Paxlovid (nirmatrelvir/ritonavir) effectiveness against hospitalization and death in N3C: A target trial emulation study
Authors: Hansen Kristen , Makkar Steve R. , Sahner David , Fessel Josh , Hotaling Nathan , Sidky Hythem 
Published: June 2023

AbstractImportanceCOVID-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 to prevent hospitalization and death. Paxlovid (nirmatrelvir/ritonavir) is a promising and potentially effective antiviral that has received emergency use authorization by the U.S. FDA.ObjectiveDetermine real world effectiveness of Paxlovid nationwide and investigate disparities between treated and untreated eligible patients.Design/Setting/ParticipantsPopulation-based cohort study emulating a target trial, using inverse probability weighted models to balance treated and untreated groups on baseline confounders. Participants were patients with a SARS-CoV-2 positive test or diagnosis (index) date between December 2021 and February 2023 selected from the National COVID Cohort Collaborative (N3C) database who were eligible for Paxlovid treatment. Namely, adults with at least one risk factor for severe COVID-19 illness, no contraindicated medical conditions, not using one or more strictly contraindicated medications, and not hospitalized within three days of index. From this cohort we identified patients who were treated with Paxlovid within 5 days of positive test or diagnosis (n = 98,060) and patients who either did not receive Paxlovid or were treated outside the 5-day window (n = 913,079 never treated; n = 1,771 treated after 5 days).ExposuresTreatment with Paxlovid within 5 days of positive COVID-19 test or diagnosis.Main Outcomes and MeasuresHospitalization and death in the 28 days following COVID-19 index date.ResultsA total of 1,012,910 COVID-19 positive patients at risk for severe COVID-19 were included, 9.7% of whom were treated with Paxlovid. Uptake varied widely by geographic region and timing, with top adoption areas near 50% and bottom near 0%. Adoption increased rapidly after EUA, reaching steady state by 6/2022. Participants who were treated with Paxlovid had a 26% (RR, 0.742; 95% CI, 0.689-0.812) reduction in hospitalization risk and 73% (RR, 0.269, 95% CI, 0.179-0.370) reduction in mortality risk in the 28 days following COVID-19 index date.Conclusions/RelevancePaxlovid is effective in preventing hospitalization and death in at-risk COVID-19 patients. These results were robust to a large number of sensitivity considerations.DisclosureThe authors report no disclosuresKey pointsQuestion:Is treatment with Paxlovid (nirmatrelvir/ritonavir) associated with a reduction in 28-day hospitalization and mortality in patients at risk for severe COVID-19?Findings:In this multi-institute retrospective cohort study of 1,012,910 patients, Paxlovid treatment within 5 days after COVID-19 diagnosis reduced 28-day hospitalization and mortality by 26% and 73% respectively, compared to no treatment with Paxlovid within 5 days. Paxlovid uptake was low overall (9.7%) and highly variable.Meaning:In Paxlovid-eligible patients, treatment was associated with decreased risk of hospitalization and death. Results align with prior randomized trials and observational studies, thus supporting the real-world effectiveness of Paxlovid.