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

Wong et al., The Lancet Infectious Diseases, doi:10.1016/S1473-3099(22)00507-2, May 2022 (preprint)

https://c19early.org/wong3pl.html

PSM retrospective 40,776 patients in Hong Kong, showing lower mortality and lower combined mortality, ventilation, ICU, and oxygen therapy with paxlovid treatment.

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 molnupiravir.

risk of death, 66.0% lower, HR 0.34, p < 0.001, treatment 890, control 890, propensity score matching.

risk of mechanical ventilation, 3.0% lower, HR 0.97, p = 0.96, treatment 890, control 890, propensity score matching.

combined death/ventilation/ICU/oxygen, 43.0% lower, HR 0.57, p < 0.001, treatment 890, control 890, propensity score matching.

hospitalization time, 4.3% lower, relative time 0.96, p = 0.32, treatment 890, control 890, propensity score matching.

Ct<30, 27.5% lower, HR 0.72, p = 0.01, treatment 890, control 890, inverted to make HR<1 favor treatment, propensity score matching.

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.

Wong et al., 20 May 2022, retrospective, China, peer-reviewed, 6 authors, study period 26 February, 2022 - 26 April, 2022. Contact: carlosho@hku.hk, bcowling@hku.hk.

This Paper Paxlovid All

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