Real-world nirmatrelvir-ritonavir outpatient treatment in reducing hospitalization for high-risk patients with COVID-19 during Omicron BA.4, BA.5 and XBB subvariants dominance in Malaysia: A retrospective cohort study
Ee Vien Low, Mohan Dass Pathmanathan, Suresh Kumar Chidambaram, Wee Ric Kim, Wei Jia Lee, Zhi Wei Teh, Maheshwara Rao Appannan, Shahanizan Mohd Zin, Faizah Muhamad Zin, Samha Bashirah Mohamed Amin, Mastura Ismail, Azah Abdul Samad, Kalaiarasu M Peariasamy
International Journal of Infectious Diseases, doi:10.1016/j.ijid.2023.08.003
Objective: To determine if nirmatrelvir-ritonavir 30 0mg/10 0mg treatment for 5 days in high-risk outpatients with mild to moderate COVID-19 symptoms was associated with a reduction in hospitalization, intensive care unit (ICU) admission, and death. Methods: This 1:1 propensity score matched cohort study from 647 public health clinics in Malaysia included all patients with COVID-19 with positive tests aged 18 years and older, who were eligible for nirmatrelvir-ritonavir treatment within 5 days of illness from July 14, 2022, to November 14, 2022. The exposed group was patients with COVID-19 initiated with nirmatrelvir-ritonavir treatment, whereas those not initiated with the drug served as the control group. Data was analyzed from July 14, 2022 to December 31, 2022. Results: A total of 20,966 COVID-19 high-risk outpatients (n = 10,483 for nirmatrelvir-ritonavir group and n = 10,483 for control group) were included in the study. Nirmatrelvir-ritonavir treatment was associated with a 36% reduction (adjusted hazard ratio 0.64 [95% CI 0.43, 0.94]) in hospitalization compared with those not given the drug. There was a single ICU admission for the control group and one death each was reported in the nirmatrelvir-ritonavir and control group, respectively. Conclusions: Nirmatrelvir-ritonavir treatment was associated with reduced hospitalization in high-risk patients with COVID-19 even in highly vaccinated populations.
Declaration of Competing Interest The authors declare that they have no conflict of interests.
Author contributions EVL, MP, SC, KP designed the study. MZ, MZ, SB, WRK, WJL, MR and TTZ collected the data. EVL and MP acquired and analyzed the data. The data was interpreted by all authors. EVL wrote the first draft of the manuscript. All authors reviewed and edited the manuscript. EVL, MD, SC, and KP performed the critical revision of the manuscript for intellectual contact. All authors had full access to all data in the studies and had final responsibility for the decision to submit for publication.
Data sharing statement The data that support the findings of this study are available upon reasonable request, and with protocol approved by the Medical Research and Ethics Committee, Ministry of Health Malaysia.
Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi: 10.1016/j.ijid.2023.08.003 .
References
Aggarwal, Molina, Beaty, Bennett, Carlson et al., 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, Lancet Infect Dis,
doi:10.1016/S1473-3099(23)00011-7Arbel, Sagy, Hoshen, Battat, Lavie et al., Nirmatrelvir use and severe Covid-19 outcomes during the omicron surge, N Engl J Med,
doi:10.1056/NEJMoa2204919Arumugam, Malaysia to get Covid-19 oral antivriral drug, Paxlovid, this month (NSTTV)
Baker, Bolt, Smith, Piasecki, Conner et al., The relationship of COVID-19 vaccination with mortality among 86,732 hospitalized patients: subpopulations, patient factors, and changes over time, J Gen Intern Med,
doi:10.1007/s11606-022-08007-0Ccider), Interim Recommendation on Clinical Management of Adult Cases with Coronavirus Disease 2019 (COVID-19), CCIDER-COVID
