Effect of Paxlovid Treatment During Acute COVID-19 on Long COVID Onset: An EHR-Based Target Trial Emulation from the N3C and RECOVER Consortia

Abstract

ABSTRACTBackgroundPreventing and treating post-acute sequelae of SARS-CoV-2 infection (PASC), commonly known as Long COVID, has become a public health priority. Researchers have begun to explore whether Paxlovid treatment in the acute phase of COVID-19 could help prevent the onset of PASC.Methods and FindingsWe used electronic health records from the National Covid Cohort Collaborative (N3C) to define a cohort of 426,352 patients who had COVID-19 since April 1, 2022, and were eligible for Paxlovid treatment due to risk for progression to severe COVID-19. We used the target trial emulation (TTE) framework to estimate the effect of Paxlovid treatment on PASC incidence. We estimated overall PASC incidence using a computable phenotype. We also measured the onset of novel cognitive, fatigue, and respiratory symptoms in the post-acute period. Paxlovid treatment did not have a significant effect on overall PASC incidence (relative risk [RR] = 0.98, 95% confidence interval [CI] 0.95-1.01). However, it had a protective effect on cognitive (RR = 0.90, 95% CI 0.84-0.96) and fatigue (RR = 0.95, 95% CI 0.91-0.98) symptom clusters.ConclusionsIn this cohort, Paxlovid had a weaker preventative effect on PASC than in prior observational studies. Differing effects by symptom cluster suggest that the etiology of cognitive and fatigue symptoms may be more closely related to viral load than that of respiratory symptoms. Ongoing clinical trials will help clarify Paxlovid’s overall effect on PASC, and future research should explore potential heterogeneous treatment effects across PASC subphenotypes.