Publication date: Sep 15, 2025
Preventing and treating post-acute sequelae of SARS-CoV-2 infection (PASC), commonly known as Long COVID, has become a public health priority. This study tests whether Paxlovid treatment in the acute phase of COVID-19 could help prevent the onset of PASC. We used electronic health records from the National Clinical Cohort Collaborative to define a cohort of 445,738 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. We emulated a series of six sequential trials: one for each day of a 5-day treatment grace period. For each sequential trial, the treatment group was defined as patients prescribed Paxlovid on the trial start day, and the control group was defined as all patients meeting eligibility criteria who remained untreated on the trial start day. We pooled individual record-level data from the sequential trials for analysis. The follow-up period was 180 days. The primary outcome was overall PASC incidence measured using a computable phenotype. Secondary outcomes were incident cognitive, fatigue, and respiratory symptoms in the post-acute period. We controlled for a wide range of demographic and medical history covariates. Compared to the control group, Paxlovid treatment did not have a significant effect on overall PASC incidence or incident respiratory symptoms. It had a small protective effect against cognitive (relative risk [RR] 0. 91; 95% CI [0. 84, 0. 98]; p = 0. 019) and fatigue (RR 0. 94; 95% CI [0. 90, 0. 98]; p = 0. 002) symptoms. Finally, we estimated Paxlovid’s effect on overall PASC incidence across strata of age, COVID-19 vaccination status, and Charlson Comorbidity Index (CCI) prior to COVID-19. We found small protective effects among patients aged 65 years or more (RR 0. 92; 95% CI [0. 88, 0. 97]; p
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| Concepts | Keywords |
|---|---|
| April | Acute |
| Comorbidity | Covid |
| Covid | Day |
| Vaccination | Group |
| Incidence | |
| Long | |
| Onset | |
| Pasc | |
| Paxlovid | |
| Period | |
| Rr | |
| Sequential | |
| Symptoms | |
| Treatment | |
| Trial |
Semantics
| Type | Source | Name |
|---|---|---|
| disease | MESH | COVID-19 |
| disease | MESH | Long COVID |
| disease | IDO | history |
| disease | MESH | Comorbidity |
| disease | IDO | process |
| disease | MESH | sequelae |
| drug | DRUGBANK | Coenzyme M |
| drug | DRUGBANK | Trestolone |