Systematic evaluation of therapeutic effectiveness of Azvudine in treating COVID-19 hospitalized patients: a retrospective cohort study
Yingkai Xu, Yuan Huang, Zihan Yuan, Wanbing Liu, Li Wang, Lei Liu
Frontiers in Cellular and Infection Microbiology, doi:10.3389/fcimb.2024.1453234
Background: Azvudine, a repurposed oral small molecule antiviral drug, has potential effects in combating the SARS-CoV-2 virus. However, studies on its clinical efficacy in patients with COVID-19 are still limited and controversial, and further research and validation are necessary. Methods: A retrospective cohort study was conducted on COVID-19 patients who were hospitalized in the General Hospital of Central Theater Command from 1 December 2022 to 31 January 2023. We included 132 patients treated with Azvudine and 132 controls after screening and propensity score matching. The primary outcomes including all-cause mortality and a composite outcome of disease progression such as non-invasive respiratory support, invasive respiratory support, admission to intensive care unit (ICU), and death were compared. Results: Azvudine recipients had a much lower incidence rate of composite disease progression outcome than controls (13.9075/1000 person-days versus 25.7731/1000 person-days, P<0.05). Azvudine recipients also possessed a lower all-cause mortality rate than controls (2.6797/1000 person-days versus 8.5910/ 1000 person-days, P<0.01). Azvudine treatment significantly reduced the risk of composite disease progression (HR: 0.37, 95% CI: 0.16-0.84, P=0.017) and allcause death (HR: 0.25, 95% CI: 0.08-0.81, P=0.021) after adjusting potential confounding factors such as age, sex, severity of COVID-19, complications, concomitant therapy, time from symptoms to treatment, and important laboratory indicators. The subgroup analyses of composite disease progression outcome and all-cause death indicated robustness of Azvudine's in treating COVID-19 patients in general.
Ethics statement The studies involving humans were approved by Research Ethics Committee of General Hospital of Central Theater Command. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants' legal guardians/next of kin in accordance with the national legislation and institutional requirements.
Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Austin, Some methods of propensity-score matching had superior performance to others: Results of an empirical investigation and monte carlo simulations, Biom J,
doi:10.1002/bimj.200810488Bai, Du, Wang, Lau, Fung et al., Public health impact of paxlovid as treatment for covid-19, United States, Emerging Infect. Dis. J,
doi:10.3201/eid3002.230835Bernal, Gomes Da Silva, Musungaie, Kovalchuk, Gonzalez et al., Molnupiravir for oral treatment of covid-19 in nonhospitalized patients, N Engl. J. Med,
doi:10.1056/NEJMoa2116044Chen, Guo, Deng, Wang, Gao et al., All-cause mortality in moderate and severe covid-19 patients with myocardial injury receiving versus not receiving azvudine: A propensity score-matched analysis, Cardiol. Plus,
doi:10.1097/CP9.0000000000000049Chen, Jiang, Rang, Zhuo, Zhou, Comparison of azvudine, molnupiravir, and nirmatrelvir/ritonavir in adult patients with mild-to-moderate covid-19: A retrospective cohort study, Sci. Rep,
doi:10.1038/s41598-024-53862-yDa Silva, Gebe Abreu Cabral, De Souza, Arruda, Cabral et al., Serial viral load analysis by ddpcr to evaluate fnc efficacy and safety in the treatment of mild cases of covid-19, Front. Med,
doi:10.37247/PAMED5ED.5.23.7Dresser, Spence, Bailey, Pharmacokineticpharmacodynamic consequences and clinical relevance of cytochrome p450 3a4 inhibition, Clin. Pharmacokinet,
doi:10.2165/00003088-200038010-00003Gao, Luo, Ren, Duan, Han et al., Antiviral effect of azvudine and nirmatrelvir-ritonavir among hospitalized patients with covid-19, J. Infect,
