By Stan Deresinski, MD, FACP, FIDSA
Clinical Professor of Medicine, Stanford University
SYNOPSIS: Paxlovid treatment of adults with post-acute sequelae of SARS-CoV-2 infection — also known as long COVID — was ineffective in a randomized controlled trial.
SOURCE: Geng LN, Bonilla H, Hedlin H, et al. Nirmatrelvir-ritonavir and symptoms in adults with postacute sequelae of SARS-CoV-2 infection: The STOP-PASC randomized clinical trial. JAMA Intern Med 2024;Jun 7:e242007. [Online ahead of print].
Geng and colleagues randomized (2:1), in a double-blind fashion, adults with post-acute sequelae of SARS-CoV-2 infection (PASC) with symptoms of longer than three months duration to receive either nirmatrelvir-ritonavir (Paxlovid) or ritonavir alone. Ritonavir does not have in vitro activity against SARS-CoV-2. The assigned therapy was taken twice daily for 15 days. Eligible patients reported at least two of the following being of moderate to severe degree: fatigue, brain fog, body aches, cardiovascular symptoms, shortness of breath, or gastrointestinal symptoms. The primary outcome was pooled severity of these symptoms at 10 weeks using a Likert score. It was estimated that a sample size of 200 would provide sufficient statistical power, but the study was aborted after a preplanned interim analysis assessed futility.
The median age of the 155 participants was 43 years, and 59% were female. There was no significant difference in 10-week outcomes in either the primary endpoint or in secondary endpoints which, among others, included reported dyspnea, change in orthostatic vital signs, and cognitive abilities. Almost all patients reported at least one adverse event over the 15 weeks of study, but these were mild and did not differ between treatment arms. The notable exception was dysgeusia, which occurred in 61.8% and 7.5% of nirmatrelvir-ritonavir and ritonavir alone recipients, respectively (and which likely resulted in loss of blinding).
COMMENTARY
The results of this study could be considered disappointing, but they were not unexpected. The authors themselves pointed out that “no reservoir of live replicating virus has been identified in individuals with PASC.” It is difficult to understand how antiviral therapy would provide benefit in such a circumstance. This is confounded further by the fact that, as the authors also pointed out, there are “no validated endpoints or biomarkers for clinical trials” for this illness.
Even the definition of PASC is a matter of discussion. Thaweethia et al stated that more than 200 symptoms have been reported, but using the RECOVER cohort, they developed a definition requiring the assessment of 37 symptoms.1 These included “postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements.”
Reference
- Thaweethai T, Jolley SE, Karlson EW, et al; RECOVER Consortium. Development of a definition of postacute sequelae of SARS-CoV-2 infection. JAMA 2023;329:1934-1946.