Dryden-Peterson, Kim, Kim, Caniglia, Lennes et al., Nirmatrelvir plus ritonavir for early COVID-19 in a Large U.S. health system: a population-based cohort study, Ann Intern Med,
doi:10.7326/M22-2141Hammond, Leister-Tebbe, Gardner, Abreu, Wisemandle, Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2118542Havers, Pham, Taylor, Whitaker, Patel et al., COVID-19-associated hospitalizations among vaccinated and unvaccinated adults 18 years or older in 13 US states, January 2021 to April 2022, JAMA Intern Med,
doi:10.1001/jamainternmed.2022.4299Karyakarte, Das, Dudhate, Agarasen, Pillai et al., Clinical characteristics and outcomes of laboratory-confirmed SARS-CoV-2 cases infected with omicron subvariants and the XBB recombinant variant, Cureus,
doi:10.7759/cureus.35261Kkm Now, The latest data on the pandemic in Malaysia
Lewnard, Mclaughlin, Malden, Hong, Puzniak et al., 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, Lancet Infect Dis,
doi:10.1016/S1473-3099(23)00118-4Najjar-Debbiny, Gronich, Weber, Khoury, Amar et al., Effectiveness of Paxlovid in reducing severe Coronavirus Disease 2019 and mortality in high-risk patients, Clin Infect Dis,
doi:10.1093/cid/penalty-@Mciac443Produk, Oleh Pyt, Pbkd, None
Sanyaolu, Okorie, Marinkovic, Patidar, Younis et al., Comorbidity and its impact on patients with COVID-19, SN Compr Clin Med,
doi:10.1007/s42399-020-00363-4Shah, Joyce, Plumb, Sahakian, Feldstein et al., Paxlovid associated with decreased hospitalization rate among adults with COVID-19 -United States, April-September 2022, MMWR Morb Mortal Wkly Rep,
doi:10.15585/mmwr.mm7148e2Vanderweele, Ding, Sensitivity analysis in observational research: introducing the E-value, Ann Intern Med,
doi:10.7326/M16-2607Wang, Liu, Zhang, Huang, Zhao et al., Differences in incidence and fatality of COVID-19 by SARS-CoV-2 Omicron variant versus Delta variant in relation to vaccine coverage: a world-wide review, J Med Virol,
doi:10.1002/jmv.28118Wong, Lau, Leung, Real-world effectiveness of nirmatrelvirritonavir against BA.4 and BA.5 omicron SARS-CoV-2 variants, Lancet Infect Dis,
doi:10.1016/S1473-3099(23)00056-7{ 'indexed': {'date-parts': [[2024, 8, 19]], 'date-time': '2024-08-19T21:54:14Z', 'timestamp': 1724104454386},
'reference-count': 30,
'publisher': 'Elsevier BV',
'license': [ { 'start': { 'date-parts': [[2023, 10, 1]],
'date-time': '2023-10-01T00:00:00Z',
'timestamp': 1696118400000},
'content-version': 'tdm',
'delay-in-days': 0,
'URL': 'https://www.elsevier.com/tdm/userlicense/1.0/'},
{ 'start': { 'date-parts': [[2023, 10, 1]],
'date-time': '2023-10-01T00:00:00Z',
'timestamp': 1696118400000},
'content-version': 'tdm',
'delay-in-days': 0,
'URL': 'https://www.elsevier.com/legal/tdmrep-license'},
{ 'start': { 'date-parts': [[2023, 8, 6]],
'date-time': '2023-08-06T00:00:00Z',
'timestamp': 1691280000000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'http://creativecommons.org/licenses/by-nc-nd/4.0/'}],
'funder': [ { 'DOI': '10.13039/501100013885',
'name': 'Kementerian Kesihatan Malaysia',
'doi-asserted-by': 'publisher',
'id': [{'id': '10.13039/501100013885', 'id-type': 'DOI', 'asserted-by': 'publisher'}]}],
'content-domain': { 'domain': [ 'clinicalkey.fr', 'clinicalkey.jp', 'clinicalkey.es', 'clinicalkey.com.au',
'clinicalkey.com', 'ijidonline.com', 'elsevier.com', 'sciencedirect.com'],
'crossmark-restriction': True},
'published-print': {'date-parts': [[2023, 10]]},
'DOI': '10.1016/j.ijid.2023.08.003',
'type': 'journal-article',
'created': {'date-parts': [[2023, 8, 9]], 'date-time': '2023-08-09T16:04:28Z', 'timestamp': 1691597068000},
'page': '77-83',
'update-policy': 'http://dx.doi.org/10.1016/elsevier_cm_policy',