doi:10.1016/j.jinf.2023.03.023Grandvuillemin, Rocher, Valnet-Rabier, Drici, Dautriche, Pharmacovigilance follow-up of patients in the context of the covid-19 pandemic, Therapie,
doi:10.1016/j.therap.2023.01.004Hammond, Leister-Tebbe, Gardner, Abreu, Bao et al., Oral nirmatrelvir for high-risk, nonhospitalized adults with covid-19, N Engl. J. Med,
doi:10.1056/NEJMoa2118542Han, Han, Wang, Wang, Cui et al., Effectiveness and Optimal timing of Azvudine in COVID-19 Patients: A Multi-center Retrospective Study in Beijing, China,
doi:10.21203/rs.3.rs-3145554/v1Jiang, Sun, Zhao, Zhang, Liu et al., Presence of the m184i mutation after short-term exposure to azvudine for covid-19 in people living with hiv, AIDS,
doi:10.1097/QAD.0000000000003564Kellogg, Equils, The role of the thymus in covid-19 disease severity: Implications for antibody treatment and immunization, Hum. Vaccines Immunotherapeutics,
doi:10.1080/21645515.2020.1818519Najjar-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/ciac443Qi, Yang, Gong, Li, Liang, Real-world effectiveness of azvudine for patients infected with the sars-cov-2 omicron subvariant ba.5 in an intensive care unit, J. Thorac. Dis,
doi:10.21037/jtd-23-1093Reis, Metzendorf, Kuehn, Popp, Gagyor et al., Nirmatrelvir combined with ritonavir for preventing and treating covid-19, Cochrane Database Syst. Rev,
doi:10.1097/QAD.0000000000003564Ren, Luo, Yu, Song, Liang et al., A randomized, openlabel, controlled clinical trial of azvudine tablets in the treatment of mild and common covid-19, a pilot study, Adv. Sci. (Weinh),
doi:10.1002/advs.202001435Sun, Jin, Dian, Shen, Zeng et al., Oral azvudine for hospitalised patients with covid-19 and pre-existing conditions: A retrospective cohort study, EClinicalMedicine,
doi:10.1016/j.eclinm.2023.101981Yan, Zhou, Zhu, Chen, Lu et al., The feasibility, safety, and efficacy of paxlovid treatment in sars-cov-2-infected children aged 6-14 years: A cohort study, Ann. Transl. Med,
doi:10.21037/atm-22-2791Yang, Liu, Liu, Zhang, Wan et al., Covid-19: immunopathogenesis and immunotherapeutics, Signal Transduction Targeted Ther,
doi:10.1038/s41392-020-00243-2Zhang, Li, Wang, Liu, Lu et al., Azvudine is a thymus-homing anti-sars-cov-2 drug effective in treating covid-19 patients, Signal Transduct Target Ther,
doi:10.1038/s41392-021-00835-6Zhu, Efficacy and safety evaluation of azvudine in the prospective treatment of covid-19 based on four phase iii clinical trials, Front. Pharmacol,
doi:10.3389/fphar.2023.1228548{ 'indexed': { 'date-parts': [[2024, 11, 8]],
'date-time': '2024-11-08T05:15:19Z',
'timestamp': 1731042919890,
'version': '3.28.0'},
'reference-count': 28,
'publisher': 'Frontiers Media SA',
'license': [ { 'start': { 'date-parts': [[2024, 11, 7]],
'date-time': '2024-11-07T00:00:00Z',
'timestamp': 1730937600000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'https://creativecommons.org/licenses/by/4.0/'}],
'content-domain': {'domain': ['frontiersin.org'], 'crossmark-restriction': True},
'abstract': '<jats:sec><jats:title>Background</jats:title><jats:p>Azvudine, a repurposed oral small '
'molecule antiviral drug, has potential effects in combating the SARS-CoV-2 virus. However, '
'studies on its clinical efficacy in patients with COVID-19 are still limited and '
'controversial, and further research and validation are '
'necessary.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>A '
'retrospective cohort study was conducted on COVID-19 patients who were hospitalized in the '
'General Hospital of Central Theater Command from 1 December 2022 to 31 January 2023. We '
'included 132 patients treated with Azvudine and 132 controls after screening and propensity '
'score matching. The primary outcomes including all-cause mortality and a composite outcome of '
'disease progression such as non-invasive respiratory support, invasive respiratory support, '
'admission to intensive care unit (ICU), and death were '
