Objective:

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.

Sources:

• The Lancet Infectious Diseases