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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  
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Mortality 37% Improvement Relative Risk ICU admission -40% Ventilatory support 20% Paxlovid for COVID-19  Choi et al.  EARLY TREATMENT Is early treatment with paxlovid beneficial for COVID-19? Retrospective 1,843 patients in China (December 2021 - January 2023) Lower mortality with paxlovid (p=0.0038) Choi et al., SSRN, January 2024 Favorspaxlovid Favorscontrol 0 0.5 1 1.5 2+
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.
Confounding by contraindication. Hoertel et al. find that over 50% of patients that died had a contraindication for the use of Paxlovid1. 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"2.
Kamo et al. show significantly increased risk of acute kidney injury. Resistant variants are likely4,5.
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
Choi et al., 8 Jan 2024, retrospective, China, preprint, 7 authors, study period 31 December, 2021 - 29 January, 2023. Contact:
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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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