Real-world effectiveness of early nirmatrelvir/ritonavir initiation after COVID-19 diagnosis in outpatient setting against severe illness, hospitalization, death, and long COVID in N3C

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Abstract Background COVID-19 has placed a monumental burden on the health care system globally. Although no longer a public health emergency, there is still a pressing need for effective treatments that prevent adverse outcomes associated with this disease. Nirmatrelvir/ritonavir (NMV-R) is a promising and potentially effective antiviral, which until recently was under emergency use authorization. Our objective was to evaluate the real-world effectiveness of NMV-R in preventing severe illness, hospitalization, death and long-COVID in a large nationwide cohort of outpatients with COVID-19. Methods Population-based retrospective cohort study of patients with a SARS-CoV-2 positive test or diagnosis (index) date between December 2021 and February 2023 within the National COVID Cohort Collaborative (N3C), with at least one risk factor for severe COVID-19, no evidence of contraindicated medical conditions or medication use, and no hospital or emergency department visit or death within 24 hours of eligibility. We emulated a sequence of target trials beginning on each of the first five days of diagnosis with COVID-19. We identified 921,034 eligible person-trials (each representing a patient’s eligibility at a given diagnosis day across sequential emulated trials), of which 77,449 were initiators and 846,585 were non-initiators of NMV-R treatment. NMV-R Initiators were matched to non-initiators in each trial. The marginal hazard ratio between initiators and non-initiators was estimated for four acute outcomes: severe illness, hospitalization or death, hospitalization, and death; and the post-COVID condition or long COVID. Results Of 921,034 eligible “person-trials”, 74,449 were initiators and 846,585 were non-initiators of NMV-R treatment. Pooled across trials, the hazard for severe illness (HR: 0.76, 95% CI: 0.71 to 0.81), hospitalization or death (HR: 0.50, 95% CI: 0.44 to 0.57), hospitalization (sdHR: 0.52, 95% CI: 0.46 to 0.60), death (HR: 0.33, 95% CI: 0.21 to 0.51), and long-COVID (sdHR: 0.85, 95% CI: 0.77 to 0.95) were significantly lower among NMV-R initiators compared to non-initiators. Results further indicated larger associations between NMV-R and reduced risk of both acute and post-acute outcomes with early versus delayed NMV-R treatment initiation, and among unvaccinated versus vaccinated patient subgroups. Conclusions NMV-R is overall effective at preventing the risk of severe acute outcomes including hospitalization and death, as well as long COVID. Results were robust across multiple sensitivity considerations. Clinical trial number Not applicable.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.