Extended Paxlovid Therapy Fails to Improve Long-COVID Symptoms: Study
A US randomized controlled trial published in The Lancet Infectious Diseases found that a 25-day course of Paxlovid (nirmatrelvir–ritonavir) provided no significant benefit over placebo for adults with long COVID. Extended antiviral treatment did not improve cognitive difficulties, autonomic symptoms such as dizziness and shortness of breath, or exercise intolerance, suggesting that prolonged Paxlovid therapy may not be effective for treating persistent long-COVID symptoms. The study was conducted by Prof. Lindsey R. and colleagues.
To assess the therapeutic effectiveness of long-term antiviral treatments, researchers conducted a randomized, double-blind, placebo-controlled trial on a total of 69 clinical sites across the United States, which was conducted between July 27, 2023, and September 6, 2024. The study involved participants who were 18 years or older and suffered from a suspected, probable, or confirmed case of SARS-CoV-2 infection along with symptoms persisting for at least 12 weeks.
The subjects were diagnosed with having at least two symptoms that could be classified as moderate or one symptom that could be classified as severe, belonging to one of the three major symptoms groups (cognitive, autonomic, or exercise-related). Eligible participants were randomly assigned in a 1:1:1 ratio to undergo a 15-day active treatment with nirmatrelvir–ritonavir and 10 days of placebo, a complete 25-day course of nirmatrelvir-ritonavir, or 25 days of ritonavir-placebo treatment.
Key findings:
- Adjusted percentage differences compared to placebo at day 90 were 3.2% (95% CI −10.4 to 16.8; p = 0.65) for the 25-day regimen and −2.2% (95% CI −15.5 to 11.1; p = 0.74) for the 15-day regimen.
- Adjusted percentage differences compared to placebo were −6.4% (95% CI −18.5 to 5.7; p = 0.30) for the 25-day regimen and −0.1% (95% CI −12.5 to 12.3; p = 0.99) for the 15-day regimen.
- Adjusted percentage differences compared to placebo were −7.8% (95% CI −19.5 to 3.8; p = 0.19) for the 25-day regimen and 0.9% (95% CI −11.4 to 13.2; p = 0.88) for the 15-day regimen.
- There were no treatment-related deaths in the study, and 52 serious adverse events occurred in 42 of 963 participants (4%), showing no new safety signals associated with extended antiviral exposure.
To conclude, extended administration of nirmatrelvir-ritonavir therapy for 15 or 25 days did not have any benefits for long COVID patients based on cognitive, autonomic or exercise phenotypes. The lack of any statistical significance improvement in all three primary categories of symptoms shows that antiviral monotherapy approach cannot provide a good remedy for patients suffering from long COVID. It is vital to develop new metrics and strategies to address the issue of long COVID.
Reference:
Baden, L. R., Shah, N. S., Liu, S. T. H., Cohen, J., Moy, J., Kumar, A., McComsey, G. A., Chen, P., Floris-Moore, M., Singer, N. G., Fernandez, I., Slandzicki, A. J., Wiley, Z., Kadl, A., Kaminsky, D. A., Hsu, H., Walker, T. A., Hope, A. A., Ostrosky-Zeichner, L., … Yendewa, G. (2026). 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. The Lancet Infectious Diseases. https://doi.org/10.1016/s1473-3099(26)00406-8