'source': 'Crossref',
'is-referenced-by-count': 6,
'special_numbering': 'C',
'title': 'Real-world nirmatrelvir-ritonavir outpatient treatment in reducing hospitalization for high-risk '
'patients with COVID-19 during Omicron BA.4, BA.5 and XBB subvariants dominance in Malaysia: A '
'retrospective cohort study',
'prefix': '10.1016',
'volume': '135',
'author': [ { 'ORCID': 'http://orcid.org/0000-0001-8596-1318',
'authenticated-orcid': False,
'given': 'Ee Vien',
'family': 'Low',
'sequence': 'first',
'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0001-8385-0315',
'authenticated-orcid': False,
'given': 'Mohan Dass',
'family': 'Pathmanathan',
'sequence': 'additional',
'affiliation': []},
{'given': 'Suresh Kumar', 'family': 'Chidambaram', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0003-1912-2940',
'authenticated-orcid': False,
'given': 'Wee Ric',
'family': 'Kim',
'sequence': 'additional',
'affiliation': []},
{ 'ORCID': 'http://orcid.org/0009-0008-4062-5829',
'authenticated-orcid': False,
'given': 'Wei Jia',
'family': 'Lee',
'sequence': 'additional',
'affiliation': []},
{'given': 'Zhi Wei', 'family': 'Teh', 'sequence': 'additional', 'affiliation': []},
{'given': 'Maheshwara Rao', 'family': 'Appannan', 'sequence': 'additional', 'affiliation': []},
{'given': 'Shahanizan Mohd', 'family': 'Zin', 'sequence': 'additional', 'affiliation': []},
{'given': 'Faizah Muhamad', 'family': 'Zin', 'sequence': 'additional', 'affiliation': []},
{ 'given': 'Samha Bashirah Mohamed',
'family': 'Amin',
'sequence': 'additional',
'affiliation': []},
{'given': 'Mastura', 'family': 'Ismail', 'sequence': 'additional', 'affiliation': []},
{'given': 'Azah Abdul', 'family': 'Samad', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0001-9279-3498',
'authenticated-orcid': False,
'given': 'Kalaiarasu M.',
'family': 'Peariasamy',
'sequence': 'additional',
'affiliation': []}],
'member': '78',
'reference': [ { 'key': '10.1016/j.ijid.2023.08.003_bib0001',
'unstructured': 'Ministry of Health Malaysia and Department of Statistics Malaysia. The '
'latest data on the pandemic in Malaysia, https://data.moh.gov.my/covid; '
'2023 [accessed 23 March 2023].'},
{ 'key': '10.1016/j.ijid.2023.08.003_bib0002',
'unstructured': 'Centers for Disease Control and Prevention. Underlying medical '
'conditions associated with higher risk for severe COVID-19: information '
'for healthcare professionals, '
'https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html; '
'2023 [accessed 25 April 2023].'},
{ 'key': '10.1016/j.ijid.2023.08.003_bib0003',
'series-title': 'National Health and Morbidity Survey (NHMS) 2019 non-communicable '
'diseases, healthcare demand, and health literacy: key Findings',
'year': '2020'},
{ 'key': '10.1016/j.ijid.2023.08.003_bib0004',
'unstructured': 'Ministry of Health Malaysia. Situasi terkini COVID-19 di Malaysia, '
'https://covid-19.moh.gov.my/terkini; 2023 [accessed 20 April, 2023].'},
{ 'key': '10.1016/j.ijid.2023.08.003_bib0005',
'series-title': 'Transition to endemic phase, prime minister of Malaysia',
'year': '2022'},
{ 'key': '10.1016/j.ijid.2023.08.003_bib0006',
'unstructured': 'Ministry of Health Malaysia and Department of Statistics Malaysia. KKM '
'Now, The latest data on the pandemic in Malaysia, '
'https://data.moh.gov.my/covid; 2023 [accessed 20 April 2023].'},
{ 'key': '10.1016/j.ijid.2023.08.003_bib0007',
'doi-asserted-by': 'crossref',
'first-page': '1069',
'DOI': '10.1007/s42399-020-00363-4',
'article-title': 'Comorbidity and its impact on patients with COVID-19',
'volume': '2',
'author': 'Sanyaolu',
'year': '2020',
'journal-title': 'SN Compr Clin Med'},
{ 'key': '10.1016/j.ijid.2023.08.003_bib0008',
