Outpatient Treatment of Confirmed COVID-19: A Living, Rapid Review for the American College of Physicians (Version 3)

BACKGROUND: Clinicians and patients need updated information on antiviral treatments for COVID-19. PURPOSE: To provide a final update on the benefits and harms of COVID-19 antiviral treatments in adult outpatients. DATA SOURCES: Ovid/MEDLINE, Epistemonikos COVID-19 L·OVE platform, and iSearch COVID-19 portfolio (22 January 2025); Ovid/MEDLINE (24 September 2025). STUDY SELECTION: Two reviewers screened 20% of abstracts and full texts, then single screening. Randomized controlled trials were included for benefits and harms, and cohort studies were included for harms. DATA EXTRACTION: One reviewer extracted data and assessed risk of bias and certainty of evidence (CoE); a second reviewer verified. DATA SYNTHESIS: = 0.011; low CoE) but probably increases adverse events (1.3% vs. 1.0%; moderate CoE). Simnotrelvir-ritonavir reduces time to recovery (-35.8 median hours; high CoE) and probably increases adverse events (28.9% vs. 21.6%; moderate CoE). There was no difference in recovery between molnupiravir and favipiravir (high CoE) and nirmatrelvir-ritonavir and molnupiravir (low CoE). LIMITATION: Evidence for many outcomes is limited. CONCLUSION: Three COVID-19 antivirals improved or accelerated recovery, with varying adverse event profiles. Molnupiravir probably offers long-term benefits. PRIMARY FUNDING SOURCE: American College of Physicians. (PROSPERO: CRD420251029146; OSF: https://osf.io/ywp6u).