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

Source PDF All Studies Meta AnalysisMeta

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.

Confounding by contraindication. Hoertel et al. find that over 50% of patients that died had a contraindication for the use of Paxlovid5. 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"6.

Kamo et al. show significantly increased risk of acute kidney injury. Resistant variants are likely8,9.

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. 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.

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

7. 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.

8. 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.

9. 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.

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

This Paper Paxlovid All

{ 'indexed': {'date-parts': [[2024, 2, 22]], 'date-time': '2024-02-22T01:03:04Z', 'timestamp': 1708563784223}, 'reference-count': 32, 'publisher': 'Oxford University Press (OUP)', 'license': [ { 'start': { 'date-parts': [[2024, 2, 21]], 'date-time': '2024-02-21T00:00:00Z', 'timestamp': 1708473600000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://academic.oup.com/pages/standard-publication-reuse-rights'}], 'funder': [ { 'name': 'University of North Carolina at Chapel Hill Center for AIDS Research', 'award': ['P30 AI50410']}, { 'DOI': '10.13039/100006108', 'name': 'National Center for Advancing Translational Sciences', 'doi-asserted-by': 'publisher'}, { 'DOI': '10.13039/100000002', 'name': 'NIH', 'doi-asserted-by': 'publisher', 'award': ['TL1TR002491']}, {'name': 'NIH-funded SeroNet Serocenter of Excellence Award', 'award': ['U54 CA260543']}, { 'DOI': '10.13039/100000060', 'name': 'National Institute of Allergy and Infectious Diseases', 'doi-asserted-by': 'publisher', 'award': ['T32 AI007001']}], 'content-domain': {'domain': [], 'crossmark-restriction': False}, 'abstract': 'Abstract\n' ' \n' ' Background\n' ' In the USA, nirmatrelvir/ritonavir is authorized for the treatment ' 'of mild-to-moderate COVID-19 in patients at least 12\u2005years of age, at high risk for ' 'progression to severe COVID-19.\n' ' \n' ' \n' ' Objectives\n' ' To estimate the impact of outpatient nirmatrelvir/ritonavir on ' 'COVID-19 hospitalization risk in a US healthcare system.\n' ' \n' ' \n' ' Methods\n' ' We conducted a cohort study using electronic health records among ' 'outpatients with a positive SARS-CoV-2 PCR test between January and August 2022. 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': 'additional', '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/0000-0002-4900-098X', 'authenticated-orcid': False, 'given': 'William A', 'family': 'Fischer', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medicine, University of North Carolina at Chapel ' 'Hill, School of Medicine , 130 Mason Farm Road, Chapel Hill, NC ' '27599 , USA'}]}, { 'given': 'Luther A', 'family': 'Bartelt', 'sequence': 'additional', '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/0000-0003-4784-3227', 'authenticated-orcid': False, 'given': 'David', 'family': 'van Duin', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medicine, University of North Carolina at Chapel ' 'Hill, School of Medicine , 130 Mason Farm Road, Chapel Hill, NC ' '27599 , USA'}]}, { 'given': 'Deana M', 'family': 'Agil', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medicine, University of North Carolina at Chapel ' 'Hill, School of Medicine , 130 Mason Farm Road, Chapel Hill, NC ' '27599 , USA'}]}, { 'given': 'Lindsay E', 'family': 'Browne', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medicine, University