Molnupiravir Use and Severe Covid-19 Outcomes During the Omicron Surge
Ronen Arbel, Yael Wolff Sagy, Erez Battat, Gil Lavie, Ruslan Sergienko, Michael Friger, Alon Peretz, Shlomit Yaron, Danielle Serby, Ariel Hammerman, Doron Netzer
doi:10.21203/rs.3.rs-2115769/v1
Background The oral antiviral molnupiravir is moderately effective in high-risk, unvaccinated non-hospitalized patients infected with early variants of SARS-CoV-2. Data regarding the effectiveness of molnupiravir against the B.1.1.529 (omicron) variant and in vaccinated populations are limited.
Methods We obtained data for all members of Clalit Health Services, 40 years of age and older, eligible for molnupiravir therapy during the omicron surge. A Cox proportional-hazards regression model with timedependent covariates was used to estimate the association between molnupiravir treatment and hospitalizations and deaths due to Covid-19, with adjustment for sociodemographic factors, coexisting conditions, and prior Covid-19 immunity status.
Results A total of 19,868 participants met the eligibility criteria, of whom 1,069 (5%) received molnupiravir during the study period. In patients 65 years and above, the rate of hospitalizations related to Covid-19 in treated compared to untreated patients was 74.6 versus 127.6 per 100,000 person-days; adjusted hazard ratio (HR) 0.55 (95% CI, 0.34 to 0.88). The adjusted HR for death due to Covid-19 was 0.26 (95% CI, 0.10 to 0.73). Among patients aged 40 to 64, the hospitalizations rate in treated compared to untreated patients was 125.8 versus 49.1 per 100,000 person-days; adjusted HR 1.80 (95% CI, 0.86 to 3.77). The adjusted HR for death was 12.8 (95% CI, 3.41 to 48.2).
Conclusions In a cohort of non-hospitalized, omicron-infected high-risk patients, molnupiravir therapy was associated with a signi cant reduction in hospitalizations and mortality due to Covid-19 in patients 65 years and above. However, no evidence of bene t was found in younger adults.
This work did not receive any nancial or in-kind support.
Con icts of Interest All authors report no Con icts of interest
References
Arbel, Sagy, Hoshen, Battat, Lavie et al., Nirmatrelvir Use and Severe Covid-19 Outcomes during the Omicron Surge, N Engl J Med,
doi:10.1056/NEJMoa2204919
Bernal, Da Silva, Musungaie, Molnupiravir for Oral Treatment of Covid-19 in Non-hospitalized Patients, N Engl J Med
Li, Wang, Lavrijsen, SARS-CoV-2 Omicron variant is highly sensitive to molnupiravir, nirmatrelvir, and the combination, Cell Res,
doi:10.1038/s41422-022-00618-w
Lévesque, Hanley, Kezouh, Problem of immortal time bias in cohort studies: example using statins for preventing progression of diabetes, BMJ,
doi:10.1136/bmj.b5087
Takashita, Kinoshita, Yamayoshi, E cacy of Antibodies and Antiviral Drugs against Covid-19 Omicron Variant, N Engl J Med,
doi:10.1056/NEJMc2119407
Takashita, Kinoshita, Yamayoshi, E cacy of Antiviral Agents against the SARS-CoV-2 Omicron Subvariant BA.2, N Engl J Med,
doi:10.1056/NEJMc2201933
Yip, Lui, Lai, Wong, Tse et al., Impact of the use of oral antiviral agents on the risk of hospitalization in community COVID-19 patients, Clin Infect Dis,
doi:10.1093/cid/ciac687
