Extended courses of the antiviral drug Paxlovid do not reduce long COVID symptoms compared to placebo, according to clinical trial results published in the journal Lancet Infectious Diseases. Despite proving safe for extended regimens in a 959-participant study funded by the National Institutes of Health, the treatment failed to show clinical benefit.
Researchers investigating treatments for long COVID faced a clinical wall when a prominent trial demonstrated that extending the duration of a familiar antiviral medication offered no relief to patients suffering from chronic post-infection symptoms. The trial is part of the NIH’s Researching COVID to Enhance Recovery Initiative, a patient-centered, integrated, adaptive research network with the goal of understanding, diagnosing, preventing, and treating long COVID.
Trial Design and Patient Cohorts Across the United States
The clinical trial recruited 959 adult patients who had long COVID from 69 sites across the United States and collected data between July 2023 and early 2025. Participants were initially evaluated after taking surveys about their long COVID symptoms and 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.
Following this categorization, participants were 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, or 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. Through lab tests, in-clinic visits, and periodic symptom self-ratings over a six-month period, study researchers relied on participants to measure the effectiveness of the treatment.
Testing the Viral-Persistence Hypothesis
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. Long COVID is a chronic health condition that can occur after a SARS-CoV-2 infection and lasts for at least three months.
While standard five-day courses of Paxlovid are approved by the Food and Drug Administration for the treatment of adults who are newly infected with SARS-CoV-2, have mild or moderate COVID symptoms, and are at high risk of complications because of age or various predisposing conditions, the extended dosing failed to clear the chronic symptoms. A five-day Paxlovid regimen has been shown to reduce recipients’ likelihood of hospitalization and death by more than 85%. An estimated 10% to 20% of SARS-CoV-2-infected people—tens of millions in the United States alone—develop long COVID. That estimate is fuzzy, because the definition of long COVID is ambiguous, with more than 200 separate symptoms having been ascribed to the syndrome.
Safety Confirmed Despite Clinical Null Results
While the prolonged antiviral dosing missed its therapeutic targets, the study showed that the longer duration did not cause serious side effects for patients.
Paxlovid contains two active substances, nirmatrelvir and ritonavir, in two different tablets. Paxlovid reduces the ability of SARS-CoV-2 to multiply in the body, where nirmatrelvir blocks the activity of an enzyme needed by the virus to multiply, and a low dose of ritonavir slows the breakdown of nirmatrelvir, enabling it to remain longer in the body at levels that affect the multiplication of the virus.