of North Carolina at Chapel ' 'Hill, School of Medicine , 130 Mason Farm Road, Chapel Hill, NC ' '27599 , USA'}]}, { 'given': 'Kuo-Ping', 'family': 'Li', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medicine, University of North Carolina at Chapel ' 'Hill, School of Medicine , 130 Mason Farm Road, Chapel Hill, NC ' '27599 , USA'}]}, { 'given': 'Amanda', 'family': 'Moy', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medicine, University of North Carolina at Chapel ' 'Hill, School of Medicine , 130 Mason Farm Road, Chapel Hill, NC ' '27599 , USA'}]}, { 'given': 'Joseph J', 'family': 'Eron', 'sequence': 'additional', '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/0000-0002-9032-3713', 'authenticated-orcid': False, 'given': 'Sonia', 'family': 'Napravnik', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medicine, University of North Carolina at Chapel ' 'Hill, School of Medicine , 130 Mason Farm Road, Chapel Hill, NC ' '27599 , USA'}]}], 'member': '286', 'published-online': {'date-parts': [[2024, 2, 21]]}, 'reference': [ {'key': '2024022113595098600_dkae042-B1', 'author': 'CDC'}, {'key': '2024022113595098600_dkae042-B2', 'author': 'CDC'}, { 'key': '2024022113595098600_dkae042-B3', 'doi-asserted-by': 'crossref', 'first-page': '362', 'DOI': '10.7326/M20-6306', 'article-title': 'Racial and ethnic disparities in COVID-19–related infections, ' 'hospitalizations, and deaths', 'volume': '174', 'author': 'Mackey', 'year': '2020', 'journal-title': 'Ann Intern Med'}, {'key': '2024022113595098600_dkae042-B4', 'author': 'CDC'}, {'key': '2024022113595098600_dkae042-B5', 'author': 'National Institutes of Health'}, {'key': '2024022113595098600_dkae042-B6', 'author': 'Pfizer'}, { 'key': '2024022113595098600_dkae042-B7', 'doi-asserted-by': 'crossref', 'first-page': '1397', 'DOI': '10.1056/NEJMoa2118542', 'article-title': 'Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19', 'volume': '386', 'author': 'Hammond', 'year': '2022', 'journal-title': 'N Engl J Med'}, { 'key': '2024022113595098600_dkae042-B8', 'doi-asserted-by': 'crossref', 'first-page': 'e064498', 'DOI': '10.1136/bmjopen-2022-064498', 'article-title': 'Drug interventions for prevention of COVID-19 progression to severe ' 'disease in outpatients: a systematic review with meta-analyses and ' 'trial sequential analyses (the LIVING project)', 'volume': '13', 'author': 'Petersen', 'year': '2023', 'journal-title': 'BMJ Open'}, { 'key': '2024022113595098600_dkae042-B9', 'doi-asserted-by': 'crossref', 'first-page': '77', 'DOI': '10.7326/M22-2141', 'article-title': 'Nirmatrelvir plus ritonavir for early COVID-19 in a large U.S. health ' 'system', 'volume': '176', 'author': 'Dryden-Peterson', 'year': '2023', 'journal-title': 'Ann Intern Med'}, { 'key': '2024022113595098600_dkae042-B10', 'doi-asserted-by': 'crossref', 'first-page': '563', 'DOI': '10.1093/cid/ciac673', 'article-title': 'Oral nirmatrelvir and ritonavir in non-hospitalized vaccinated patients ' 'with Covid-19', 'volume': '76', 'author': 'Ganatra', 'year': '2023', 'journal-title': 'Clin Infect Dis'}, { 'key': '2024022113595098600_dkae042-B11', 'doi-asserted-by': 'crossref', 'first-page': 'e26', 'DOI': '10.1093/cid/ciac687', 'article-title': 'Impact of the use of oral antiviral agents on the risk of ' 'hospitalization in community COVID-19 patients', 'volume': '76', 'author': 'Yip', 'year': '2023', 'journal-title': 'Clin Infect Dis'}, { 'key': '2024022113595098600_dkae042-B12', 'doi-asserted-by': 'crossref', 'first-page': 'E220', 'DOI': '10.1503/cmaj.221608', 'article-title': 'Population-based evaluation of the effectiveness of ' 'nirmatrelvir-ritonavir for reducing hospital admissions and mortality ' 'from COVID-19', 