'compared.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Azvudine '
'recipients had a much lower incidence rate of composite disease progression outcome than '
'controls (13.9075/1000 person-days versus 25.7731/1000 person-days, '
'<jats:italic>P</jats:italic>&lt;0.05). Azvudine recipients also possessed a lower '
'all-cause mortality rate than controls (2.6797/1000 person-days versus 8.5910/1000 '
'person-days, <jats:italic>P</jats:italic>&lt;0.01). Azvudine treatment significantly '
'reduced the risk of composite disease progression (HR: 0.37, 95% CI: 0.16-0.84, '
'<jats:italic>P</jats:italic>=0.017) and all-cause death (HR: 0.25, 95% CI: 0.08-0.81, '
'<jats:italic>P</jats:italic>=0.021) after adjusting potential confounding factors such as '
'age, sex, severity of COVID-19, complications, concomitant therapy, time from symptoms to '
'treatment, and important laboratory indicators. The subgroup analyses of composite disease '
'progression outcome and all-cause death indicated robustness of Azvudine’s in treating '
'COVID-19 patients in '
'general.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our study '
'demonstrates that Azvudine has a significant positive impact on the clinical recovery of '
'hospitalized patients with COVID-19. These findings provide important support for the use of '
'Azvudine as a therapeutic option for COVID-19, given the current divergent views on its '
'therapeutic efficacy and its importance in public health and medical '
'care.</jats:p></jats:sec>',
'DOI': '10.3389/fcimb.2024.1453234',
'type': 'journal-article',
'created': {'date-parts': [[2024, 11, 7]], 'date-time': '2024-11-07T06:12:18Z', 'timestamp': 1730959938000},
'update-policy': 'http://dx.doi.org/10.3389/crossmark-policy',
'source': 'Crossref',
'is-referenced-by-count': 0,
'title': 'Systematic evaluation of therapeutic effectiveness of Azvudine in treating COVID-19 hospitalized '
'patients: a retrospective cohort study',
'prefix': '10.3389',
'volume': '14',
'author': [ {'given': 'Yingkai', 'family': 'Xu', 'sequence': 'first', 'affiliation': []},
{'given': 'Yuan', 'family': 'Huang', 'sequence': 'additional', 'affiliation': []},
{'given': 'Zihan', 'family': 'Yuan', 'sequence': 'additional', 'affiliation': []},
{'given': 'Wanbing', 'family': 'Liu', 'sequence': 'additional', 'affiliation': []},
{'given': 'Li', 'family': 'Wang', 'sequence': 'additional', 'affiliation': []},
{'given': 'Lei', 'family': 'Liu', 'sequence': 'additional', 'affiliation': []}],
'member': '1965',
'published-online': {'date-parts': [[2024, 11, 7]]},
'reference': [ { 'key': 'B1',
'doi-asserted-by': 'publisher',
'first-page': '171',
'DOI': '10.1002/bimj.200810488',
'article-title': 'Some methods of propensity-score matching had superior performance to '
'others: Results of an empirical investigation and monte carlo '
'simulations',
'volume': '51',
'author': 'Austin',
'year': '2009',
'journal-title': 'Biom J.'},
{ 'key': 'B2',
'doi-asserted-by': 'publisher',
'first-page': '262',
'DOI': '10.3201/eid3002.230835',
'article-title': 'Public health impact of paxlovid as treatment for covid-19, United '
'States',
'volume': '30',
'author': 'Bai',
'year': '2024',
'journal-title': 'Emerging Infect. Dis. J.'},
{ 'key': 'B3',
'doi-asserted-by': 'publisher',
'first-page': '138882',
'DOI': '10.1016/j.scitotenv.2020.138882',
'article-title': 'Covid-19 outbreak: Migration, effects on society, global environment '
'and prevention',
'volume': '728',
'author': 'Chakraborty',
'year': '2020',
'journal-title': 'Sci. Total Environ.'},
{ 'key': 'B4',
'doi-asserted-by': 'publisher',
'first-page': '103',
'DOI': '10.1097/CP9.0000000000000049',
'article-title': 'All-cause mortality in moderate and severe covid-19 patients with '
'myocardial injury receiving versus not receiving azvudine: A propensity '
'score-matched analysis',
'volume': '8',
