Results from a clinical trial funded by the National Institutes of Health (NIH) and published today in the journal Lancet Infectious Diseases show that the antiviral drug, PAXLOVID, commonly prescribed to treat acute COVID-19, does not have an impact on Long COVID symptoms when compared to placebo.
Long COVID is a chronic health condition that can occur after a SARS-CoV-2 infection and lasts for at least three months. This trial is part of the NIH's Researching COVID to Enhance Recovery (RECOVER) Initiative , a patient-centered, integrated, adaptive research network with the goal of understanding, diagnosing, preventing and treating Long COVID.
The clinical trial, known as RECOVER-VITAL Viral Persistence (PAXLOVID), studied whether PAXLOVID, which combines two drugs (nirmatrelvir and ritonavir) and is used to treat mild-to-moderate COVID-19, can be used to treat Long COVID. When a person is given PAXLOVID for an active case of COVID-19, they usually take the drug for five days, and it works to stop the virus that causes COVID-19 from multiplying. Researchers sought to determine if the drug could reduce Long COVID symptoms by treating virus that may still be lingering in the body.
The study recruited 959 adult patients who had Long COVID from 69 sites across the United States and collected data between July 2023 and early 2025. After taking surveys about their Long COVID symptoms, participants were assigned to one of three symptom groups: cognitive dysfunction (trouble thinking clearly or "brain fog"), autonomic dysfunction (dizziness, fast heart rate, shortness of breath, or blood pressure changes), or exercise intolerance/post-exertional malaise (exhaustion or low energy that interferes with daily activities). There were about 320 participants in each of these symptom groups.
After being assigned to a symptom group based on their reported symptoms, participants were then assigned by chance to one of three study treatment groups:
- 25 days of PAXLOVID (nirmatrelvir and ritonavir)
- 15 days of PAXLOVID plus 10 days of ritonavir and a placebo for nirmatrelvir
- 25 days of ritonavir and a placebo for nirmatrelvir
Because study treatment groups were assigned by chance, participants within the same symptom group may have been assigned to different study treatment groups.
In addition to lab tests and in-clinic visits, study researchers relied on participants to periodically rate their symptoms to measure the effectiveness of the treatment over a six-month period. Although PAXLOVID did not appear to improve Long COVID symptoms compared to placebo, the study showed that the longer duration did not cause serious side effects for participants.
"This study contributes important findings to the science of studying Long COVID and viral persistence," said Lindsey Baden, MD, of Mass General Brigham and co-Principal Investigator for the trial. "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."
The RECOVER-VITAL team included a group of Patient, Caregiver, and Community Representatives who helped design the study protocol and provided feedback throughout the trial. The study teams at each of the 69 sites also helped to advise on the project to enhance participants' experiences. The full site list is available on ClinicalTrials.gov .
RECOVER Clinical Trials includes seven additional studies exploring possible treatments for symptoms that Long COVID patients reported to affect their quality of life. For more details on all the trials, visit trials.recoverCOVID.org .
Authorship: In addition to Baden, Mass General Brigham authors include David R. Walt, Bruce D. Levy, and Susan Redline. Additional authors include colleagues from institutions across the United States, for the RECOVER-VITAL Clinical Trial Group.
Disclosures: Baden reports funding to his institution from the National Institutes of Health, Harvard Medical School, Wellcome Trust and the Gates Foundation; participation on advisory boards for the National Institutes of Health and the U.S. Food and Drug Administration; and involvement in HIV and SARS-CoV-2 vaccine clinical trials conducted in collaboration with academic, government and industry partners. Additional author disclosures can be found in the paper.
Funding: This research was funded by the National Institutes of Health through the RECOVER Initiative (agreement OT2HL156812). Pfizer donated study medication and contributed to study design discussions but did not participate in study conduct, data interpretation or initial drafting of the manuscript.
Paper cited: Baden LR 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 Infectious Diseases DOI: 10.1016/S1473-3099(26)00406-8
