Real-World Efficacy of Ensitrelvir in Hospitalized Patients With COVID-19 in Japan: A Retrospective Observational Study
Ryohei Yoshida, Takaaki Sasaki, Yoshinobu Ohsaki
Cureus, doi:10.7759/cureus.61048
Background and aim: The coronavirus disease 2019 (COVID-19) pandemic necessitates continuously evaluating antiviral treatments, especially for high-risk groups, including older individuals. This study aimed to compare the efficacy of three antiviral drugs, including remdesivir, molnupiravir, and ensitrelvir, in hospitalized patients as measured by our own institution's antigen test, focusing on outcomes, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen levels, hospitalization duration, and fever resolution. Methods: This retrospective observational study was conducted at Yoshida Hospital, Asahikawa City, Japan, enrolling 154 patients who received antiviral treatment upon COVID-19 diagnosis from July 1, 2022, to September 15, 2023. The diagnosis was confirmed by proprietary antigen tests or loop-mediated isothermal amplification assays. Patients who received treatment outside the hospital or with consistently negative antigen results were excluded. Drug administration was determined by attending physicians, considering oral administration challenges and renal dysfunction. The data were statistically analyzed using an unpaired two-tailed Student's t-test and one-way analysis of variance complemented by the Tukey post-hoc test for detailed group comparisons. Results: No significant differences were observed in the initial antigen levels among the treatment groups. By day 10, the ensitrelvir group showed lower antigen levels than the other groups, but not significantly. The ensitrelvir group had a higher antigen-negative conversion rate and a significantly shorter hospital stay than the molnupiravir group. However, no significant differences were noted in the fever resolution time among the groups. Conclusion: This study suggests the potential benefits of ensitrelvir in reducing antigen levels and hospitalization duration. However, the overall efficacy of the antiviral agents for symptomatic relief appears similar. These findings underscore the need for further research to optimize COVID-19 management by considering personalized treatment approaches and long-term outcomes.
Additional Information Author Contributions All authors have reviewed the final version to be published and agreed to be accountable for all aspects of the work.
Concept and design: Ryohei Yoshida, Yoshinobu Ohsaki Drafting of the manuscript: Ryohei Yoshida Acquisition, analysis, or interpretation of data: Takaaki Sasaki Critical review of the manuscript for important intellectual content: Takaaki Sasaki, Yoshinobu Ohsaki Supervision: Takaaki Sasaki, Yoshinobu Ohsaki
Disclosures Human subjects: Consent was obtained or waived by all participants in this study. The Institutional Review Board of Yoshida Hospital issued approval 20230809003. The study protocol was approved by the Institutional Review Board of Yoshida Hospital (approval no. 20230809003) and conducted in accordance with the principles of the Declaration of Helsinki. Informed consent was obtained from all study patients using the opt-out method. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other..
References
Bernal, Da Silva, Musungaie, Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients, N Engl J Med,
doi:10.1056/NEJMoa2116044Dessie, Zewotir, Mortality-related risk factors of COVID-19: a systematic review and meta-analysis of 42 studies and 423,117 patients, BMC Infect Dis,
doi:10.1186/s12879-021-06536-3Hashimoto, Yahiro, Khan, Seroprevalence kinetics of SARS-CoV-2 antibodies in pediatric patients visiting a hospital during COVID-19 pandemic in Japan, J Infect Chemother,
doi:10.1016/j.jiac.2023.09.020Huang, Wang, Liu, COVID-19 patients with hypertension have more severe disease: a multicenter retrospective observational study, Hypertens Res,
doi:10.1038/s41440-020-0485-2Li, Hilgenfeld, Whitley, Clercq, Therapeutic strategies for COVID-19: progress and lessons learned, Nat Rev Drug Discov,