'volume': '195', 'author': 'Schwartz', 'year': '2023', 'journal-title': 'CMAJ'}, { 'key': '2024022113595098600_dkae042-B13', 'doi-asserted-by': 'crossref', 'first-page': '790', 'DOI': '10.1056/NEJMoa2204919', 'article-title': 'Nirmatrelvir use and severe Covid-19 outcomes during the Omicron surge', 'volume': '387', 'author': 'Arbel', 'year': '2022', 'journal-title': 'N Engl J Med'}, { 'key': '2024022113595098600_dkae042-B14', 'doi-asserted-by': 'crossref', 'first-page': 'e342', 'DOI': '10.1093/cid/ciac443', 'article-title': 'Effectiveness of Paxlovid in reducing severe coronavirus disease 2019 ' 'and mortality in high-risk patients', 'volume': '76', 'author': 'Najjar-Debbiny', 'year': '2023', 'journal-title': 'Clin Infect Dis'}, { 'key': '2024022113595098600_dkae042-B15', 'doi-asserted-by': 'crossref', 'first-page': '1213', 'DOI': '10.1016/S0140-6736(22)01586-0', 'article-title': 'Real-world effectiveness of molnupiravir and nirmatrelvir plus ' 'ritonavir against mortality, hospitalisation, and in-hospital outcomes ' 'among community-dwelling, ambulatory patients with confirmed SARS-CoV-2 ' 'infection during the omicron wave in Hong Kong: an observational study', 'volume': '400', 'author': 'Wong', 'year': '2022', 'journal-title': 'Lancet'}, { 'key': '2024022113595098600_dkae042-B16', 'article-title': 'Real-World Effectiveness of Nirmatrelvir/Ritonavir in Preventing ' 'Hospitalization Among Patients With COVID-19 at High Risk for Severe ' 'Disease in the United States: A Nationwide Population-Based Cohort ' 'Study', 'author': 'Zhou', 'year': '2022', 'journal-title': 'medRxiv'}, { 'key': '2024022113595098600_dkae042-B17', 'doi-asserted-by': 'crossref', 'first-page': '805', 'DOI': '10.1093/cid/ciad287', 'article-title': 'Real-world effectiveness of nirmatrelvir/ritonavir on coronavirus ' 'disease 2019–associated hospitalization prevention: a population-based ' 'cohort study in the province of Quebec, Canada', 'volume': '77', 'author': 'Kaboré', 'year': '2023', 'journal-title': 'Clin Infect Dis'}, { 'key': '2024022113595098600_dkae042-B18', 'doi-asserted-by': 'crossref', 'first-page': '1531', 'DOI': '10.15585/mmwr.mm7148e2', 'article-title': 'Paxlovid associated with decreased hospitalization rate among adults ' 'with COVID-19—United States, April-September 2022', 'volume': '71', 'author': 'Shah', 'year': '2022', 'journal-title': 'MMWR Morb Mortal Wkly Rep'}, { 'key': '2024022113595098600_dkae042-B19', 'doi-asserted-by': 'crossref', 'first-page': '696', 'DOI': '10.1016/S1473-3099(23)00011-7', 'article-title': 'Real-world use of nirmatrelvir–ritonavir in outpatients with COVID-19 ' 'during the era of omicron variants including BA.4 and BA.5 in Colorado, ' 'USA: a retrospective cohort study', 'volume': '23', 'author': 'Aggarwal', 'year': '2023', 'journal-title': 'Lancet Infect Dis'}, { 'key': '2024022113595098600_dkae042-B20', 'doi-asserted-by': 'crossref', 'first-page': '806', 'DOI': '10.1016/S1473-3099(23)00118-4', 'article-title': 'Effectiveness of nirmatrelvir–ritonavir in preventing hospital ' 'admissions and deaths in people with COVID-19: a cohort study in a ' 'large US health-care system', 'volume': '23', 'author': 'Lewnard', 'year': '2023', 'journal-title': 'Lancet Infect Dis'}, { 'key': '2024022113595098600_dkae042-B21', 'doi-asserted-by': 'crossref', 'first-page': '199', 'DOI': '10.1214/ss/1009213726', 'article-title': 'Statistical modeling: the two cultures', 'volume': '16', 'author': 'Breiman', 'year': '2001', 'journal-title': 'Stat Sci'}, { 'key': '2024022113595098600_dkae042-B22', 'doi-asserted-by': 'crossref', 'first-page': '373', 'DOI': '10.1016/0021-9681(87)90171-8', 'article-title': 'A new method of classifying