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
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. 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. 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. 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. Not applicable.