doi:10.1038/s41573-023-00672-yMukae, Yotsuyanagi, Ohmagari, A Randomized Phase 2/3 Study of Ensitrelvir, a Novel Oral SARS-CoV-2 3C-Like Protease Inhibitor, in Japanese Patients with Mild-to-Moderate COVID-19 or Asymptomatic SARS-CoV-2 Infection: Results of the Phase 2a Part, Antimicrob Agents Chemother,
doi:10.1128/aac.00697-22Mukae, Yotsuyanagi, Ohmagari, Efficacy and Safety of Ensitrelvir in Patients With Mild-to-Moderate Coronavirus Disease 2019: The Phase 2b Part of a Randomized, Placebo-Controlled, Phase 2/3 Study, Clin Infect Dis,
doi:10.1093/cid/ciac933Nobori, Fukao, Kuroda, Efficacy of ensitrelvir against SARS-CoV-2 in a delayed-treatment mouse model, J Antimicrob Chemother,
doi:10.1093/jac/dkac257Pan, Peto, Henao-Restrepo, Repurposed Antiviral Drugs for Covid-19 -Interim WHO Solidarity Trial Results, N Engl J Med,
doi:10.1056/NEJMoa2023184Richardson, Hirsch, Narasimhan, Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area, JAMA,
doi:10.1001/jama.2020.6775Wong, Au, Lau, Lau, Cowling et al., Real-world effectiveness of molnupiravir and nirmatrelvir plus ritonavir against mortality, hospitalisation, and in-hospital outcomes among communitydwelling, ambulatory patients with confirmed SARS-CoV-2 infection during the omicron wave in Hong Kong: an observational study, Lancet,
doi:10.1016/S0140-6736(22)01586-0Yotsuyanagi, Ohmagari, Doi, Efficacy and Safety of 5-Day Oral Ensitrelvir for Patients With Mild to Moderate COVID-19: The SCORPIO-SR Randomized Clinical Trial, JAMA Netw Open,
doi:10.1001/jamanetworkopen.2023.54991{ 'indexed': {'date-parts': [[2024, 5, 26]], 'date-time': '2024-05-26T00:16:02Z', 'timestamp': 1716682562854},
'reference-count': 18,
'publisher': 'Springer Science and Business Media LLC',
'content-domain': {'domain': [], 'crossmark-restriction': False},
'published-print': {'date-parts': [[2024, 5, 25]]},
'DOI': '10.7759/cureus.61048',
'type': 'journal-article',
'created': {'date-parts': [[2024, 5, 25]], 'date-time': '2024-05-25T11:56:11Z', 'timestamp': 1716638171000},
'source': 'Crossref',
'is-referenced-by-count': 0,
'title': 'Real-World Efficacy of Ensitrelvir in Hospitalized Patients With COVID-19 in Japan: A '
'Retrospective Observational Study',
'prefix': '10.7759',
'author': [ {'given': 'Ryohei', 'family': 'Yoshida', 'sequence': 'first', 'affiliation': []},
{'given': 'Takaaki', 'family': 'Sasaki', 'sequence': 'additional', 'affiliation': []},
{'given': 'Yoshinobu', 'family': 'Ohsaki', 'sequence': 'additional', 'affiliation': []}],
'member': '297',
'reference': [ { 'key': 'ref1',
'doi-asserted-by': 'publisher',
'DOI': '10.1056/NEJMoa2035389',
'article-title': 'Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine',
'volume': '384',
'author': 'Baden LR',
'year': '2021',
'unstructured': 'Baden LR, El Sahly HM, Essink B, et al.. Efficacy and Safety of the '
'mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. 2021, 384:403-16. '
'10.1056/NEJMoa2035389',
'journal-title': 'N Engl J Med'},
{ 'key': 'ref2',
'doi-asserted-by': 'publisher',
'DOI': '10.1056/NEJMoa2034577',
'article-title': 'Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine',
'volume': '383',
'author': 'Polack FP',
'year': '2020',
'unstructured': 'Polack FP, Thomas SJ, Kitchin N, et al.. Safety and Efficacy of the '
'BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020, 383:2603-15. '
'10.1056/NEJMoa2034577',
'journal-title': 'N Engl J Med'},
{ 'key': 'ref3',
'doi-asserted-by': 'publisher',
'DOI': '10.1186/s12879-021-06536-3',
'article-title': 'Mortality-related risk factors of COVID-19: a systematic review and '
'meta-analysis of 42 studies and 423,117 patients',
'volume': '21',
'author': 'Dessie ZG',
'year': '2021',
'unstructured': 'Dessie ZG, Zewotir T. Mortality-related risk factors of COVID-19: a '
'systematic review and meta-analysis of 42 studies and 423,117 patients. '
'BMC Infect Dis. 2021, 21:855. 10.1186/s12879-021-06536-3',
'journal-title': 'BMC Infect Dis'},
{ 'key': 'ref4',
'doi-asserted-by': 'publisher',
'DOI': '10.1001/jama.2020.6775',
'article-title': 'Presenting Characteristics, Comorbidities, and Outcomes Among 5700 '
'Patients Hospitalized With COVID-19 in the New York City Area',
'volume': '323',
