Molnupiravir and nirmatrelvir-ritonavir reduce mortality risk during post-acute COVID-19 phase

Wan et al., Journal of Infection, doi:10.1016/j.jinf.2023.02.029, Feb 2023

https://c19early.org/wan.html

Retrospective 30,040 hospitalized patients in Hong Kong, showing lower mortality with paxlovid treatment. Patients with contraindications to paxlovid were not excluded.

Resistance. Variants may be resistant to paxlovid1-6. Use may promote the emergence of variants that weaken host immunity and potentially contribute to long COVID7.

Confounding by contraindication. Hoertel et al. find that over 50% of patients that died had a contraindication for the use of Paxlovid8. 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 paxlovid"9.

Kidney and liver injury. Studies show significantly increased risk of acute kidney injury10 and liver injury11.

Standard of Care (SOC) for COVID-19 in the study country, China, is poor with low average efficacy for approved treatments12.

Important missing comments or errors? Let us know.

Study covers molnupiravir and paxlovid.

risk of death, 28.0% lower, HR 0.72, p < 0.001, treatment 541 of 6,604 (8.2%), control 2,541 of 17,283 (14.7%), adjusted per study, multivariable, Cox proportional hazards.

risk of hospitalization, 24.0% lower, HR 0.76, p < 0.001, treatment 1,772 of 6,604 (26.8%), control 2,541 of 17,283 (14.7%), adjusted per study, multivariable, Cox proportional hazards.

risk of progression, 18.0% lower, HR 0.82, p < 0.001, treatment 1,816 of 6,604 (27.5%), control 2,541 of 17,283 (14.7%), adjusted per study, A&E admission, multivariable, Cox proportional hazards.

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. 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.

8. 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.

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

10. 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.

11. 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.

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

Wan et al., 22 Feb 2023, retrospective, China, peer-reviewed, 13 authors, study period 26 February, 2022 - 30 September, 2022. Contact: ewchan@hku.hk, wongick@hku.hk.

This Paper Paxlovid All

Molnupiravir and nirmatrelvir-ritonavir reduce mortality risk during post-acute COVID-19 phase

Eric Yuk Fai Wan, MPH Boyuan Wang, BSc Sukriti Mathur, Cheyenne I Ying Chan, Vincent Ka Chun Yan, Francisco Tsz Tsun Lai, Celine Sze Ling Chui, PhD Xue Li, Carlos King Ho Wong, Chak Philip Hei Li, Chak Sing Lau, Prof Ian Chi Kei Wong, Dr Esther Wai Yin Chan

Journal of Infection, doi:10.1016/j.jinf.2023.02.029

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Ethics approval This study was approved by the Central Institutional Review Board of the Hospital Authority of Hong Kong (CIRB-2021-005-4) and the DH Ethics Committee (LM171/2021). Data sharing Data will not be made available to others because the data custodians have not given permission. Sources of funding

References

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Ledford, Long-COVID treatments: why the world is still waiting, Nature

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Yip, Lui, Lai, Wong, Tse et al., Impact of the Use of Oral Antiviral Agents on the Risk of Hospitalization in Community Coronavirus Disease, Clinical Infectious Diseases

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Late treatment
is less effective

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