'unstructured': 'Food and Drug Administration. Emergency use authorizations for drugs and '
'non-vaccine biological products, '
'https://www.fda.gov/drugs/emergency-preparedness-drugs/emergency-use-authorizations-drugs-and-non-vaccine-biological-products; '
'2023 [accessed 20 April 2023].'},
{ 'key': '10.1016/j.ijid.2023.08.003_bib0009',
'unstructured': 'Food and Drug Administration. Fact sheet for healthcare providers: '
'emergency use authorization for PaxlovidTM, '
'https://www.fda.gov/media/155050/download; 2021 [accessed 20 April '
'2023].'},
{ 'key': '10.1016/j.ijid.2023.08.003_bib0010',
'series-title': 'Annex 2e: Clinical management of confirmed COVID-19 case in adult and '
'paediatric',
'year': '2022'},
{ 'key': '10.1016/j.ijid.2023.08.003_bib0011',
'series-title': 'National Pharmaceutical Regulatory Agency, PRODUK S, DILULUSKAN OLEH '
'PYT, DADAH PBK (PBKD) DALAM MESYUARAT PBKD KALI KE –370',
'year': '2022'},
{ 'key': '10.1016/j.ijid.2023.08.003_sbref0012',
'series-title': 'Malaysia to get Covid-19 oral antivriral drug, Paxlovid, this month '
'(NSTTV)',
'author': 'Arumugam',
'year': '2022'},
{ 'key': '10.1016/j.ijid.2023.08.003_bib0013',
'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/j.ijid.2023.08.003_bib0014',
'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': '10.1016/j.ijid.2023.08.003_bib0015',
'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': '10.1016/j.ijid.2023.08.003_bib0016',
'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': '10.1016/j.ijid.2023.08.003_bib0017',
'doi-asserted-by': 'crossref',
'first-page': '268',
'DOI': '10.7326/M16-2607',
'article-title': 'Sensitivity analysis in observational research: introducing the E-value',
'volume': '167',
'author': 'VanderWeele',
'year': '2017',
'journal-title': 'Ann Intern Med'},
{ 'key': '10.1016/j.ijid.2023.08.003_bib0018',
'unstructured': 'Our world in data. SARS-CoV-2 Variants in analyzed sequences, Malaysia, '
'https://ourworldindata.org/grapher/covid-variants-area?time=2022-07-04.2023-01-02&country=∼MYS; '
'2023 [accessed 20 April 2023].'},
{ 'key': '10.1016/j.ijid.2023.08.003_bib0019',
'doi-asserted-by': 'crossref',
'first-page': '1248',
'DOI': '10.1007/s11606-022-08007-0',
'article-title': 'The relationship of COVID-19 vaccination with mortality among 86,732 '
'hospitalized patients: subpopulations, patient factors, and changes '
'over time',
'volume': '38',
'author': 'Baker',
'year': '2023',
'journal-title': 'J Gen Intern Med'},
{ 'key': '10.1016/j.ijid.2023.08.003_bib0020',
'doi-asserted-by': 'crossref',
'first-page': '1071',
'DOI': '10.1001/jamainternmed.2022.4299',
'article-title': 'COVID-19-associated hospitalizations among vaccinated and unvaccinated '
'adults 18 years or older in 13 US states, January 2021 to April 2022',
'volume': '182',
'author': 'Havers',
'year': '2022',
'journal-title': 'JAMA Intern Med'},
{ 'key': '10.1016/j.ijid.2023.08.003_bib0021',
'article-title': 'Differences in case-fatality-rate of emerging SARS-CoV-2 variants',
'volume': '5',
'author': 'Liu',
'year': '2023',
'journal-title': 'Public Health Pract (Oxf)'},
{ 'key': '10.1016/j.ijid.2023.08.003_bib0022',
'first-page': 'e35261',
'article-title': 'Clinical characteristics and outcomes of laboratory-confirmed '
'SARS-CoV-2 cases infected with omicron subvariants and the XBB '
'recombinant variant',
'volume': '15',
'author': 'Karyakarte',
'year': '2023',
'journal-title': 'Cureus'},
{ 'key': '10.1016/j.ijid.2023.08.003_bib0023',
'doi-asserted-by': 'crossref',
'first-page': 'e28118',
'DOI': '10.1002/jmv.28118',
'article-title': 'Differences in incidence and fatality of COVID-19 by SARS-CoV-2 Omicron '
'variant versus Delta variant in relation to vaccine coverage: a '
