Paxlovid Shows no Benefit for Long COVID

Extended-duration nirmatrelvir and ritonavir (Paxlovid; Pfizer) did not reduce Long COVID symptoms compared with placebo in the RECOVER-VITAL Viral Persistence (Paxlovid) trial. Results were published in The Lancet Infectious Diseases and funded by the National Institutes of Health as part of the Researching COVID to Enhance Recovery Initiative.¹

Investigators pointed to methodological lessons from the trial beyond the negative primary result.

"This study contributes important findings to the science of studying Long COVID and viral persistence," Lindsey Baden, MD, of Mass General Brigham and co-principal investigator for the trial, said in a statement. "We learned how to better characterize and measure the symptoms our patients with Long COVID are suffering from. Unfortunately treating viral persistence with this antiviral medication did not show evidence of clinical benefit."²

The symptom-group stratification approach used in RECOVER-VITAL offers a model for characterizing and measuring heterogeneous Long COVID presentations in future studies.

What the Study Data Showed

Investigators tested 3 treatment durations across 959 adults with Long COVID enrolled at 69 sites nationwide. Investigators randomized participants across three arms: 25 days of Paxlovid, 15 days of Paxlovid followed by 10 days of ritonavir plus placebo nirmatrelvir, or 25 days of ritonavir plus placebo nirmatrelvir. Before randomization, each participant was assigned to one of three symptom groups based on self-reported Long COVID complaints: cognitive dysfunction, autonomic dysfunction, or exercise intolerance and post-exertional malaise. Roughly 320 participants fell into each symptom group, though treatment-arm assignment operated independently of symptom classification, meaning participants within a single symptom group could land in any of the three dosing arms.

Over six months, participants completed periodic surveys rating symptom severity alongside in-clinic visits and laboratory testing. None of the three symptom groups showed meaningful improvement with extended Paxlovid dosing relative to placebo. The uniform lack of benefit across cognitive, autonomic, and exercise-related symptom clusters suggests viral persistence, if present, may not drive Long COVID symptoms in the way investigators hypothesized. Notably, the longer 25-day course did not raise new safety concerns compared with the standard regimen.

About the RECOVER trial

The trial is one of eight RECOVER Clinical Trials evaluating interventions for symptoms affecting Long COVID patients' quality of life. Enrollment ran from July 2023 through early 2025, and investigators grouped participants by predominant symptom domain before randomization. This design allowed comparisons across cognitive, autonomic, and exercise-related symptom clusters within a single trial framework.

The RECOVER Initiative is an NIH-funded, patient-centered research network established to understand, diagnose, prevent, and treat Long COVID, a chronic condition persisting for at least three months after SARS-CoV-2 infection. Along with Mass General Brigham’s Baden serving as co-principal investigator for RECOVER-VITAL, a group of patient, caregiver, and community representatives helped design the trial protocol and advised on participant experience throughout enrollment.

Site-level details for all 69 participating locations are available through ClinicalTrials.gov, and additional information on the broader RECOVER trial portfolio is available at trials.recoverCOVID.org.

References

1. Baden LR, Shah NS, Liu STH, et al. Nirmatrelvir-ritonavir targeting viral persistence in post-COVID-19 condition (long COVID) in the USA (RECOVER-VITAL): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Infect Dis. Published online August 31, 2026. doi:10.1016/S1473-3099(26)00406-8

2.RECOVER-VITAL clinical trial finds no benefit of extended duration of PAXLOVID for Long COVID. Brigham and Women's Hospital. News release. August 31, 2026. September 2, 2026.
https://www.eurekalert.org/news-releases/1142039?