Early Paxlovid linked to modestly lower long COVID risk

Clinical takeaway: Prescribe Paxlovid for eligible patients with acute COVID-19. Reducing long COVID risk may be an additional benefit for high-risk patients.

Paxlovid (nirmatrelvir/ritonavir) is used early in acute COVID-19 to reduce hospitalization and death among high-risk patients. Whether it also helps prevent long COVID remains uncertain, with previous studies reporting mixed results.

Researchers analyzed electronic health records from the NIH RECOVER Initiative for nonhospitalized adults diagnosed with COVID-19 from March 2022 through February 2023. The study, published in PLOS Global Public Health, used an observational design intended to mimic a randomized trial.

The high-risk analysis compared 159,659 patients prescribed Paxlovid within 5 days of documented infection with 272,048 who received no COVID-19 treatment during the acute illness. Patients were considered high risk if they were 50 years or older or had at least one underlying condition that increased their risk of severe COVID-19.

Researchers assessed outcomes 30–180 days after infection. Long COVID was identified from newly recorded diagnoses across 24 condition groups, including fatigue, cognitive problems, and shortness of breath.

After adjustment, the estimated risk of a newly recorded long COVID–related condition during days 30–180 was 30.5% among Paxlovid recipients versus 33.5% among untreated patients.

Among high-risk patients, estimated hospitalization risk during days 30–180 after infection was 6.1% in the Paxlovid group versus 8.4% in the untreated group. Estimated death risk over the same period was 0.28% with Paxlovid versus 0.52% without treatment.

In a separate analysis of patients without documented risk factors for severe COVID-19, Paxlovid was not associated with a clear reduction in long COVID risk.

The observational design could not establish causation, and residual confounding remained possible. Prescription records did not confirm medication adherence, and medical records could miss unreported symptoms.

“Current guidelines recommend the use of Paxlovid for treating acute COVID-19; our findings suggest that its potential to reduce the risk of Long COVID conditions among high-risk patients should also be considered,” the authors wrote.

Source: Zang C, et al. (2026 Oct 28) PLOS Glob Public Health. Real-world effectiveness of Paxlovid in protecting Long COVID for outpatient adult patients: A target trial emulation study from the RECOVER Initiative