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
Dr Joseph A Lewnard, PhD John M Mclaughlin, Debbie Malden, Vennis Hong, PhD, L Jodar PhD Laura Puzniak, MD Bradley K Ackerson, Bruno J Lewin, PhD Jeniffer S Kim, Sally F Shaw, Harpreet Takhar, Luis Jodar, Sara Y Tartof
The Lancet Infectious Diseases, doi:10.1016/s1473-3099(23)00118-4
Background In the USA, oral nirmatrelvir-ritonavir is authorised for use in patients aged 12 years or older with mildto-moderate COVID-19 who are at risk of progression to severe disease and hospitalisation. We aimed to establish the effectiveness of nirmatrelvir-ritonavir in preventing hospital admissions and death in people with COVID-19 in an outpatient prescribing context in the USA. Methods In this matched observational outpatient cohort study in the Kaiser Permanente Southern California (CA, USA) health-care system, data were extracted from electronic health records of non-hospitalised patients aged 12 years or older who received a positive SARS-CoV-2 PCR test result (their index test) between April 8 and Oct 7, 2022, and had not received another positive test result within the preceding 90 days. We compared outcomes between people who received nirmatrelvir-ritonavir and those who did not receive nirmatrelvir-ritonavir by matching cases by date, age, sex, clinical status (including care received, the presence or absence of acute COVID-19 symptoms at testing, and time from symptom onset to testing), vaccination history, comorbidities, health-care seeking during the previous year, and BMI. Our primary endpoint was the estimated effectiveness of nirmatrelvir-ritonavir in preventing hospital admissions or death within 30 days of a positive test for SARS-CoV-2. Findings 7274 nirmatrelvir-ritonavir recipients and 126 152 non-recipients with positive SARS-CoV-2 tests were included in our study. 5472 (75•2%) treatment recipients and 84 657 (67•1%) non-recipients were tested within 5 days of symptom onset. Nirmatrelvir-ritonavir had an overall estimated effectiveness of 53•6% (95% CI 6•6-77•0) in preventing hospital admission or death within 30 days of a positive test for SARS-CoV-2, which increased to 79•6% (33•9-93•8) when nirmatrelvir-ritonavir was dispensed within 5 days of symptom onset. Within the subgroup of patients tested within 5 days of symptom onset and whose treatment was dispensed on the day of their test, the estimated effectiveness of nirmatrelvir-ritonavir was 89•6% (50•2-97•8). Interpretation In a setting with high levels of COVID-19 vaccine uptake, nirmatrelvir-ritonavir effectively reduced the risk of hospital admission or death within 30 days of a positive outpatient SARS-CoV-2 test.
References
Andrejko, Myers, Fukui, Real-world uptake of COVID-19 vaccination among individuals expressing vaccine hesitancy: a registry-linkage study, medRxiv,
doi:10.1101/2022.08.02.22278300Arbel, Sagy, Hoshen, Nirmatrelvir use and severe COVID-19 outcomes during the omicron surge, N Engl J Med
Bajema, Wang, Hynes, Early adoption of anti-SARS-CoV-2 pharmacotherapies among US veterans with mild to moderate COVID-19, January and February 2022, JAMA Netw Open
Black, (9•5%) 9981 (7•9%) Hispanic 3061, non-Hispanic
Bmi, None, kg/m²
Clarke, Jones, Deng, Seroprevalence of infectioninduced SARS-CoV-2 antibodies-United States, September 2021-February 2022, MMWR Morb Mortal Wkly Rep
Dryden-Peterson, Kim, Kim, Nirmatrelvir plus ritonavir for early COVID-19 and hospitalization in a large US health system, medRxiv,
doi:10.1101/2022.06.14.22276393Hammond, Leister-Tebbe, Gardner, Oral nirmatrelvir for high-risk, nonhospitalized adults with COVID-19, N Engl J Med
