Head-to-head comparison of azvudine and nirmatrelvir/ritonavir for the hospitalized patients with COVID-19: a real-world retrospective cohort study with propensity score matching

Wei et al., Frontiers in Pharmacology, doi:10.3389/fphar.2023.1274294, Oct 2023

https://c19early.org/wei2pl.html

PSM retrospective 725 hospitalized COVID-19 patients in China compared the effectiveness and safety of the oral antivirals azvudine and paxlovid. There was no significant difference in the risk of disease progression between groups, but azvudine was associated with lower ICU admission and invasive ventilation use.

Resistance. Variants may be resistant to paxlovid1-8. Use may promote the emergence of variants that weaken host immunity and potentially contribute to long COVID9.

Confounding by contraindication. Hoertel et al. find that over 50% of patients that died had a contraindication for the use of Paxlovid10. Retrospective studies that do not exclude contraindicated patients may significantly overestimate efficacy.

Black box warning. The FDA notes that severe, life-threatening, and/or fatal adverse reactions due to drug interactions have been reported in patients treated with paxlovid11.

Kidney and liver injury. Studies show significantly increased risk of acute kidney injury12 and liver injury13.

Standard of Care (SOC) for COVID-19 in the study country, China, is average with moderate efficacy for approved treatments14.

Important missing comments or errors? Let us know.

Study covers paxlovid and azvudine.

risk of death, 0.2% lower, RR 1.00, p = 1.00, treatment 36 of 264 (13.6%), control 63 of 461 (13.7%), NNT 3381.

risk of mechanical ventilation, 38.3% higher, RR 1.38, p = 0.04, treatment 61 of 264 (23.1%), control 77 of 461 (16.7%).

risk of ICU admission, 122.2% higher, RR 2.22, p = 0.05, treatment 14 of 264 (5.3%), control 11 of 461 (2.4%).

risk of progression, 28.3% higher, RR 1.28, p = 0.07, treatment 72 of 264 (27.3%), control 98 of 461 (21.3%), ICU admission, invasive mechanical ventilation, and in-hospital death, primary outcome.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

1. Zhou et al., Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system, Science Advances, doi:10.1126/sciadv.add7197.science.org, doi.org.

2. Moghadasi et al., Rapid resistance profiling of SARS-CoV-2 protease inhibitors, npj Antimicrobials and Resistance, doi:10.1038/s44259-023-00009-0.nature.com, doi.org.

3. Jochmans et al., The Substitutions L50F, E166A, and L167F in SARS-CoV-2 3CLpro Are Selected by a Protease Inhibitor In Vitro and Confer Resistance To Nirmatrelvir, mBio, doi:10.1128/mbio.02815-22.asm.org, doi.org.

4. Lopez et al., SARS-CoV-2 Resistance to Small Molecule Inhibitors, Current Clinical Microbiology Reports, doi:10.1007/s40588-024-00229-6.springer.com, doi.org.

5. Zvornicanin et al., Molecular Mechanisms of Drug Resistance and Compensation in SARS-CoV-2 Main Protease: The Interplay Between E166 and L50, bioRxiv, doi:10.1101/2025.01.24.634813.biorxiv.org, doi.org.

6. Vukovikj et al., Impact of SARS-CoV-2 variant mutations on susceptibility to monoclonal antibodies and antiviral drugs: a non-systematic review, April 2022 to October 2024, Eurosurveillance, doi:10.2807/1560-7917.ES.2025.30.10.2400252.eurosurveillance.org, doi.org.

7. Deschenes et al., Functional and structural characterization of treatment-emergent nirmatrelvir resistance mutations at low frequencies in the main protease (Mpro) reveals a unique evolutionary route for SARS-CoV-2 to gain resistance, The Journal of Infectious Diseases, doi:10.1093/infdis/jiaf294.oup.com, doi.org.

8. Zhou (B) et al., SARS-CoV-2 Mpro inhibitor ensitrelvir: asymmetrical cross-resistance with nirmatrelvir and emerging resistance hotspots, Emerging Microbes & Infections, doi:10.1080/22221751.2025.2552716.tandfonline.com, doi.org.

9. Thomas et al., Nirmatrelvir-Resistant Mutations in SARS-CoV-2 Mpro Enhance Host Immune Evasion via Cleavage of NF-κB Essential Modulator, bioRxiv, doi:10.1101/2024.10.18.619137.biorxiv.org, doi.org.

10. Hoertel et al., Prevalence of Contraindications to Nirmatrelvir-Ritonavir Among Hospitalized Patients With COVID-19 at Risk for Progression to Severe Disease, JAMA Network Open, doi:10.1001/jamanetworkopen.2022.42140.jamanetwork.com, doi.org.

