Paxlovid: meta-analysis of COVID-19 studies
Meta-analysis of paxlovid COVID-19 studies. Pfizer has denied access to paxlovid for independent RCTs1. Pfizer RCTs report very good results, while non-Pfizer RCTs show relatively poor results2,3. Variants may be resistant to paxlovid4-11. Hoertel et al. find that >50% of patients that died had a contraindication for paxlovid. 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 paxlovid13. Use may promote the emergence of variants that weaken host immunity and potentially contribute to long COVID14. Population studies often do not account for the different expected outcomes for the class of patients that seek out and receive early treatment. Studies show significantly increased risk of acute kidney injury15 and liver injury16.
All studies
Exclusions
Mortality
Ventilation
ICU
Hospitalization
Serious outcomes
Recovery
Cases
Viral clearance
RCTs
RCT mortality
RCT COI
Peer-reviewed
All outcomes
References
Ledford et al., African clinical trial denied access to key COVID drug Paxlovid, Nature, doi:10.1038/d41586-022-00919-5.
Liu et al., Efficacy and safety of Paxlovid in severe adult patients with SARS-Cov-2 infection: a multicenter randomized controlled study, The Lancent Regional Health, doi:10.1016/j.lanwpc.2023.100694.
Yu et al., Efficacy and safety of Huashi Baidu granule plus Nirmatrelvir-Ritonavir combination therapy in patients with high-risk factors infected with Omicron (B.1.1.529): A multi-arm single-center, open-label, randomized controlled trial, Phytomedicine, doi:10.1016/j.phymed.2023.155025.
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.
Moghadasi et al., Rapid resistance profiling of SARS-CoV-2 protease inhibitors, npj Antimicrobials and Resistance, doi:10.1038/s44259-023-00009-0.
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.
Lopez et al., SARS-CoV-2 Resistance to Small Molecule Inhibitors, Current Clinical Microbiology Reports, doi:10.1007/s40588-024-00229-6.
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.
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.
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.
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.
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.
FDA, Fact sheet for healthcare providers: emergency use authorization for paxlovid, www.fda.gov/media/155050/download.
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.