Huynh, Millan, Quijada, John, Khan et al., Description and early results of the Kaiser Permanente Southern California COVID-19 home monitoring program, Permanente J
Iketani, Liu, Guo, Antibody evasion properties of SARS-CoV-2 omicron sublineages, Nature
Lewnard, Hong, Patel, Kahn, Lipsitch et al., Clinical outcomes associated with SARS-CoV-2 omicron (B.1.1.529) variant and BA.1/BA.1.1 or BA.2 subvariant infection in southern California, Nat Med
Lewnard, Patel, Jewell, Theoretical framework for retrospective studies of the effectiveness of SARS-CoV-2 vaccines, Epidemiology
Malden, Hong, Lewin, Hospitalization and emergency department encounters for COVID-19 after Paxlovid treatment-California, December 2021-May 2022, MMWR Morb Mortal Wkly Rep
Malden, Tartof, Ackerson, Natural language processing for improved COVID-19 characterization: evidence from more than 350,000 patients in a large integrated health care system, JMIR Public Health Surveill
Messer, Laraia, Kaufman, The development of a standardized neighborhood deprivation index, J Urban Health
Najjar-Debbiny, Gronich, Weber, Effectiveness of Paxlovid in reducing severe COVID-19 and mortality in high-risk patients, Clin Infect Dis
Rubin, Multiple imputation after 18+ years, J Am Stat Assoc
Schoenfeld, Partial residuals for the proportional hazards regression model, Biometrika
Shah, Joyce, Plumb, Paxlovid associated with decreased hospitalization rate among adults with COVID-19-United States, April-September, 2022, MMWR Morb Mortal Wkly Rep
Stowe, Andrews, Kirsebom, Ramsay, Bernal, Effectiveness of COVID-19 vaccines against omicron and delta hospitalization: a test-negative case-control study, Nat Comm
Sundarajan, Henderson, Perry, Muggivan, Quan et al., New ICD-10 version of the Charlson comorbidity index predicted in-hospital mortality, J Clin Epidemiol
Tartof, Qian, Hong, Obesity and mortality among patients diagnosed with COVID-19: results from an integrated health care organization, Ann Intern Med
Vasan, Foote, Long, Ensuring widespread and equitable access to treatments for COVID-19, JAMA
Villalobos, Ott, Klett-Tammen, Effect modification of the association between comorbidities and severe course of COVID-19 disease by age of study participants: a systematic review and meta-analysis, Syst Rev
White, None, non-Hispanic
Wong, Au, Lau, Lau, Cowling et al., Real-world effectiveness of early molnupiravir or nirmatrelvirritonavir in hospitalized patients with COVID-19 without supplemental oxygen requirement on admission during Hong Kong's omicron BA.2 wave: a retrospective cohort study, Lancet Infect Dis
Wong, Au, Lau, Lau, Cowling et al., 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, Lancet
Yip, Lui, Lai, Impact of the use of oral antiviral agents on the risk of hospitalization in community COVID-19 patients, Clin Infect Dis
{ 'indexed': {'date-parts': [[2023, 3, 29]], 'date-time': '2023-03-29T19:30:26Z', 'timestamp': 1680118226334},
'reference-count': 25,
'publisher': 'Elsevier BV',
'license': [ { 'start': { 'date-parts': [[2023, 3, 1]],
'date-time': '2023-03-01T00:00:00Z',
'timestamp': 1677628800000},
'content-version': 'tdm',
'delay-in-days': 0,
'URL': 'https://www.elsevier.com/tdm/userlicense/1.0/'},
{ 'start': { 'date-parts': [[2023, 2, 22]],
'date-time': '2023-02-22T00:00:00Z',
'timestamp': 1677024000000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'http://creativecommons.org/licenses/by/4.0/'}],
'content-domain': { 'domain': [ 'clinicalkey.fr', 'clinicalkey.jp', 'clinicalkey.es', 'clinicalkey.com.au',
'clinicalkey.com', 'em-consulte.com', 'thelancet.com', 'elsevier.com',