'author': 'Chen',
'year': '2023',
'journal-title': 'Cardiol. Plus'},
{ 'key': 'B5',
'doi-asserted-by': 'publisher',
'first-page': '3318',
'DOI': '10.1038/s41598-024-53862-y',
'article-title': 'Comparison of azvudine, molnupiravir, and nirmatrelvir/ritonavir in '
'adult patients with mild-to-moderate covid-19: A retrospective cohort '
'study',
'volume': '14',
'author': 'Chen',
'year': '2024',
'journal-title': 'Sci. Rep.'},
{ 'key': 'B6',
'doi-asserted-by': 'publisher',
'first-page': '1143485',
'DOI': '10.37247/PAMED5ED.5.23.7',
'article-title': 'Serial viral load analysis by ddpcr to evaluate fnc efficacy and safety '
'in the treatment of mild cases of covid-19',
'volume': '10',
'author': 'da Silva',
'year': '2023',
'journal-title': 'Front. Med. (Lausanne)'},
{ 'key': 'B7',
'doi-asserted-by': 'publisher',
'first-page': '41',
'DOI': '10.2165/00003088-200038010-00003',
'article-title': 'Pharmacokinetic-pharmacodynamic consequences and clinical relevance of '
'cytochrome p450 3a4 inhibition',
'volume': '38',
'author': 'Dresser',
'year': '2000',
'journal-title': 'Clin. Pharmacokinet.'},
{ 'key': 'B8',
'doi-asserted-by': 'publisher',
'first-page': 'e158',
'DOI': '10.1016/j.jinf.2023.03.023',
'article-title': 'Antiviral effect of azvudine and nirmatrelvir-ritonavir among '
'hospitalized patients with covid-19',
'volume': '86',
'author': 'Gao',
'year': '2023',
'journal-title': 'J. Infect.'},
{ 'key': 'B9',
'doi-asserted-by': 'publisher',
'first-page': '523',
'DOI': '10.1016/j.therap.2023.01.004',
'article-title': 'Pharmacovigilance follow-up of patients in the context of the covid-19 '
'pandemic',
'volume': '78',
'author': 'Grandvuillemin',
'year': '2023',
'journal-title': 'Therapie'},
{ 'key': 'B10',
'doi-asserted-by': 'publisher',
'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': 'B11',
'volume-title': 'Effectiveness and Optimal timing of Azvudine in COVID-19 Patients: A '
'Multi-center Retrospective Study in Beijing, China',
'author': 'Han',
'year': '2023'},
{ 'key': 'B12',
'doi-asserted-by': 'publisher',
'first-page': '509',
'DOI': '10.1056/NEJMoa2116044',
'article-title': 'Molnupiravir for oral treatment of covid-19 in nonhospitalized patients',
'volume': '386',
'author': 'Jayk Bernal',
'year': '2022',
'journal-title': 'N Engl. J. Med.'},
{ 'key': 'B13',
'doi-asserted-by': 'publisher',
'first-page': '1341',
'DOI': '10.1097/QAD.0000000000003564',
'article-title': 'Presence of the m184i mutation after short-term exposure to azvudine '
'for covid-19 in people living with hiv',
'volume': '37',
'author': 'Jiang',
'year': '2023',
'journal-title': 'AIDS'},
{ 'key': 'B14',
'doi-asserted-by': 'publisher',
'first-page': '638',
'DOI': '10.1080/21645515.2020.1818519',
'article-title': 'The role of the thymus in covid-19 disease severity: Implications for '
'antibody treatment and immunization',
'volume': '17',
'author': 'Kellogg',
'year': '2021',
'journal-title': 'Hum. Vaccines Immunotherapeutics'},
{ 'key': 'B15',
'doi-asserted-by': 'publisher',
'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': 'B16',
'doi-asserted-by': 'publisher',
'first-page': '4925',
'DOI': '10.21037/jtd-23-1093',
'article-title': 'Real-world effectiveness of azvudine for patients infected with the '
'sars-cov-2 omicron subvariant ba.5 in an intensive care unit',
'volume': '15',
'author': 'Qi',
'year': '2023',
'journal-title': 'J. Thorac. Dis.'},
{ 'key': 'B17',
'doi-asserted-by': 'publisher',
'first-page': 'Cd015395',
'DOI': '10.1097/QAD.0000000000003564',
'article-title': 'Nirmatrelvir combined with ritonavir for preventing and treating '
'covid-19',
'volume': '11',
'author': 'Reis',
'year': '2023',
'journal-title': 'Cochrane Database Syst. Rev.'},
{ 'key': 'B18',
'doi-asserted-by': 'publisher',
'DOI': '10.1002/advs.202001435',
'article-title': 'A randomized, open-label, controlled clinical trial of azvudine tablets '
