IMPORTANCE: The optimal antiviral drug for treatment of nonsevere influenza remains unclear. OBJECTIVE: To compare effects of antiviral drugs for treating nonsevere influenza. DATA SOURCES: MEDLINE, Embase, CENTRAL, CINAHL, Global Health, Epistemonikos, and ClinicalTrials.gov were searched from database inception to September 20, 2023. STUDY SELECTION: Randomized clinical trials comparing direct-acting influenza antiviral drugs to placebo, standard care, or another antiviral drug for treating people with nonsevere influenza. DATA EXTRACTION AND SYNTHESIS: Paired reviewers independently performed data extraction and risk of bias assessment. A frequentist network meta-analysis was performed to summarize the evidence and the certainty of evidence was evaluated using the GRADE approach. MAIN OUTCOMES AND MEASURES: Mortality, admission to hospital, admission to the intensive care unit, duration of hospitalization, time to alleviation of symptoms, emergence of resistance, and adverse events. RESULTS: Overall, 73 trials with 34 332 participants proved eligible. Compared with standard care or placebo, all antiviral drugs had little or no effect on mortality for low-risk patients and high-risk patients (all high certainty). All antiviral drugs (no data for peramivir and amantadine) had little or no effect on hospital admission for low-risk patients (high certainty). For hospital admission in high-risk patients, oseltamivir (risk difference [RD], -0.4%
95% CI, -1.0 to 0.4
high certainty) had little or no effect and baloxavir may have reduced risk (RD, -1.6%
95% CI, -2.0 to 0.4
low certainty)
all other drugs may have had little or uncertain effect. For time to alleviation of symptoms, baloxavir probably reduced symptom duration (mean difference [MD], -1.02 days
95% CI, -1.41 to -0.63
moderate certainty)
umifenovir may have reduced symptom duration (MD, -1.10 days
95% CI, -1.57 to -0.63
low certainty)
oseltamivir probably had no important effect (MD, -0.75 days
95% CI, -0.93 to -0.57
moderate certainty). For adverse events related to treatment, baloxavir (RD, -3.2%
95% CI, -5.2 to -0.6
high certainty) had few or no adverse events
oseltamivir (RD, 2.8%
95% CI, 1.2 to 4.8
moderate certainty) probably increased adverse events. CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis found that baloxavir probably reduced risk of hospital admission for high-risk patients and may reduce time to alleviation of symptoms, without increasing adverse events related to treatment in patients with nonsevere influenza. All other antiviral drugs either probably have little or no effect, or uncertain effects on patient-important outcomes.