Taking the antiviral drug Paxlovid (nirmatrelvir–ritonavir) for up to 25 days did not improve cognitive issues, autonomic symptoms like dizziness and shortness of breath, or exercise intolerance in adults with long COVID, according to a US randomized controlled trial published yesterday in The Lancet Infectious Diseases.
A leading theory about how the condition called long COVID—typically COVID-related symptoms for three months or more—develops is viral persistence, or the continued presence of SARS-CoV-2 in the body after initial infection. For the phase 2 RECOVER-VITAL trial, researchers led by a team at Mass General Brigham (MGB) tested whether an extended course of Paxlovid could target lingering SARS-CoV-2 in the body.
Previous research had showed no benefit of taking Paxlovid for up to 15 days, but researchers wondered about longer regimens.
“This study contributes important findings to the science of studying long COVID and viral persistence,” says lead author Lindsey Baden, MD, an infectious diseases specialist at MGB, in an MGB news release. “Unfortunately, treating viral persistence with this antiviral medication did not show evidence of clinical benefit.”
Longer regimen no better than placebo
The double-blind study included 959 adults with long-COVID symptoms from 69 medical centers in 27 states. Participants were classified into one of three groups based on symptoms—cognitive dysfunction, autonomic symptoms, and exercise intolerance—with roughly 330 in each group. Long COVID was defined as symptoms lasting for at least 12 weeks.
Participants were randomly assigned to receive Paxlovid for 25 days, Paxlovid for 15 days followed by 10 days of a placebo, ritonavir plus a placebo for 25 days. (Because low-dose ritonavir, which is used to treat HIV, has a recognizable taste, it was given to placebo participants to mask their inclusion in the placebo group.)
Participants were assessed with lab tests, in-clinic visits, and questionnaires over six months. No statistically significant benefits were observed in any of the symptom groups for those who took longer courses of Paxlovid compared to placebo.
Many participants improved—with or without Paxlovid
Across all three symptom groups, a significant number of participants improved, especially when measured by self-assessment questionnaires.
This prompted caution from the authors: While the Hawthorne effect, or the psychological phenomenon in which people change or improve because they know they are being observed, is common in clinical trials, “the proportion improving in RECOVER-VITAL exceeded assumptions used for initial sample size calculations, perhaps limiting the possibility of detecting effect with the final sample size.”
The researchers also note that the high rate of reported improvement wasn’t likely caused by the low-dose ritonavir administered in each group, because previous research has suggested “no meaningful biological activity of ritonavir against SARS-CoV-2, especially when used at a low dose.”
Unfortunately, treating viral persistence with this antiviral medication did not show evidence of clinical benefit.
Nevertheless, they continue, “the high proportion improving in the placebo–ritonavir group cautions against overinterpretation of uncontrolled observations and highlights the need for placebo control in studies of long COVID to better define therapeutic improvement.”
There was a slight increase in mild nausea and diarrhea among participants who received the 25-day course of Paxlovid, but overall the treatment was well tolerated. Serious adverse events were uncommon, and no new safety concerns were observed.
To continue to test the hypothesis that long-COVID symptoms are related to viral persistence, the researchers say future research should focus on biomarker screening to look for the presence of the virus at baseline, longer courses of Paxlovid, and treatment with combination antivirals or other therapies.