'sciencedirect.com'],
'crossmark-restriction': True},
'published-print': {'date-parts': [[2023, 3]]},
'DOI': '10.1016/s1473-3099(23)00118-4',
'type': 'journal-article',
'created': {'date-parts': [[2023, 3, 15]], 'date-time': '2023-03-15T23:41:11Z', 'timestamp': 1678923671000},
'update-policy': 'http://dx.doi.org/10.1016/elsevier_cm_policy',
'source': 'Crossref',
'is-referenced-by-count': 1,
'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',
'prefix': '10.1016',
'author': [ {'given': 'Joseph A', 'family': 'Lewnard', 'sequence': 'first', 'affiliation': []},
{'given': 'John M', 'family': 'McLaughlin', 'sequence': 'additional', 'affiliation': []},
{'given': 'Debbie', 'family': 'Malden', 'sequence': 'additional', 'affiliation': []},
{'given': 'Vennis', 'family': 'Hong', 'sequence': 'additional', 'affiliation': []},
{'given': 'Laura', 'family': 'Puzniak', 'sequence': 'additional', 'affiliation': []},
{'given': 'Bradley K', 'family': 'Ackerson', 'sequence': 'additional', 'affiliation': []},
{'given': 'Bruno J', 'family': 'Lewin', 'sequence': 'additional', 'affiliation': []},
{'given': 'Jeniffer S', 'family': 'Kim', 'sequence': 'additional', 'affiliation': []},
{'given': 'Sally F', 'family': 'Shaw', 'sequence': 'additional', 'affiliation': []},
{'given': 'Harpreet', 'family': 'Takhar', 'sequence': 'additional', 'affiliation': []},
{'given': 'Luis', 'family': 'Jodar', 'sequence': 'additional', 'affiliation': []},
{'given': 'Sara Y', 'family': 'Tartof', 'sequence': 'additional', 'affiliation': []}],
'member': '78',
'reference': [ { 'key': '10.1016/S1473-3099(23)00118-4_bib2',
'doi-asserted-by': 'crossref',
'first-page': '553',
'DOI': '10.1038/s41586-022-04594-4',
'article-title': 'Antibody evasion properties of SARS-CoV-2 omicron sublineages',
'volume': '604',
'author': 'Iketani',
'year': '2022',
'journal-title': 'Nature'},
{ 'key': '10.1016/S1473-3099(23)00118-4_bib3',
'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': '10.1016/S1473-3099(23)00118-4_bib4',
'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': '10.1016/S1473-3099(23)00118-4_bib5',
'article-title': 'Nirmatrelvir plus ritonavir for early COVID-19 and hospitalization in a '
'large US health system',
'author': 'Dryden-Peterson',
'year': '2022',
'journal-title': 'medRxiv'},
{ 'key': '10.1016/S1473-3099(23)00118-4_bib6',
'doi-asserted-by': 'crossref',
'first-page': 'e342',
'DOI': '10.1093/cid/ciac443',
'article-title': 'Effectiveness of Paxlovid in reducing severe COVID-19 and mortality in '
'high-risk patients',
'volume': '76',
'author': 'Najjar-Debbiny',
'year': '2022',
'journal-title': 'Clin Infect Dis'},
{ 'key': '10.1016/S1473-3099(23)00118-4_bib7',
'doi-asserted-by': 'crossref',
'first-page': '1213',
'DOI': '10.1016/S0140-6736(22)01586-0',
'volume': '400',
'author': 'Wong',
'year': '2022',
'journal-title': 'Lancet'},
{ 'key': '10.1016/S1473-3099(23)00118-4_bib8',
'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': '2022',
'journal-title': 'Clin Infect Dis'},
{ 'key': '10.1016/S1473-3099(23)00118-4_bib9',
'doi-asserted-by': 'crossref',
'first-page': '1681',
'DOI': '10.1016/S1473-3099(22)00507-2',
'article-title': 'Real-world effectiveness of early molnupiravir or '
'nirmatrelvir–ritonavir in hospitalized patients with COVID-19 without '
"supplemental oxygen requirement on admission during Hong Kong's omicron "
'BA.2 wave: a retrospective cohort study',
'volume': '22',
'author': 'Wong',
'year': '2022',
'journal-title': 'Lancet Infect Dis'},
{ 'key': '10.1016/S1473-3099(23)00118-4_bib10',
'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': '10.1016/S1473-3099(23)00118-4_bib11',