11. FDA, Fact sheet for healthcare providers: emergency use authorization for paxlovid, www.fda.gov/media/155050/downloadfda.gov.

12. Kamo et al., Association of Antiviral Drugs for the Treatment of COVID-19 With Acute Renal Failure, In Vivo, doi:10.21873/invivo.13637.iiarjournals.org, doi.org.

13. Wang et al., Development and validation of a nomogram to assess the occurrence of liver dysfunction in patients with COVID-19 pneumonia in the ICU, BMC Infectious Diseases, doi:10.1186/s12879-025-10684-1.biomedcentral.com, doi.org.

14. c19early.org, c19early.org/soc/china.html.

Wei et al., 13 Oct 2023, retrospective, China, peer-reviewed, 8 authors, study period 1 December, 2022 - 31 January, 2023, this trial compares with another treatment - results may be better when compared to placebo. Contact: 13620327@qq.com, ld_2069@163.com.

This Paper Paxlovid All

DOI record: { "DOI": "10.3389/fphar.2023.1274294", "ISSN": [ "1663-9812" ], "URL": "http://dx.doi.org/10.3389/fphar.2023.1274294", "abstract": "Background: Nirmatrelvir/ritonavir and azvudine have been approved for the early treatment of COVID-19 in China, however, limited real-world data exists regarding their effectiveness and safety.Methods: We conducted a retrospective cohort study involving the hospitalized COVID-19 patients in China between December 2022 and January 2023. Demographic, clinical, and safety variables were recorded.Results: Among the 6,616 hospitalized COVID-19 patients, we included a total of 725 patients including azvudine recipients (N = 461) and nirmatrelvir/ritonavir (N = 264) recipients after exclusions and propensity score matching (1:2). There was no significant difference in the composite disease progression events between azvudine (98, 21.26%) and nirmatrelvir/ritonavir (72, 27.27%) groups (p = 0.066). Azvudine was associated with a significant reduction in secondary outcomes, including the percentage of intensive care unit admission (p = 0.038) and the need for invasive mechanical ventilation (p = 0.035), while the in-hospital death event did not significantly differ (p = 0.991). As for safety outcomes, 33 out of 461 patients (7.16%) in azvudine group and 22 out of 264 patients (8.33%) in nirmatrelvir/ritonavir group experienced drug-related adverse events between the day of admission (p = 0.565).Conclusion: In our real-world setting, azvudine treatment demonstrated similar safety compared to nirmatrelvir/ritonavir in hospitalized COVID-19 patients. Additionally, it showed slightly better clinical benefits in this population. However, further confirmation through additional clinical trials is necessary.", "alternative-id": [ "10.3389/fphar.2023.1274294" ], "author": [ { "affiliation": [], "family": "Wei", "given": "An-Hua", "sequence": "first" }, { "affiliation": [], "family": "Zeng", "given": "Lu", "sequence": "additional" }, { "affiliation": [], "family": "Wang", "given": "Lu", "sequence": "additional" }, { "affiliation": [], "family": "Gui", "given": "Lin", "sequence": "additional" }, { "affiliation": [], "family": "Zhang", "given": "Wen-Ting", "sequence": "additional" }, { "affiliation": [], "family": "Gong", "given": "Xue-Peng", "sequence": "additional" }, { "affiliation": [], "family": "Li", "given": "Juan", "sequence": "additional" }, { "affiliation": [], "family": "Liu", "given": "Dong", "sequence": "additional" } ], "container-title": "Frontiers in Pharmacology", "container-title-short": "Front. Pharmacol.", "content-domain": { "crossmark-restriction": true, "domain": [ "frontiersin.org" ] }, "created": { "date-parts": [ [ 2023, 10, 13 ] ], "date-time": "2023-10-13T05:02:57Z", "timestamp": 1697173377000 }, "deposited": { "date-parts": [ [ 2023, 10, 13 ] ], "date-time": "2023-10-13T05:03:00Z", "timestamp": 1697173380000 }, "indexed": { "date-parts": [ [ 2023, 10, 14 ] ], "date-time": "2023-10-14T11:46:17Z", "timestamp": 1697283977332 }, "is-referenced-by-count": 0, "issued": { "date-parts": [ [ 2023, 10, 13 ] ] }, "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2023, 10, 13 ] ], "date-time": "2023-10-13T00:00:00Z", "timestamp": 1697155200000 } } ], "link": [ { "URL": "https://www.frontiersin.org/articles/10.3389/fphar.2023.1274294/full", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "1965", "original-title": [], "prefix": "10.3389", "published": { "date-parts": [ [ 2023, 10, 13 ] ] }, "published-online": { "date-parts": [ [ 2023, 