prognostic comorbidity in longitudinal ' 'studies: development and validation', 'volume': '40', 'author': 'Charlson', 'year': '1987', 'journal-title': 'J Chronic Dis'}, {'key': '2024022113595098600_dkae042-B23', 'author': 'CDC'}, {'key': '2024022113595098600_dkae042-B24', 'author': 'US Census Bureau'}, {'key': '2024022113595098600_dkae042-B25', 'author': 'Lundberg', 'year': '2017'}, {'key': '2024022113595098600_dkae042-B26', 'author': 'CDC'}, { 'key': '2024022113595098600_dkae042-B27', 'doi-asserted-by': 'crossref', 'first-page': '1359', 'DOI': '10.15585/mmwr.mm7143a2', 'article-title': 'Racial and ethnic disparities in outpatient treatment of COVID-19 — ' 'United States, January–July 2022', 'volume': '71', 'author': 'Boehmer', 'year': '2022', 'journal-title': 'MMWR Morb Mortal Wkly Rep'}, { 'key': '2024022113595098600_dkae042-B28', 'doi-asserted-by': 'crossref', 'first-page': '1384', 'DOI': '10.15585/mmwr.mm7143a3', 'article-title': 'Notes from the field: dispensing of oral antiviral drugs for treatment ' 'of COVID-19 by zip code-level social vulnerability—United States, ' 'December 23, 2021-August 28, 2022', 'volume': '71', 'author': 'Sullivan', 'year': '2022', 'journal-title': 'MMWR Morb Mortal Wkly Rep'}, { 'key': '2024022113595098600_dkae042-B29', 'doi-asserted-by': 'crossref', 'first-page': '825', 'DOI': '10.15585/mmwr.mm7125e1', 'article-title': 'Dispensing of oral antiviral drugs for treatment of COVID-19 by zip ' 'code–level social vulnerability—United States, December 23, 2021–May ' '21, 2022', 'volume': '71', 'author': 'Gold', 'year': '2022', 'journal-title': 'MMWR Morb Mortal Wkly Rep'}, { 'key': '2024022113595098600_dkae042-B30', 'doi-asserted-by': 'crossref', 'first-page': '1415', 'DOI': '10.1001/jama.2022.17876', 'article-title': 'Association of primary and booster vaccination and prior infection with ' 'SARS-CoV-2 infection and severe COVID-19 outcomes', 'volume': '328', 'author': 'Lin', 'year': '2022', 'journal-title': 'JAMA'}, { 'key': '2024022113595098600_dkae042-B31', 'doi-asserted-by': 'crossref', 'first-page': 'e0000619', 'DOI': '10.1371/journal.pgph.0000619', 'article-title': 'SARS-CoV-2 seroprevalence and risk factors among meat packing, produce ' 'processing, and farm workers', 'volume': '2', 'author': 'Klein', 'year': '2022', 'journal-title': 'PLoS Glob Public Health'}, { 'key': '2024022113595098600_dkae042-B32', 'doi-asserted-by': 'crossref', 'first-page': '617', 'DOI': '10.1001/jama.2022.0335', 'article-title': 'COVID-19 therapeutics for nonhospitalized patients', 'volume': '327', 'author': 'Gandhi', 'year': '2022', 'journal-title': 'JAMA'}], 'container-title': 'Journal of Antimicrobial Chemotherapy', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://academic.oup.com/jac/advance-article-pdf/doi/10.1093/jac/dkae042/56726755/dkae042.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'syndication'}, { 'URL': 'https://academic.oup.com/jac/advance-article-pdf/doi/10.1093/jac/dkae042/56726755/dkae042.pdf', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2024, 2, 21]], 'date-time': '2024-02-21T15:52:46Z', 'timestamp': 1708530766000}, 'score': 1, 'resource': { 'primary': { 'URL': 'https://academic.oup.com/jac/advance-article/doi/10.1093/jac/dkae042/7611865'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2024, 2, 21]]}, 'references-count': 32, 'URL': 'http://dx.doi.org/10.1093/jac/dkae042', 'relation': {}, 'ISSN': ['0305-7453', '1460-2091'], 'subject': ['Infectious Diseases', 'Pharmacology (medical)', 'Pharmacology', 'Microbiology (medical)'], 'published': {'date-parts': [[2024, 2, 21]]}}

Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.

Submit

Post

@CovidAnalysis

FAQ

Public domain CC0 1.0