To evaluate the efficacy of nirmatrelvir–ritonavir treatment for up to 25 days in improving cognitive dysfunction, autonomic dysfunction, or exercise intolerance in patients with long COVID.
Approach:
Study Design: Randomized, double-blind, placebo-controlled phase 2 RECOVER-VITAL trial conducted at 69 US sites.
Participants: Adults aged 18 years or older with persistent symptoms for at least 12 weeks following SARS-CoV-2 infection.
Intervention: Patients were assigned to receive either nirmatrelvir–ritonavir for 15 days followed by placebo, nirmatrelvir–ritonavir for 25 days, or placebo for 25 days.
Outcomes: Primary outcome was improvement at day 90 on phenotype-specific patient-reported measures; secondary outcomes included performance measures.
Key Findings:
58% of cognitive dysfunction patients improved with 25 days of treatment compared to 55% with placebo, with an adjusted difference of 3%.
62% of autonomic dysfunction patients improved with 25 days of treatment compared to 70% with placebo, with an adjusted difference of -6%.
25% of exercise phenotype patients improved with 25 days of treatment compared to 33% with placebo, with an adjusted difference of -8%.
No new safety signals were observed; serious adverse events occurred in 4% of patients.
Interpretation:
The findings did not support the use of nirmatrelvir–ritonavir for up to 25 days for the studied long COVID phenotypes.
Limitations:
Challenges in establishing long COVID with homogeneous specificity.
Absence of validated long COVID-specific symptom assessment tools.
Study population was predominantly White, limiting generalizability.
Patients had prolonged symptoms before enrollment, possibly affecting treatment efficacy.
The trial did not establish which patients had viral persistence at baseline.
Conclusion:
Antiviral treatment with nirmatrelvir–ritonavir did not improve cognitive, autonomic, or exercise symptomatology in long COVID patients as measured by symptom-specific PROMs and performance measures.