10, 13 ] ] }, "publisher": "Frontiers Media SA", "reference": [ { "DOI": "10.1002/jmv.28441", "article-title": "Efficacy and safety of nirmatrelvir/ritonavir (Paxlovid) for COVID-19: a rapid review and meta-analysis", "author": "Amani", "doi-asserted-by": "publisher", "first-page": "e28441", "journal-title": "J. Med. virology", "key": "B1", "volume": "95", "year": "2023" }, { "DOI": "10.1056/NEJMoa2204919", "article-title": "Nirmatrelvir use and severe covid-19 outcomes during the omicron surge", "author": "Arbel", "doi-asserted-by": "publisher", "first-page": "790", "journal-title": "N. Engl. J. Med.", "key": "B2", "volume": "387", "year": "2022" }, { "DOI": "10.1002/jmv.28471", "article-title": "Nirmatrelvir-ritonavir for the treatment of COVID-19 patients: a systematic review and meta-analysis", "author": "Cheema", "doi-asserted-by": "publisher", "first-page": "e28471", "journal-title": "J. Med. virology", "key": "B3", "volume": "95", "year": "2023" }, { "DOI": "10.1016/j.jfma.2023.08.029", "article-title": "Antiviral therapy of coronavirus disease 2019 (COVID-19)", "author": "Chen", "doi-asserted-by": "publisher", "journal-title": "J. Formos. Med. Assoc. = Taiwan yi zhi.", "key": "B4", "year": "2023" }, { "DOI": "10.1002/jmv.28756", "article-title": "Real-world effectiveness of Azvudine versus nirmatrelvir-ritonavir in hospitalized patients with COVID-19: a retrospective cohort study", "author": "Deng", "doi-asserted-by": "publisher", "first-page": "e28756", "journal-title": "J. Med. virology", "key": "B5", "volume": "95", "year": "2023" }, { "DOI": "10.1016/j.jinf.2023.03.023", "article-title": "Antiviral effect of azvudine and nirmatrelvir-ritonavir among hospitalized patients with COVID-19", "author": "Gao", "doi-asserted-by": "publisher", "first-page": "e158", "journal-title": "J. Infect.", "key": "B6", "volume": "86", "year": "2023" }, { "DOI": "10.3390/vaccines10101731", "article-title": "Nirmatrelvir/ritonavir and molnupiravir in the treatment of mild/moderate COVID-19: results of a real-life study", "author": "Gentile", "doi-asserted-by": "publisher", "first-page": "1731", "journal-title": "Vaccines", "key": "B7", "volume": "10", "year": "2022" }, { "DOI": "10.1056/NEJMoa2118542", "article-title": "Oral nirmatrelvir for high-risk, nonhospitalized adults with covid-19", "author": "Hammond", "doi-asserted-by": "publisher", "first-page": "1397", "journal-title": "N. Engl. J. Med.", "key": "B8", "volume": "386", "year": "2022" }, { "DOI": "10.3390/ijms23179866", "article-title": "The mechanism-based inactivation of CYP3A4 by ritonavir: what mechanism?", "author": "Loos", "doi-asserted-by": "publisher", "first-page": "9866", "journal-title": "Int. J. Mol. Sci.", "key": "B9", "volume": "23", "year": "2022" }, { "DOI": "10.1155/2022/7341493", "article-title": "Paxlovid: mechanism of action, synthesis, and in silico study", "author": "Marzi", "doi-asserted-by": "publisher", "first-page": "7341493", "journal-title": "BioMed Res. Int.", "key": "B10", "volume": "2022", "year": "2022" }, { "DOI": "10.1002/jmv.28660", "article-title": "Risk of hospitalization and sequelae in patients with COVID-19 treated with 3-day early remdesivir vs. controls in the vaccine and Omicron era: a real-life cohort study", "author": "Mazzitelli", "doi-asserted-by": "publisher", "first-page": "e28660", "journal-title": "J. Med. virology", "key": "B11", "volume": "95", "year": "" }, { "DOI": "10.3390/v15020384", "article-title": "Molnupiravir and nirmatrelvir/ritonavir: tolerability, safety, and adherence in a retrospective cohort study", "author": "Mazzitelli", "doi-asserted-by": "publisher", "first-page": "384", "journal-title": "Viruses", "key": "B12", "volume": "15", "year": "" }, { "DOI": "10.1002/rmv.2439", "article-title": "Clinical efficacy of anti-SARS-CoV-2 monoclonal antibodies in preventing hospitalisation and mortality among patients infected with Omicron variants: a systematic review and meta-analysis", "author": "Miljanovic", "doi-asserted-by": "publisher", "first-page": "e2439", "journal-title": "Rev. Med. virology", "key": "B13", "volume": "33", "year": "2023" }, { "DOI": "10.1038/s41581-022-00642-4", "article-title": "Therapeutic advances in COVID-19", "author": "Murakami", "doi-asserted-by": "publisher", "first-page": "38", "journal-title": "Nat. Rev. Nephrol.", "key": "B14", "volume": "19", "year": "2023" }, { "DOI": "10.1093/cid/ciac443", "article-title": "Effectiveness