Is Paxlovid Any Better Than Placebo for Long COVID?

Nirmatrelvir-ritonavir (Paxlovid) wasn’t any more effective at relieving long COVID symptoms than placebo, according to a large double-blind phase II trial.

At 90 days in RECOVER-VITAL, symptoms meaningfully improved among the three clinical phenotype groups studied — cognitive dysfunction, autonomic dysfunction, and exercise intolerance — at similar rates for patients randomized to 15 or 25 days of nirmatrelvir-ritonavir and those assigned to placebo-ritonavir:

• Cognitive: 53-58% vs 55%, respectively (P=0.65)
• Autonomic: 62-70% vs 70% (P=0.30)
• Exercise: 25-34% vs 33% (P=0.88)

To maintain blinding, ritonavir was paired with placebo because of its distinctive taste and lack of action against SARS-CoV-2, according to investigators led by Lindsey Baden, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston.

“Benefit was not seen at any assessment timepoints or in either the 15-day or 25-day course of therapy,” Baden and colleagues wrote in Lancet Infectious Diseases. “These findings are consistent with data from smaller studies assessing the role of 15 days of nirmatrelvir-ritonavir for treatment of long COVID in all patients reporting long COVID without careful clinical phenotype assessment and consideration.”

Also known as post-acute sequelae of SARS-C0V-2 infection, long COVID is a chronic condition affecting more than 5% of U.S. adults, with 1% facing significant activity limitations from it. The condition’s predominant symptoms fall into the phenotypes of cognitive dysfunction, autonomic dysfunction, and exercise intolerance.

Long COVID’s causes remain unclear. Viral persistence could be a possible culprit, with ongoing low-level SARS-CoV-2 replication driving symptoms long after a primary infection. If so, treating long COVID with the antiviral nirmatrelvir-ritonavir — first authorized in 2021 and then formally approved 2 years later for acute COVID — might target viral persistence and improve symptoms.

RECOVER-VITAL’s results may have fallen short of the hypothesis’ promise for several reasons, Baden and colleagues noted. Optimal endpoint timing in long COVID trials isn’t clear, and the trial didn’t restrict enrollment only to patients with evidence of viral persistence — a population likely to benefit the most from the antiviral approach.

“As long COVID probably has more than one pathogenesis driving symptomatology, the question of whether nirmatrelvir-ritonavir leads to symptom improvement and associated viral clearance among those with evidence of viral persistence at baseline remains unanswered,” the researchers wrote.

In addition, substantial percentages of placebo patients among all three phenotype groups showed more improvement based on patient-reported outcomes measures than based on performance measures. The placebo-ritonavir patients’ improvement “cautions against overinterpretation of uncontrolled observations,” the researchers noted, and “highlights the need for placebo control in studies of long COVID.”

Part of the National Institute of Health’s RECOVER initiative for long COVID, the RECOVER-VITAL trial enrolled 959 adult patients at 69 U.S. sites from July 2023 to September 2024. Participants had a previous suspected, probable, or confirmed COVID-19 case and at least two moderate or one severe symptom in one of the three long COVID phenotypes.

The investigators randomized patients to one of three regimens:

• 15 days of 300 mg nirmatrelvir/100 mg ritonavir twice daily, then 10 days of 100 mg ritonavir-placebo
• 25 days of 300 mg nirmatrelvir/100 mg ritonavir twice daily
• 25 days of 100 mg ritonavir-placebo

Among the trial’s participants, two-thirds were women, median age was 49 years, 78% were white, and 11% were Hispanic, Latino, or Spanish. Most patients (80%) had confirmed COVID-19 infections, and most had received a COVID-19 vaccine (range 74-83%).

Treatment-related adverse event rates were similar between groups, at 58% among placebo-ritonavir recipients and 64-66% of the nirmatrelvir-ritonavir recipients.

“Nirmatrelvir-ritonavir has been used extensively to treat acute COVID, typically for 5 days,” noted Baden and co-authors. “Extending the course to 25 days did not reveal any new safety concerns. A slight increase in transient mild nausea and diarrhea was observed compared to ritonavir alone. Overall, treatment was well tolerated with few significant adverse events or discontinuations.”

Study limitations included the lack of homogenous definitions of a long COVID diagnosis, lack of validated symptom assessment tools specific to long COVID, and lack of certainty about whether long COVID caused by viral persistence would require longer therapy courses.