. The 28\u2005' 'day cumulative incidence of hospitalization was 0.06% (95% CI: 0.02%–0.17%) among ' 'nirmatrelvir/ritonavir recipients and 0.52% (95% CI: 0.46%–0.60%) among non-recipients. For ' 'nirmatrelvir/ritonavir versus no therapy, the age-adjusted HR was 0.08 (95% CI: 0.03–0.26); ' 'the fully adjusted HR was 0.16 (95% CI: 0.05–0.50). In the machine-learning model, the ' 'primary features reducing predicted hospitalization risk were nirmatrelvir/ritonavir, younger ' 'age, vaccination, female gender and residence in a higher socioeconomic status ' 'area.\n' ' \n' ' \n' ' Conclusions\n' ' COVID-19 hospitalization risk was reduced by 84% among ' 'nirmatrelvir/ritonavir recipients in a large, diverse healthcare system during the Omicron ' 'wave. These results suggest that nirmatrelvir/ritonavir remained highly effective in a ' 'setting substantially different than the original clinical trials.\n' ' ', 'DOI': '10.1093/jac/dkae042', 'type': 'journal-article', 'created': {'date-parts': [[2024, 2, 21]], 'date-time': '2024-02-21T15:52:32Z', 'timestamp': 1708530752000}, 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'COVID-19 hospitalization risk after outpatient nirmatrelvir/ritonavir use, January to August ' '2022, North Carolina', 'prefix': '10.1093', 'author': [ { 'ORCID': 'http://orcid.org/0000-0002-2197-3149', 'authenticated-orcid': False, 'given': 'Heather I', 'family': 'Henderson', 'sequence': 'first', 'affiliation': [ { 'name': 'Department of Medicine, University of North Carolina at Chapel ' 'Hill, School of Medicine , 130 Mason Farm Road, Chapel Hill, NC ' '27599 , USA'}]}, { 'ORCID': 'http://orcid.org/0000-0002-7764-0212', 'authenticated-orcid': False, 'given': 'David A', 'family': 'Wohl', 'sequence': 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