{ 'indexed': {'date-parts': [[2022, 8, 24]], 'date-time': '2022-08-24T21:41:53Z', 'timestamp': 1661377313466},
'reference-count': 12,
'publisher': 'Massachusetts Medical Society',
'content-domain': {'domain': [], 'crossmark-restriction': False},
'DOI': '10.1056/nejmoa2204919',
'type': 'journal-article',
'created': {'date-parts': [[2022, 8, 24]], 'date-time': '2022-08-24T21:00:10Z', 'timestamp': 1661374810000},
'source': 'Crossref',
'is-referenced-by-count': 0,
'title': 'Nirmatrelvir Use and Severe Covid-19 Outcomes during the Omicron Surge',
'prefix': '10.1056',
'author': [ { 'ORCID': 'http://orcid.org/0000-0002-6058-8665',
'authenticated-orcid': False,
'given': 'Ronen',
'family': 'Arbel',
'sequence': 'first',
'affiliation': [ { 'name': 'From the Division of Community Medical Services (R.A., A.P., '
'S.Y., D.S., A.H., D.N.), the Branch of Planning and Strategy '
'(Y.W.S., M.H., E.B., G.L.), and the Clalit Research Institute, '
'Division of Innovation (J.G.W., N.D., R.B., Y.B.-S.), Clalit '
'Health Services, Tel Aviv, the Maximizing Health Outcomes '
'Research Lab, Sapir College, Sderot (R.A.), the Department of '
'Bioinformatics, Jerusalem College of Technology, Jerusalem '
'(M.H.), the Ruth and Bruce Rappaport Faculty of Medicine, '
'Technion, Israel Institute...'}]},
{ 'given': 'Yael',
'family': 'Wolff Sagy',
'sequence': 'additional',
'affiliation': [ { 'name': 'From the Division of Community Medical Services (R.A., A.P., '
'S.Y., D.S., A.H., D.N.), the Branch of Planning and Strategy '
'(Y.W.S., M.H., E.B., G.L.), and the Clalit Research Institute, '
'Division of Innovation (J.G.W., N.D., R.B., Y.B.-S.), Clalit '
'Health Services, Tel Aviv, the Maximizing Health Outcomes '
'Research Lab, Sapir College, Sderot (R.A.), the Department of '
'Bioinformatics, Jerusalem College of Technology, Jerusalem '
'(M.H.), the Ruth and Bruce Rappaport Faculty of Medicine, '
'Technion, Israel Institute...'}]},
{ 'given': 'Moshe',
'family': 'Hoshen',
'sequence': 'additional',
'affiliation': [ { 'name': 'From the Division of Community Medical Services (R.A., A.P., '
'S.Y., D.S., A.H., D.N.), the Branch of Planning and Strategy '
'(Y.W.S., M.H., E.B., G.L.), and the Clalit Research Institute, '
'Division of Innovation (J.G.W., N.D., R.B., Y.B.-S.), Clalit '
'Health Services, Tel Aviv, the Maximizing Health Outcomes '
'Research Lab, Sapir College, Sderot (R.A.), the Department of '
'Bioinformatics, Jerusalem College of Technology, Jerusalem '
'(M.H.), the Ruth and Bruce Rappaport Faculty of Medicine, '
'Technion, Israel Institute...'}]},
{ 'given': 'Erez',
'family': 'Battat',
'sequence': 'additional',
'affiliation': [ { 'name': 'From the Division of Community Medical Services (R.A., A.P., '
'S.Y., D.S., A.H., D.N.), the Branch of Planning and Strategy '
'(Y.W.S., M.H., E.B., G.L.), and the Clalit Research Institute, '
'Division of Innovation (J.G.W., N.D., R.B., Y.B.-S.), Clalit '
'Health Services, Tel Aviv, the Maximizing Health Outcomes '
'Research Lab, Sapir College, Sderot (R.A.), the Department of '
'Bioinformatics, Jerusalem College of Technology, Jerusalem '
'(M.H.), the Ruth and Bruce Rappaport Faculty of Medicine, '
'Technion, Israel Institute...'}]},
{ 'given': 'Gil',