of paxlovid in reducing severe coronavirus disease 2019 and mortality in high-risk patients", "author": "Najjar-Debbiny", "doi-asserted-by": "publisher", "first-page": "e342", "journal-title": "Clin. Infect. Dis.", "key": "B15", "volume": "76", "year": "2023" }, { "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", "author": "Ren", "doi-asserted-by": "publisher", "first-page": "e2001435", "journal-title": "Adv. Sci. (Weinheim, Baden-Wurttemberg, Ger.", "key": "B16", "volume": "7", "year": "2020" }, { "DOI": "10.1101/2023.01.23.23284899", "article-title": "Real-world effectiveness of Azvudine in hospitalized patients with COVID-19: a retrospective cohort study", "author": "Shen", "doi-asserted-by": "publisher", "key": "B17", "year": "2023" }, { "DOI": "10.1016/j.xcrm.2022.100549", "article-title": "Antiviral agents for the treatment of COVID-19: progress and challenges", "author": "Singh", "doi-asserted-by": "publisher", "first-page": "100549", "journal-title": "Cell. Rep. Med.", "key": "B18", "volume": "3", "year": "2022" }, { "DOI": "10.1371/journal.pone.0105617", "article-title": "Azvudine, a novel nucleoside reverse transcriptase inhibitor showed good drug combination features and better inhibition on drug-resistant strains than lamivudine in vitro", "author": "Wang", "doi-asserted-by": "publisher", "first-page": "e105617", "journal-title": "PloS one", "key": "B19", "volume": "9", "year": "2014" }, { "DOI": "10.1080/07853890.2022.2034936", "article-title": "Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19: a meta-analysis", "author": "Wen", "doi-asserted-by": "publisher", "first-page": "516", "journal-title": "Ann. Med.", "key": "B20", "volume": "54", "year": "2022" }, { "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", "author": "Wong", "doi-asserted-by": "publisher", "first-page": "1213", "journal-title": "Lancet (London, Engl.", "key": "B21", "volume": "400", "year": "" }, { "DOI": "10.1016/S1473-3099(22)00507-2", "article-title": "Real-world effectiveness of early molnupiravir or nirmatrelvir-ritonavir in hospitalised patients with COVID-19 without supplemental oxygen requirement on admission during Hong Kong's omicron BA.2 wave: a retrospective cohort study", "author": "Wong", "doi-asserted-by": "publisher", "first-page": "1681", "journal-title": "Lancet. Infect. Dis.", "key": "B22", "volume": "22", "year": "" }, { "DOI": "10.1016/j.xinn.2022.100321", "article-title": "The first Chinese oral anti-COVID-19 drug Azvudine launched", "author": "Yu", "doi-asserted-by": "publisher", "first-page": "100321", "journal-title": "Innov. Camb. (Mass.))", "key": "B23", "volume": "3", "year": "2022" }, { "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", "author": "Zhang", "doi-asserted-by": "publisher", "first-page": "414", "journal-title": "Signal Transduct. Target. Ther.", "key": "B24", "volume": "6", "year": "2021" }, { "DOI": "10.1016/j.jinf.2022.09.027", "article-title": "Efficacy and safety of Paxlovid for COVID-19:a meta-analysis", "author": "Zheng", "doi-asserted-by": "publisher", "first-page": "66", "journal-title": "J. Infect.", "key": "B25", "volume": "86", "year": "2023" }, { "DOI": "10.1101/2022.09.13.22279908", "article-title": "Real-world effectiveness of nirmatrelvir/ritonavir in preventing hospitalization among patients with COVID-19 at high risk for severe disease in the United States: a nationwide population-based cohort study", "author": "Zhou", "doi-asserted-by": "publisher", "key": "B26", "year": "2022" } ], "reference-count": 26, "references-count": 26, "relation": {}, "resource": { "primary": { "URL": "https://www.frontiersin.org/articles/10.3389/fphar.2023.1274294/full" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [ "Pharmacology (medical)", "Pharmacology" ], "subtitle": [], "title": "Head-to-head comparison of azvudine and nirmatrelvir/ritonavir for the hospitalized patients with COVID-19: a real-world retrospective cohort study with propensity score matching", "type": "journal-article", "update-policy": "http://dx.doi.org/10.3389/crossmark-policy", "volume": "14" }

Late treatment
is less effective

Please send us corrections, updates, or comments. c19early involves the extraction of 200,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. IMA and WCH provide treatment protocols.

Submit

Post

@CovidAnalysis

FAQ

Public domain CC0 1.0