'doi-asserted-by': 'crossref',
'first-page': '705',
'DOI': '10.1001/jama.2022.13554',
'article-title': 'Ensuring widespread and equitable access to treatments for COVID-19',
'volume': '328',
'author': 'Vasan',
'year': '2022',
'journal-title': 'JAMA'},
{ 'key': '10.1016/S1473-3099(23)00118-4_bib12',
'doi-asserted-by': 'crossref',
'DOI': '10.1001/jamanetworkopen.2022.41434',
'article-title': 'Early adoption of anti-SARS-CoV-2 pharmacotherapies among US veterans '
'with mild to moderate COVID-19, January and February 2022',
'volume': '5',
'author': 'Bajema',
'year': '2022',
'journal-title': 'JAMA Netw Open'},
{ 'key': '10.1016/S1473-3099(23)00118-4_bib13',
'doi-asserted-by': 'crossref',
'first-page': '606',
'DOI': '10.15585/mmwr.mm7117e3',
'article-title': 'Seroprevalence of infection-induced SARS-CoV-2 antibodies—United '
'States, September 2021–February 2022',
'volume': '71',
'author': 'Clarke',
'year': '2022',
'journal-title': 'MMWR Morb Mortal Wkly Rep'},
{ 'key': '10.1016/S1473-3099(23)00118-4_bib14',
'doi-asserted-by': 'crossref',
'first-page': '1933',
'DOI': '10.1038/s41591-022-01887-z',
'article-title': 'Clinical outcomes associated with SARS-CoV-2 omicron (B.1.1.529) '
'variant and BA.1/BA.1.1 or BA.2 subvariant infection in southern '
'California',
'volume': '28',
'author': 'Lewnard',
'year': '2022',
'journal-title': 'Nat Med'},
{ 'key': '10.1016/S1473-3099(23)00118-4_bib15',
'doi-asserted-by': 'crossref',
'first-page': '830',
'DOI': '10.15585/mmwr.mm7125e2',
'article-title': 'Hospitalization and emergency department encounters for COVID-19 after '
'Paxlovid treatment—California, December 2021–May 2022',
'volume': '71',
'author': 'Malden',
'year': '2022',
'journal-title': 'MMWR Morb Mortal Wkly Rep'},
{ 'key': '10.1016/S1473-3099(23)00118-4_bib16',
'article-title': 'Real-world uptake of COVID-19 vaccination among individuals expressing '
'vaccine hesitancy: a registry-linkage study',
'author': 'Andrejko',
'year': '2022',
'journal-title': 'medRxiv'},
{ 'key': '10.1016/S1473-3099(23)00118-4_bib17',
'doi-asserted-by': 'crossref',
'DOI': '10.2196/41529',
'article-title': 'Natural language processing for improved COVID-19 characterization: '
'evidence from more than 350,000 patients in a large integrated health '
'care system',
'volume': '8',
'author': 'Malden',
'year': '2022',
'journal-title': 'JMIR Public Health Surveill'},
{ 'key': '10.1016/S1473-3099(23)00118-4_bib18',
'doi-asserted-by': 'crossref',
'first-page': '1041',
'DOI': '10.1007/s11524-006-9094-x',
'article-title': 'The development of a standardized neighborhood deprivation index',
'volume': '83',
'author': 'Messer',
'year': '2006',
'journal-title': 'J Urban Health'},
{ 'key': '10.1016/S1473-3099(23)00118-4_bib19',
'doi-asserted-by': 'crossref',
'first-page': '1288',
'DOI': '10.1016/j.jclinepi.2004.03.012',
'article-title': 'New ICD-10 version of the Charlson comorbidity index predicted '
'in-hospital mortality',
'volume': '57',
'author': 'Sundarajan',
'year': '2004',
'journal-title': 'J Clin Epidemiol'},
{ 'key': '10.1016/S1473-3099(23)00118-4_bib20',
'doi-asserted-by': 'crossref',
'first-page': '1',
'DOI': '10.7812/TPP/20.281',
'article-title': 'Description and early results of the Kaiser Permanente Southern '
'California COVID-19 home monitoring program',
'volume': '25',
'author': 'Huynh',
'year': '2021',
'journal-title': 'Permanente J'},
{ 'key': '10.1016/S1473-3099(23)00118-4_bib21',
'doi-asserted-by': 'crossref',
'first-page': '239',
'DOI': '10.1093/biomet/69.1.239',
'article-title': 'Partial residuals for the proportional hazards regression model',
'volume': '69',
