Paxlovid cuts Long COVID risk in high-risk adults, large study finds

Adults at high risk of severe COVID-19 who took Paxlovid within five days of infection had a lower risk of developing Long COVID, according to a large target trial emulation study using electronic health records from the PCORnet RECOVER repository, published in PLOS Global Public Health.

Researchers led by Chengxi Zang of the RECOVER Consortium analyzed data from 497,499 patients who tested positive for SARS-CoV-2 between March 1, 2022, and February 28, 2023. Among patients with at least one documented risk factor for severe COVID-19, 159,659 were treated with at least one dose of Paxlovid (nirmatrelvir/ritonavir) within five days of infection, while 272,048 received neither Paxlovid nor other COVID-19 treatments during the acute infection period.

Compared with the untreated group, Paxlovid treatment was associated with a reduced risk of Long COVID, with a hazard ratio of 0.88 (95% CI, 0.87 to 0.89), corresponding to an absolute risk reduction of 2.99 events per 100 persons (95% CI, 2.65 to 3.32). The treated high-risk patients also had a lower risk of all-cause hospitalization or death in the post-acute period, defined as 30 to 180 days after infection.

The picture was different for patients without documented risk factors for severe COVID-19. In this low-risk group, the association between Paxlovid and Long COVID was inconclusive: the hazard ratio was 1.03 (95% CI, 0.95 to 1.11), with an estimated risk change of 0.80 events per 100 persons (95% CI, -0.84 to 2.45), an interval that includes both possible reductions and increases in risk. The authors note that evidence on whether acute Paxlovid use protects against Post-Acute Sequelae of SARS-CoV-2 infection (PASC), or Long COVID, had previously been mixed in high-risk patients and lacking in low-risk patients.

As an observational target trial emulation rather than a randomized trial, the study estimates associations from real-world electronic health record data, and the findings apply to outpatient adults treated within five days of infection during the study period. Within that scope, the results indicate that high-risk, nonhospitalized adults with COVID-19 who received Paxlovid early had a lower risk of Long COVID and of post-acute hospitalization or death, while no such risk reduction was observed in low-risk patients.

Subject of Research: Real-world effectiveness of Paxlovid in preventing Long COVID among outpatient adults

Article Title: Real-world effectiveness of Paxlovid in protecting Long COVID for outpatient adult patients: A target trial emulation study from the RECOVER Initiative

Article References: Zang, C., Li, H., Khullar, D., Zhang, Y., Strobel, S., Chen, Y., Sala, M. A., Patel, P. B., Comellas, A. P., Wylam, A., Weiner, M., Forrest, C. B., Carton, T., Wang, F., Kaushal, R., & on behalf of the RECOVER Consortium (2026). Real-world effectiveness of Paxlovid in protecting Long COVID for outpatient adult patients: A target trial emulation study from the RECOVER Initiative. PLOS Global Public Health, 6(10), e0005771. https://doi.org/10.1371/journal.pgph.0005771

Image Credits: AI Generated

DOI: 10.1371/journal.pgph.0005771

Keywords: Paxlovid, Long COVID, PASC, SARS-CoV-2, RECOVER Initiative, target trial emulation, electronic health records, nirmatrelvir, hospitalization, PCORnet, COVID-19, Real-world