'family': 'Lavie',
'sequence': 'additional',
'affiliation': [ { 'name': 'From the Division of Community Medical Services (R.A., A.P., '
'S.Y., D.S., A.H., D.N.), the Branch of Planning and Strategy '
'(Y.W.S., M.H., E.B., G.L.), and the Clalit Research Institute, '
'Division of Innovation (J.G.W., N.D., R.B., Y.B.-S.), Clalit '
'Health Services, Tel Aviv, the Maximizing Health Outcomes '
'Research Lab, Sapir College, Sderot (R.A.), the Department of '
'Bioinformatics, Jerusalem College of Technology, Jerusalem '
'(M.H.), the Ruth and Bruce Rappaport Faculty of Medicine, '
'Technion, Israel Institute...'}]},
{ 'given': 'Ruslan',
'family': 'Sergienko',
'sequence': 'additional',
'affiliation': [ { 'name': 'From the Division of Community Medical Services (R.A., A.P., '
'S.Y., D.S., A.H., D.N.), the Branch of Planning and Strategy '
'(Y.W.S., M.H., E.B., G.L.), and the Clalit Research Institute, '
'Division of Innovation (J.G.W., N.D., R.B., Y.B.-S.), Clalit '
'Health Services, Tel Aviv, the Maximizing Health Outcomes '
'Research Lab, Sapir College, Sderot (R.A.), the Department of '
'Bioinformatics, Jerusalem College of Technology, Jerusalem '
'(M.H.), the Ruth and Bruce Rappaport Faculty of Medicine, '
'Technion, Israel Institute...'}]},
{ 'given': 'Michael',
'family': 'Friger',
'sequence': 'additional',
'affiliation': [ { 'name': 'From the Division of Community Medical Services (R.A., A.P., '
'S.Y., D.S., A.H., D.N.), the Branch of Planning and Strategy '
'(Y.W.S., M.H., E.B., G.L.), and the Clalit Research Institute, '
'Division of Innovation (J.G.W., N.D., R.B., Y.B.-S.), Clalit '
'Health Services, Tel Aviv, the Maximizing Health Outcomes '
'Research Lab, Sapir College, Sderot (R.A.), the Department of '
'Bioinformatics, Jerusalem College of Technology, Jerusalem '
'(M.H.), the Ruth and Bruce Rappaport Faculty of Medicine, '
'Technion, Israel Institute...'}]},
{ 'given': 'Jacob G.',
'family': 'Waxman',
'sequence': 'additional',
'affiliation': [ { 'name': 'From the Division of Community Medical Services (R.A., A.P., '
'S.Y., D.S., A.H., D.N.), the Branch of Planning and Strategy '
'(Y.W.S., M.H., E.B., G.L.), and the Clalit Research Institute, '
'Division of Innovation (J.G.W., N.D., R.B., Y.B.-S.), Clalit '
'Health Services, Tel Aviv, the Maximizing Health Outcomes '
'Research Lab, Sapir College, Sderot (R.A.), the Department of '
'Bioinformatics, Jerusalem College of Technology, Jerusalem '
'(M.H.), the Ruth and Bruce Rappaport Faculty of Medicine, '
'Technion, Israel Institute...'}]},
{ 'ORCID': 'http://orcid.org/0000-0001-8811-7825',
'authenticated-orcid': False,
'given': 'Noa',
'family': 'Dagan',
'sequence': 'additional',
'affiliation': [ { 'name': 'From the Division of Community Medical Services (R.A., A.P., '
'S.Y., D.S., A.H., D.N.), the Branch of Planning and Strategy '
'(Y.W.S., M.H., E.B., G.L.), and the Clalit Research Institute, '
'Division of Innovation (J.G.W., N.D., R.B., Y.B.-S.), Clalit '
'Health Services, Tel Aviv, the Maximizing Health Outcomes '
'Research Lab, Sapir College, Sderot (R.A.), the Department of '
'Bioinformatics, Jerusalem College of Technology, Jerusalem '
'(M.H.), the Ruth and Bruce Rappaport Faculty of Medicine, '
