Comparative Efficacy of Combination Treatment with Nirmatrelvir-Ritonavir and Remdesivir Versus Remdesivir Monotherapy in Hospitalised COVID-19 Patients: A Target Trial Emulation Study

Choi et al., SSRN, doi:10.2139/ssrn.4683854, Jan 2024

https://c19early.org/choi5.html

Retrospective 1,843 hospitalized COVID-19 patients in Hong Kong showing lower mortality with paxlovid. All patients received remdesivir. No significant difference was found for ICU admission or ventilatory support.

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.

risk of death, 37.0% lower, HR 0.63, p = 0.004, treatment 251, control 1,592, day 90.

risk of ICU admission, 40.0% higher, HR 1.40, p = 0.78, treatment 251, control 1,592, day 90.

ventilatory support, 20.0% lower, HR 0.80, p = 0.66, treatment 251, control 1,592, day 90.

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.

Choi et al., 8 Jan 2024, retrospective, China, preprint, 7 authors, study period 31 December, 2021 - 29 January, 2023. Contact: ivanhung@hku.hk.

This Paper Paxlovid All

Comparative Efficacy of Combination Treatment with Nirmatrelvir-Ritonavir and Remdesivir versus Remdesivir Monotherapy in Hospitalised COVID-19 Patients: A Target Trial Emulation Study

Ming Hong Choi, Eric Yuk Fai, Ian Chi, Kei Wong, Esther Wai, Yin Chan, Ming Wing, Chu, Anthony Raymond Tam, Ivan Fan Ngai, Professor Ivan Fn Hung

Background Remdesivir (Veklury®) and nirmatrelvir-ritonavir (Paxlovid®) are the two commonly used antiviral agents for hospitalised patients suffering from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in Hong Kong. Although current therapeutic studies demonstrate the clinical effectiveness of remdesivir in coronavirus disease 2019 (COVID-19) patients by shortening the time to clinical recovery and hospital stay, there is a significant proportion of high-risk individuals in Hong Kong who fail to achieve optimal clinical response after a course of standard antiviral monotherapy regimen. Preclinical data has shown the in vitro synergy between remdesivir and nirmatrelvir-ritonavir, which can potentially hasten the virologic and clinical recovery in hospitalised patients with COVID-19. Methods We conducted a target trial emulation study to critically analyse the current evidence of a combination of remdesivir and nirmatrelvir-ritonavir versus remdesivir alone in the management of COVID-19 in Hong Kong and dissect the aspects of their safety and efficacy. This study utilised the territory-wide electronic health records databases. Patients aged ≥ 18 years with an initial diagnosis of COVID-19 who received either combination treatment with nirmatrelvir-ritonavir and remdesivir or remdesivir between 16 March 2022 and 31 December

Supplementary Table 1 . Target trial specification and emulation using observational data Protocol component Specification Emulation using observational data Eligible criteria Age ≥ 18, hospitalized with COVID-19 during the inclusion period 1 Exclude patients who:  had a history of COVID-19 infection before baseline;  had contraindications to nirmatrelvir-ritonavir or remdesivir 2 The index date was the prescription date of nirmatrelvir-ritonavir or remdesivir. Same as for specification. The date of COVID-19 infection was determined based on the date of the first positive polymerase chain reaction or rapid antigen test result during the study inclusion period. Individuals who initiated nirmatrelvir-ritonavir or remdesivir more than 5 days after the date of COVID-19 infection were excluded from the analysis. Treatment strategy Combination treatment with nirmatrelvir-ritonavir and remdesivir versus Remdesivir monotherapy Patients were expected to complete one full course of combination treatment with nirmatrelvir-ritonavir and remdesivir or remdesivir monotherapy according to the regimen approved by the U.S. Food and Drug Administration, unless clinical conditions prevented them from completing the treatment (e.g. oral intake no longer possible, severe adverse effects). Patients are allowed to receive additional concurrent treatments, such as steroids, based on clinical judgment in both treatment groups. Same as for specification. It was assumed that upon the..

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