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

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Abstract
Clinicians and patients need updated information on antiviral treatments for COVID-19. To provide a final update on the benefits and harms of COVID-19 antiviral treatments in adult outpatients. Ovid/MEDLINE, Epistemonikos COVID-19 L·OVE platform, and iSearch COVID-19 portfolio (22 January 2025); Ovid/MEDLINE (24 September 2025). 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. One reviewer extracted data and assessed risk of bias and certainty of evidence (CoE); a second reviewer verified. Seven studies from the Omicron period were included. 125 mg of ensitrelvir may not reduce time to recovery and may result in no difference in serious adverse events (both low CoE) but may increase adverse events (44.2% vs. 24.8%; low CoE). Molnupiravir probably improves recovery (31.8% vs. 22.6%) and reduces time to recovery (9 vs. 15 median days) and persistent symptoms from 3 to 6 months (8.5% vs. 11.0%), with no effect on mortality, hospitalization, serious adverse events, and adverse events (all moderate CoE). Nirmatrelvir-ritonavir may increase recovery (70.7% vs. 53.6%; low CoE) and reduce time to recovery (no data, P = 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). Evidence for many outcomes is limited. Three COVID-19 antivirals improved or accelerated recovery, with varying adverse event profiles. Molnupiravir probably offers long-term benefits. American College of Physicians. (PROSPERO: CRD420251029146; OSF: https://osf.io/ywp6u).

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