'Technion, Israel Institute...'}]},
{ 'given': 'Ran',
'family': 'Balicer',
'sequence': 'additional',
'affiliation': [ { 'name': 'From the Division of Community Medical Services (R.A., A.P., '
'S.Y., D.S., A.H., D.N.), the Branch of Planning and Strategy '
'(Y.W.S., M.H., E.B., G.L.), and the Clalit Research Institute, '
'Division of Innovation (J.G.W., N.D., R.B., Y.B.-S.), Clalit '
'Health Services, Tel Aviv, the Maximizing Health Outcomes '
'Research Lab, Sapir College, Sderot (R.A.), the Department of '
'Bioinformatics, Jerusalem College of Technology, Jerusalem '
'(M.H.), the Ruth and Bruce Rappaport Faculty of Medicine, '
'Technion, Israel Institute...'}]},
{ 'given': 'Yatir',
'family': 'Ben-Shlomo',
'sequence': 'additional',
'affiliation': [ { 'name': 'From the Division of Community Medical Services (R.A., A.P., '
'S.Y., D.S., A.H., D.N.), the Branch of Planning and Strategy '
'(Y.W.S., M.H., E.B., G.L.), and the Clalit Research Institute, '
'Division of Innovation (J.G.W., N.D., R.B., Y.B.-S.), Clalit '
'Health Services, Tel Aviv, the Maximizing Health Outcomes '
'Research Lab, Sapir College, Sderot (R.A.), the Department of '
'Bioinformatics, Jerusalem College of Technology, Jerusalem '
'(M.H.), the Ruth and Bruce Rappaport Faculty of Medicine, '
'Technion, Israel Institute...'}]},
{ 'given': 'Alon',
'family': 'Peretz',
'sequence': 'additional',
'affiliation': [ { 'name': 'From the Division of Community Medical Services (R.A., A.P., '
'S.Y., D.S., A.H., D.N.), the Branch of Planning and Strategy '
'(Y.W.S., M.H., E.B., G.L.), and the Clalit Research Institute, '
'Division of Innovation (J.G.W., N.D., R.B., Y.B.-S.), Clalit '
'Health Services, Tel Aviv, the Maximizing Health Outcomes '
'Research Lab, Sapir College, Sderot (R.A.), the Department of '
'Bioinformatics, Jerusalem College of Technology, Jerusalem '
'(M.H.), the Ruth and Bruce Rappaport Faculty of Medicine, '
'Technion, Israel Institute...'}]},
{ 'given': 'Shlomit',
'family': 'Yaron',
'sequence': 'additional',
'affiliation': [ { 'name': 'From the Division of Community Medical Services (R.A., A.P., '
'S.Y., D.S., A.H., D.N.), the Branch of Planning and Strategy '
'(Y.W.S., M.H., E.B., G.L.), and the Clalit Research Institute, '
'Division of Innovation (J.G.W., N.D., R.B., Y.B.-S.), Clalit '
'Health Services, Tel Aviv, the Maximizing Health Outcomes '
'Research Lab, Sapir College, Sderot (R.A.), the Department of '
'Bioinformatics, Jerusalem College of Technology, Jerusalem '
'(M.H.), the Ruth and Bruce Rappaport Faculty of Medicine, '
'Technion, Israel Institute...'}]},
{ 'given': 'Danielle',
'family': 'Serby',
'sequence': 'additional',
'affiliation': [ { 'name': 'From the Division of Community Medical Services (R.A., A.P., '
'S.Y., D.S., A.H., D.N.), the Branch of Planning and Strategy '
'(Y.W.S., M.H., E.B., G.L.), and the Clalit Research Institute, '
'Division of Innovation (J.G.W., N.D., R.B., Y.B.-S.), Clalit '
'Health Services, Tel Aviv, the Maximizing Health Outcomes '
'Research Lab, Sapir College, Sderot (R.A.), the Department of '
'Bioinformatics, Jerusalem College of Technology, Jerusalem '
'(M.H.), the Ruth and Bruce Rappaport Faculty of Medicine, '
