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

Background: Preventing 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 findings: We used electronic health records from the National Clinical Cohort Collaborative (N3C) to define a cohort of 410,026 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 framework to estimate the effect of Paxlovid treatment on PASC incidence. The treatment group was defined as outpatients prescribed Paxlovid within five days of COVID-19 index, and the control group was defined as all patients meeting eligibility criteria not in the treatment group. The follow-up period was 180 days. We estimated overall PASC incidence using a computable phenotype. We also measured incident cognitive, fatigue, and respiratory symptoms in the post-acute period. Paxlovid treatment had a small effect on overall PASC incidence (relative risk [RR] 0.94; 95% CI [0.90, 0.99]; p=0.011). It had a slightly stronger protective effect against cognitive (RR 0.86; 95% CI [0.77, 0.95]; p<0.001) and fatigue (RR 0.92; 95% CI [0.86, 0.97]; p=0.002) symptoms.

Conclusions: In this study, Paxlovid had a weaker preventative effect on PASC than in prior observational studies, suggesting that Paxlovid is unlikely to become a definitive solution for preventing PASC. 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. Future research should explore potential heterogeneous treatment effects across PASC subphenotypes.

Figure 1:

CONSORT Diagram: Study Cohort and Flow of Emulated Trial (PCR: polymerase chain reaction; PASC: post-acute sequelae of COVID-19)

Figure 2:

Covariate balance before and after stabilized and trimmed inverse probability of treatment weighting (IPTW)

Figure 3:

Estimated Treatment Effects (Risk Ratios) of Paxlovid on PASC, across all analyses (PASC: post-acute sequelae of COVID-19; VA: United States Department of Veterans Affairs; CP: computable phenotype)

Figure 4:

Cumulative incidence of PASC in Paxlovid treated vs. Non-Paxlovid-Treated patients by outcome measure; between 29–180 days. Any GBD Symptom = any symptom from the cognitive, fatigue, and respiratory PASC symptom clusters proposed in the Global Burden of Disease study.