'world-wide review',
'volume': '95',
'author': 'Wang',
'year': '2023',
'journal-title': 'J Med Virol'},
{ 'key': '10.1016/j.ijid.2023.08.003_bib0024',
'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/j.ijid.2023.08.003_bib0025',
'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: a population-based cohort study',
'volume': '176',
'author': 'Dryden-Peterson',
'year': '2023',
'journal-title': 'Ann Intern Med'},
{ 'key': '10.1016/j.ijid.2023.08.003_bib0026',
'doi-asserted-by': 'crossref',
'first-page': '639',
'DOI': '10.1016/S1473-3099(23)00056-7',
'article-title': 'Real-world effectiveness of nirmatrelvir-ritonavir against BA.4 and '
'BA.5 omicron SARS-CoV-2 variants',
'volume': '23',
'author': 'Wong',
'year': '2023',
'journal-title': 'Lancet Infect Dis'},
{ 'key': '10.1016/j.ijid.2023.08.003_bib0027',
'unstructured': 'Hospital Authority Central Committee on Infectious Disease and Emergency '
'Response (CCIDER). Interim Recommendation on Clinical Management of '
'Adult Cases with Coronavirus Disease 2019 (COVID-19). '
'CCIDER-COVID19-001(v1.12) (Issue Date: 14 April 2022)'},
{ 'key': '10.1016/j.ijid.2023.08.003_bib0028',
'unstructured': 'News.gov.hk. COVID-19 antiviral eligibility relaxed. '
'https://www.news.gov.hk/eng/2022/07/20220729/20220729_170528_537.html; '
'2022 [accessed 20 April 2023].'},
{ 'key': '10.1016/j.ijid.2023.08.003_bib0029',
'unstructured': 'National Institutes of Health. COVID-19 Treatment Guidelines Panel, '
'Coronavirus Disease, '
'https://www.covid19treatmentguidelines.nih.gov/overview/prioritization-of-therapeutics/; '
'2019 [accessed 20 April 2023].'},
{ 'key': '10.1016/j.ijid.2023.08.003_bib0030',
'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'}],
'container-title': 'International Journal of Infectious Diseases',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://api.elsevier.com/content/article/PII:S1201971223006884?httpAccept=text/xml',
'content-type': 'text/xml',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'https://api.elsevier.com/content/article/PII:S1201971223006884?httpAccept=text/plain',
'content-type': 'text/plain',
'content-version': 'vor',
'intended-application': 'text-mining'}],
'deposited': { 'date-parts': [[2024, 5, 11]],
'date-time': '2024-05-11T14:51:11Z',
'timestamp': 1715439071000},
'score': 1,
'resource': {'primary': {'URL': 'https://linkinghub.elsevier.com/retrieve/pii/S1201971223006884'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2023, 10]]},
'references-count': 30,
'alternative-id': ['S1201971223006884'],
'URL': 'http://dx.doi.org/10.1016/j.ijid.2023.08.003',
'relation': {},
'ISSN': ['1201-9712'],
'subject': [],
'container-title-short': 'International Journal of Infectious Diseases',
'published': {'date-parts': [[2023, 10]]},
'assertion': [ {'value': 'Elsevier', 'name': 'publisher', 'label': 'This article is maintained by'},
{ 'value': 'Real-world nirmatrelvir-ritonavir outpatient treatment in reducing '
'hospitalization for high-risk patients with COVID-19 during Omicron BA.4, BA.5 '
'and XBB subvariants dominance in Malaysia: A retrospective cohort study',
'name': 'articletitle',
'label': 'Article Title'},
{ 'value': 'International Journal of Infectious Diseases',
'name': 'journaltitle',
'label': 'Journal Title'},
{ 'value': 'https://doi.org/10.1016/j.ijid.2023.08.003',
'name': 'articlelink',
'label': 'CrossRef DOI link to publisher maintained version'},
{'value': 'article', 'name': 'content_type', 'label': 'Content Type'},
{ 'value': '© 2023 The Author(s). Published by Elsevier Ltd on behalf of International '
'Society for Infectious Diseases.',
'name': 'copyright',
'label': 'Copyright'}]}