'Technion, Israel Institute...'}]},
{ 'ORCID': 'http://orcid.org/0000-0002-4396-5246',
'authenticated-orcid': False,
'given': 'Ariel',
'family': 'Hammerman',
'sequence': 'additional',
'affiliation': [ { 'name': 'From the Division of Community Medical Services (R.A., A.P., '
'S.Y., D.S., A.H., D.N.), the Branch of Planning and Strategy '
'(Y.W.S., M.H., E.B., G.L.), and the Clalit Research Institute, '
'Division of Innovation (J.G.W., N.D., R.B., Y.B.-S.), Clalit '
'Health Services, Tel Aviv, the Maximizing Health Outcomes '
'Research Lab, Sapir College, Sderot (R.A.), the Department of '
'Bioinformatics, Jerusalem College of Technology, Jerusalem '
'(M.H.), the Ruth and Bruce Rappaport Faculty of Medicine, '
'Technion, Israel Institute...'}]},
{ 'given': 'Doron',
'family': 'Netzer',
'sequence': 'additional',
'affiliation': [ { 'name': 'From the Division of Community Medical Services (R.A., A.P., '
'S.Y., D.S., A.H., D.N.), the Branch of Planning and Strategy '
'(Y.W.S., M.H., E.B., G.L.), and the Clalit Research Institute, '
'Division of Innovation (J.G.W., N.D., R.B., Y.B.-S.), Clalit '
'Health Services, Tel Aviv, the Maximizing Health Outcomes '
'Research Lab, Sapir College, Sderot (R.A.), the Department of '
'Bioinformatics, Jerusalem College of Technology, Jerusalem '
'(M.H.), the Ruth and Bruce Rappaport Faculty of Medicine, '
'Technion, Israel Institute...'}]}],
'member': '150',
'published-online': {'date-parts': [[2022, 8, 24]]},
'reference': [ {'key': 'r1', 'doi-asserted-by': 'publisher', 'DOI': '10.1056/NEJMe2202699'},
{'key': 'r4', 'doi-asserted-by': 'publisher', 'DOI': '10.1056/NEJMoa2118542'},
{'key': 'r5', 'doi-asserted-by': 'publisher', 'DOI': '10.1056/NEJMe2202160'},
{'key': 'r6', 'doi-asserted-by': 'publisher', 'DOI': '10.1056/NEJMoa2101765'},
{'key': 'r7', 'doi-asserted-by': 'publisher', 'DOI': '10.1056/NEJMoa2115624'},
{'key': 'r8', 'doi-asserted-by': 'publisher', 'DOI': '10.1136/bmj.b5087'},
{'key': 'r9', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41591-022-01832-0'},
{'key': 'r12', 'doi-asserted-by': 'publisher', 'DOI': '10.1056/NEJMc2119407'},
{'key': 'r13', 'doi-asserted-by': 'publisher', 'DOI': '10.1056/NEJMc2201933'},
{'key': 'r14', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41422-022-00618-w'},
{'key': 'r15', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.antiviral.2022.105252'},
{'key': 'r16', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/d41586-021-03614-z'}],
'container-title': 'New England Journal of Medicine',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'http://www.nejm.org/doi/pdf/10.1056/NEJMoa2204919',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2022, 8, 24]],
'date-time': '2022-08-24T21:00:12Z',
'timestamp': 1661374812000},
'score': 1,
'resource': {'primary': {'URL': 'http://www.nejm.org/doi/10.1056/NEJMoa2204919'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2022, 8, 24]]},
'references-count': 12,
'alternative-id': ['10.1056/NEJMoa2204919'],
'URL': 'http://dx.doi.org/10.1056/NEJMoa2204919',
'relation': {},
'ISSN': ['0028-4793', '1533-4406'],
'subject': ['General Medicine'],
'container-title-short': 'N Engl J Med',
'published': {'date-parts': [[2022, 8, 24]]}}