Molnupiravir and nirmatrelvir-ritonavir reduce mortality risk during post-acute COVID-19 phase
et al., Journal of Infection, doi:10.1016/j.jinf.2023.02.029, Feb 2023
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 paxlovid1-8. 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.
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.
2.
Moghadasi et al., Rapid resistance profiling of SARS-CoV-2 protease inhibitors, npj Antimicrobials and Resistance, doi:10.1038/s44259-023-00009-0.
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.
4.
Lopez et al., SARS-CoV-2 Resistance to Small Molecule Inhibitors, Current Clinical Microbiology Reports, doi:10.1007/s40588-024-00229-6.
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.
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.
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.
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.
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.
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.
11.
FDA, Fact sheet for healthcare providers: emergency use authorization for paxlovid, www.fda.gov/media/155050/download.
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.
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.
Molnupiravir and nirmatrelvir-ritonavir reduce mortality risk during post-acute COVID-19 phase
Journal of Infection, doi:10.1016/j.jinf.2023.02.029
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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
Agarwal, Rochwerg, Lamontagne, Siemieniuk, Agoritsas et al., A living WHO guideline on drugs for covid-19, BMJ
Evans, Qi, Adebayo, Underwood, Coulson et al., among higher-risk patients with COVID-19 in Wales: a retrospective cohort study
Ledford, Long-COVID treatments: why the world is still waiting, Nature
Wan, Chui, Lai, Chan, Li et al., Bell's palsy following vaccination with mRNA (BNT162b2) and inactivated (CoronaVac) SARS-CoV-2 vaccines: a case series and nested casecontrol study, The Lancet Infectious Diseases
Wan, Mok, Yan, Wang, Zhang et al., Vaccine effectiveness of BNT162b2 and CoronaVac against SARS-CoV-2 Omicron BA. 2 infection, hospitalisation, severe complications, cardiovascular disease and mortality in patients with diabetes mellitus: A case control study, Journal of Infection
Wan, Mok, Yan, Wang, Zhang et al., Vaccine effectiveness of BNT162b2 and CoronaVac against SARS-CoV-2 Omicron BA.2 infection, hospitalisation, severe complications, cardiovascular disease and mortality in patients with diabetes mellitus: A case control study, Journal of Infection
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Yan, Wan, Ye, Mok, Lai et al., Effectiveness of BNT162b2 and CoronaVac vaccinations against mortality and severe complications after SARS-CoV-2 Omicron BA. 2 infection: a case-control study, Emerging Microbes & Infections
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
is less effective