'in the treatment of mild and common covid-19, a pilot study',
'volume': '7',
'author': 'Ren',
'year': '2020',
'journal-title': 'Adv. Sci. (Weinh)'},
{ 'key': 'B19',
'doi-asserted-by': 'publisher',
'first-page': '1267',
'DOI': '10.1007/s40265-020-01367-z',
'article-title': 'Pharmaco-immunomodulatory therapy in covid-19',
'volume': '80',
'author': 'Rizk',
'year': '2020',
'journal-title': 'Drugs'},
{ 'key': 'B20',
'doi-asserted-by': 'publisher',
'first-page': '101981',
'DOI': '10.1016/j.eclinm.2023.101981',
'article-title': 'Oral azvudine for hospitalised patients with covid-19 and pre-existing '
'conditions: A retrospective cohort study',
'volume': '59',
'author': 'Sun',
'year': '2023',
'journal-title': 'EClinicalMedicine'},
{ 'key': 'B21',
'doi-asserted-by': 'publisher',
'first-page': '815',
'DOI': '10.3748/wjg.v29.i5.815',
'article-title': 'Outcomes of covid-19 among patients with liver disease',
'volume': '29',
'author': 'Vujčić',
'year': '2023',
'journal-title': 'World J. Gastroenterol.'},
{ 'key': 'B22',
'doi-asserted-by': 'publisher',
'first-page': '619',
'DOI': '10.21037/atm-22-2791',
'article-title': 'The feasibility, safety, and efficacy of paxlovid treatment in '
'sars-cov-2-infected children aged 6-14 years: A cohort study',
'volume': '10',
'author': 'Yan',
'year': '2022',
'journal-title': 'Ann. Transl. Med.'},
{ 'key': 'B23',
'doi-asserted-by': 'publisher',
'first-page': '128',
'DOI': '10.1038/s41392-020-00243-2',
'article-title': 'Covid-19: immunopathogenesis and immunotherapeutics',
'volume': '5',
'author': 'Yang',
'year': '2020',
'journal-title': 'Signal Transduction Targeted Ther.'},
{ 'key': 'B24',
'doi-asserted-by': 'publisher',
'first-page': '236',
'DOI': '10.1038/s41392-020-00351-z',
'article-title': 'Azvudine (fnc): A promising clinical candidate for covid-19 treatment',
'volume': '5',
'author': 'Yu',
'year': '2020',
'journal-title': 'Signal Transduct Target Ther.'},
{ 'key': 'B25',
'doi-asserted-by': 'publisher',
'first-page': '100321',
'DOI': '10.1016/j.xinn.2022.100321',
'article-title': 'The first chinese oral anti-covid-19 drug azvudine launched',
'volume': '3',
'author': 'Yu',
'year': '2022',
'journal-title': 'Innovation (Camb)'},
{ 'key': 'B26',
'doi-asserted-by': 'publisher',
'first-page': '121',
'DOI': '10.1186/s12985-021-01593-1',
'article-title': 'Liver injury in covid-19: Clinical features and treatment management',
'volume': '18',
'author': 'Yu',
'year': '2021',
'journal-title': 'Virol. J.'},
{ 'key': 'B27',
'doi-asserted-by': 'publisher',
'first-page': '414',
'DOI': '10.1038/s41392-021-00835-6',
'article-title': 'Azvudine is a thymus-homing anti-sars-cov-2 drug effective in treating '
'covid-19 patients',
'volume': '6',
'author': 'Zhang',
'year': '2021',
'journal-title': 'Signal Transduct Target Ther.'},
{ 'key': 'B28',
'doi-asserted-by': 'publisher',
'DOI': '10.3389/fphar.2023.1228548',
'article-title': 'Efficacy and safety evaluation of azvudine in the prospective treatment '
'of covid-19 based on four phase iii clinical trials',
'volume': '14',
'author': 'Zhu',
'year': '2023',
'journal-title': 'Front. Pharmacol.'}],
'container-title': 'Frontiers in Cellular and Infection Microbiology',
'original-title': [],
'link': [ { 'URL': 'https://www.frontiersin.org/articles/10.3389/fcimb.2024.1453234/full',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2024, 11, 7]],
'date-time': '2024-11-07T06:12:20Z',
'timestamp': 1730959940000},
'score': 1,
'resource': {'primary': {'URL': 'https://www.frontiersin.org/articles/10.3389/fcimb.2024.1453234/full'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2024, 11, 7]]},
'references-count': 28,
'alternative-id': ['10.3389/fcimb.2024.1453234'],
'URL': 'http://dx.doi.org/10.3389/fcimb.2024.1453234',
'relation': {},
'ISSN': ['2235-2988'],
'subject': [],
'container-title-short': 'Front. Cell. Infect. Microbiol.',
'published': {'date-parts': [[2024, 11, 7]]}}