'author': 'Richardson S',
'year': '2020',
'unstructured': 'Richardson S, Hirsch JS, Narasimhan M, et al.. Presenting '
'Characteristics, Comorbidities, and Outcomes Among 5700 Patients '
'Hospitalized With COVID-19 in the New York City Area. JAMA. 2020, '
'323:2052-9. 10.1001/jama.2020.6775',
'journal-title': 'JAMA'},
{ 'key': 'ref5',
'doi-asserted-by': 'publisher',
'DOI': '10.1038/s41440-020-0485-2',
'article-title': 'COVID-19 patients with hypertension have more severe disease: a '
'multicenter retrospective observational study',
'volume': '43',
'author': 'Huang S',
'year': '2020',
'unstructured': 'Huang S, Wang J, Liu F, et al.. COVID-19 patients with hypertension have '
'more severe disease: a multicenter retrospective observational study. '
'Hypertens Res. 2020, 43:824-31. 10.1038/s41440-020-0485-2',
'journal-title': 'Hypertens Res'},
{ 'key': 'ref6',
'doi-asserted-by': 'publisher',
'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 CK',
'year': '2022',
'unstructured': 'Wong CK, Au IC, Lau KT, Lau EH, Cowling BJ, Leung GM. 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. 2022, 400:1213-22. 10.1016/S0140-6736(22)01586-0',
'journal-title': 'Lancet'},
{ 'key': 'ref7',
'doi-asserted-by': 'publisher',
'DOI': '10.1056/NEJMoa2023184',
'article-title': 'Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial '
'Results',
'volume': '384',
'author': 'Pan H',
'year': '2021',
'unstructured': 'Pan H, Peto R, Henao-Restrepo AM, et al.. Repurposed Antiviral Drugs for '
'Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med. 2021, '
'384:497-511. 10.1056/NEJMoa2023184',
'journal-title': 'N Engl J Med'},
{ 'key': 'ref8',
'doi-asserted-by': 'publisher',
'DOI': '10.1038/s41573-023-00672-y',
'article-title': 'Therapeutic strategies for COVID-19: progress and lessons learned',
'volume': '22',
'author': 'Li G',
'year': '2023',
'unstructured': 'Li G, Hilgenfeld R, Whitley R, De Clercq E. Therapeutic strategies for '
'COVID-19: progress and lessons learned. Nat Rev Drug Discov. 2023, '
'22:449-75. 10.1038/s41573-023-00672-y',
'journal-title': 'Nat Rev Drug Discov'},
{ 'key': 'ref9',
'doi-asserted-by': 'publisher',
'DOI': '10.1056/NEJMoa2007764',
'article-title': 'Remdesivir for the Treatment of Covid-19 - Final Report',
'volume': '383',
'author': 'Beigel JH',
'year': '2020',
'unstructured': 'Beigel JH, Tomashek KM, Dodd LE, et al.. Remdesivir for the Treatment of '
'Covid-19 - Final Report. N Engl J Med. 2020, 383:1813-26. '
'10.1056/NEJMoa2007764',
'journal-title': 'N Engl J Med'},
{ 'key': 'ref10',
'doi-asserted-by': 'publisher',
'DOI': '10.1056/NEJMoa2116044',
'article-title': 'Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients',
'volume': '386',
'author': 'Jayk Bernal A',
'year': '2022',
'unstructured': 'Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al.. Molnupiravir for '
'Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med. '
'2022, 386:509-20. 10.1056/NEJMoa2116044',
'journal-title': 'N Engl J Med'},
{ 'key': 'ref11',
'doi-asserted-by': 'publisher',
'DOI': '10.1093/cid/ciac933',
'article-title': 'Efficacy and Safety of Ensitrelvir in Patients With Mild-to-Moderate '
'Coronavirus Disease 2019: The Phase 2b Part of a Randomized, '
'Placebo-Controlled, Phase 2/3 Study',
'volume': '76',
'author': 'Mukae H',
'year': '2023',
'unstructured': 'Mukae H, Yotsuyanagi H, Ohmagari N, et al.. Efficacy and Safety of '
'Ensitrelvir in Patients With Mild-to-Moderate Coronavirus Disease 2019: '
'The Phase 2b Part of a Randomized, Placebo-Controlled, Phase 2/3 Study. '
'Clin Infect Dis. 2023, 76:1403-11. 10.1093/cid/ciac933',
'journal-title': 'Clin Infect Dis'},
{ 'key': 'ref12',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/S2666-5247(21)00278-0',
'article-title': 'The emergence of powerful oral anti-COVID-19 drugs in the post-vaccine '
'era',
'volume': '3',
'author': 'Fan H',
'year': '2022',
'unstructured': 'Fan H, Lou F, Fan J, Li M, Tong Y. The emergence of powerful oral '
'anti-COVID-19 drugs in the post-vaccine era. Lancet Microbe. 2022, '
'3:e91. 10.1016/S2666-5247(21)00278-0',
'journal-title': 'Lancet Microbe'},
{ 'key': 'ref13',
'doi-asserted-by': 'publisher',