'author': 'Schoenfeld',
'year': '1982',
'journal-title': 'Biometrika'},
{ 'key': '10.1016/S1473-3099(23)00118-4_bib22',
'doi-asserted-by': 'crossref',
'first-page': '773',
'DOI': '10.7326/M20-3742',
'article-title': 'Obesity and mortality among patients diagnosed with COVID-19: results '
'from an integrated health care organization',
'volume': '173',
'author': 'Tartof',
'year': '2020',
'journal-title': 'Ann Intern Med'},
{ 'key': '10.1016/S1473-3099(23)00118-4_bib23',
'doi-asserted-by': 'crossref',
'first-page': '194',
'DOI': '10.1186/s13643-021-01732-3',
'article-title': 'Effect modification of the association between comorbidities and severe '
'course of COVID-19 disease by age of study participants: a systematic '
'review and meta-analysis',
'volume': '10',
'author': 'Fernández Villalobos',
'year': '2021',
'journal-title': 'Syst Rev'},
{ 'key': '10.1016/S1473-3099(23)00118-4_bib24',
'doi-asserted-by': 'crossref',
'first-page': '473',
'DOI': '10.1080/01621459.1996.10476908',
'article-title': 'Multiple imputation after 18+ years',
'volume': '91',
'author': 'Rubin',
'year': '1996',
'journal-title': 'J Am Stat Assoc'},
{ 'key': '10.1016/S1473-3099(23)00118-4_bib26',
'doi-asserted-by': 'crossref',
'first-page': '508',
'DOI': '10.1097/EDE.0000000000001366',
'article-title': 'Theoretical framework for retrospective studies of the effectiveness of '
'SARS-CoV-2 vaccines',
'volume': '32',
'author': 'Lewnard',
'year': '2021',
'journal-title': 'Epidemiology'},
{ 'key': '10.1016/S1473-3099(23)00118-4_bib27',
'doi-asserted-by': 'crossref',
'DOI': '10.1038/s41467-022-33378-7',
'article-title': 'Effectiveness of COVID-19 vaccines against omicron and delta '
'hospitalization: a test-negative case-control study',
'volume': '13',
'author': 'Stowe',
'year': '2022',
'journal-title': 'Nat Comm'}],
'container-title': 'The Lancet Infectious Diseases',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://api.elsevier.com/content/article/PII:S1473309923001184?httpAccept=text/xml',
'content-type': 'text/xml',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'https://api.elsevier.com/content/article/PII:S1473309923001184?httpAccept=text/plain',
'content-type': 'text/plain',
'content-version': 'vor',
'intended-application': 'text-mining'}],
'deposited': { 'date-parts': [[2023, 3, 15]],
'date-time': '2023-03-15T23:41:29Z',
'timestamp': 1678923689000},
'score': 1,
'resource': {'primary': {'URL': 'https://linkinghub.elsevier.com/retrieve/pii/S1473309923001184'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2023, 3]]},
'references-count': 25,
'alternative-id': ['S1473309923001184'],
'URL': 'http://dx.doi.org/10.1016/S1473-3099(23)00118-4',
'relation': {},
'ISSN': ['1473-3099'],
'subject': ['Infectious Diseases'],
'container-title-short': 'The Lancet Infectious Diseases',
'published': {'date-parts': [[2023, 3]]},
'assertion': [ {'value': 'Elsevier', 'name': 'publisher', 'label': 'This article is maintained by'},
{ 'value': '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',
'name': 'articletitle',
'label': 'Article Title'},
{ 'value': 'The Lancet Infectious Diseases',
'name': 'journaltitle',
'label': 'Journal Title'},
{ 'value': 'https://doi.org/10.1016/S1473-3099(23)00118-4',
'name': 'articlelink',
'label': 'CrossRef DOI link to publisher maintained version'},
{ 'value': 'https://doi.org/10.1016/S1473-3099(23)00180-9',
'name': 'associatedlink',
'label': 'CrossRef DOI link to the associated document'},
{'value': 'article', 'name': 'content_type', 'label': 'Content Type'},
{ 'value': '© 2023 The Author(s). Published by Elsevier Ltd.',
'name': 'copyright',
'label': 'Copyright'}]}