'DOI': '10.1128/aac.00697-22',
'article-title': 'A Randomized Phase 2/3 Study of Ensitrelvir, a Novel Oral SARS-CoV-2 '
'3C-Like Protease Inhibitor, in Japanese Patients with Mild-to-Moderate '
'COVID-19 or Asymptomatic SARS-CoV-2 Infection: Results of the Phase 2a '
'Part',
'volume': '66',
'author': 'Mukae H',
'year': '2022',
'unstructured': 'Mukae H, Yotsuyanagi H, Ohmagari N, et al.. A Randomized Phase 2/3 Study '
'of Ensitrelvir, a Novel Oral SARS-CoV-2 3C-Like Protease Inhibitor, in '
'Japanese Patients with Mild-to-Moderate COVID-19 or Asymptomatic '
'SARS-CoV-2 Infection: Results of the Phase 2a Part. Antimicrob Agents '
'Chemother. 2022, 66:e0069722. 10.1128/aac.00697-22',
'journal-title': 'Antimicrob Agents Chemother'},
{ 'key': 'ref14',
'doi-asserted-by': 'publisher',
'DOI': '10.1093/jac/dkac257',
'article-title': 'Efficacy of ensitrelvir against SARS-CoV-2 in a delayed-treatment mouse '
'model',
'volume': '77',
'author': 'Nobori H',
'year': '2022',
'unstructured': 'Nobori H, Fukao K, Kuroda T, et al.. Efficacy of ensitrelvir against '
'SARS-CoV-2 in a delayed-treatment mouse model. J Antimicrob Chemother. '
'2022, 77:2984-91. 10.1093/jac/dkac257',
'journal-title': 'J Antimicrob Chemother'},
{ 'key': 'ref15',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.jiac.2023.09.020',
'article-title': 'Seroprevalence kinetics of SARS-CoV-2 antibodies in pediatric patients '
'visiting a hospital during COVID-19 pandemic in Japan',
'volume': '30',
'author': 'Hashimoto T',
'year': '2024',
'unstructured': 'Hashimoto T, Yahiro T, Khan S, et al.. Seroprevalence kinetics of '
'SARS-CoV-2 antibodies in pediatric patients visiting a hospital during '
'COVID-19 pandemic in Japan. J Infect Chemother. 2024, 30:169-71. '
'10.1016/j.jiac.2023.09.020',
'journal-title': 'J Infect Chemother'},
{ 'key': 'ref16',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.jiph.2020.07.014',
'article-title': 'COVID-19 and comorbidities: Deleterious impact on infected patients',
'volume': '13',
'author': 'Ejaz H',
'year': '2020',
'unstructured': 'Ejaz H, Alsrhani A, Zafar A, et al.. COVID-19 and comorbidities: '
'Deleterious impact on infected patients. J Infect Public Health. 2020, '
'13:1833-9. 10.1016/j.jiph.2020.07.014',
'journal-title': 'J Infect Public Health'},
{ 'key': 'ref17',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.arr.2020.101205',
'article-title': 'Aging in COVID-19: Vulnerability, immunity and intervention',
'volume': '65',
'author': 'Chen Y',
'year': '2021',
'unstructured': 'Chen Y, Klein SL, Garibaldi BT, et al.. Aging in COVID-19: '
'Vulnerability, immunity and intervention. Ageing Res Rev. 2021, '
'65:101205. 10.1016/j.arr.2020.101205',
'journal-title': 'Ageing Res Rev'},
{ 'key': 'ref18',
'doi-asserted-by': 'publisher',
'DOI': '10.1001/jamanetworkopen.2023.54991',
'article-title': 'Efficacy and Safety of 5-Day Oral Ensitrelvir for Patients With Mild to '
'Moderate COVID-19: The SCORPIO-SR Randomized Clinical Trial',
'volume': '7',
'author': 'Yotsuyanagi H',
'year': '2024',
'unstructured': 'Yotsuyanagi H, Ohmagari N, Doi Y, et al.. Efficacy and Safety of 5-Day '
'Oral Ensitrelvir for Patients With Mild to Moderate COVID-19: The '
'SCORPIO-SR Randomized Clinical Trial. JAMA Netw Open. 2024, 7:e2354991. '
'10.1001/jamanetworkopen.2023.54991',
'journal-title': 'JAMA Netw Open'}],
'container-title': 'Cureus',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://www.cureus.com/articles/242222-real-world-efficacy-of-ensitrelvir-in-hospitalized-patients-with-covid-19-in-japan-a-retrospective-observational-study',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2024, 5, 25]],
'date-time': '2024-05-25T11:56:14Z',
'timestamp': 1716638174000},
'score': 1,
'resource': { 'primary': { 'URL': 'https://www.cureus.com/articles/242222-real-world-efficacy-of-ensitrelvir-in-hospitalized-patients-with-covid-19-in-japan-a-retrospective-observational-study'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2024, 5, 25]]},
'references-count': 18,
'URL': 'http://dx.doi.org/10.7759/cureus.61048',
'relation': {},
'ISSN': ['2168-8184'],
'subject': [],
'published': {'date-parts': [[2024, 5, 25]]}}
