Antivirals for treatment of non-severe influenza: a systematic review and network meta-analysis of randomized controlled trials

Abstract

Background: The optimal antiviral drug for treatment of non-severe influenza remains unclear. To support an update of WHO guidelines on antiviral treatment for influenza, this systematic review compared effects of antiviral drugs for treating non-severe influenza. Methods: We systematically searched Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Global Health, Epistemonikos, and ClinicalTrials.gov for randomized controlled trials published between database inception and 20 September 2023, comparing direct-acting influenza antiviral drugs, including but not limited to baloxavir, favipiravir, laninamivir, oseltamivir, peramivir, umifenovir, and zanamivir, to placebo, standard care, or another antiviral drug for treating people with non-severe influenza. We performed frequentist network meta-analyses to summarize the evidence and evaluated the certainty of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. We registered the protocol with PROSPERO, CRD42023456650. Findings: We identified 11878 records, of which 73 trials with 34332 participants proved eligible. Compared with standard care or placebo, all antiviral drugs have little or no effect on mortality for low-risk patients (risk difference (RD) varied from 0.12 fewer to 0.02 fewer per 1000) and high-risk patients (RD varied from 1.22 fewer to 0.24 fewer per 1000) (all high certainty). All antivirals (no data for peramivir and amantadine) have little or no effect on admission to hospital (RD varied from 2 fewer to 1 more per 1000) for low-risk patients (high certainty). With respect to hospital admission, for high-risk patients, oseltamivir (RD 4 fewer per 1000, 95% CI 10 fewer to 4 more; high certainty) and zanamivir (RD 4 more per 1000, 95% CI 4 fewer to 15 more; high certainty) have little or no effect; baloxavir may reduce risk (RD 16 fewer per 1000, 95% CI 20 fewer to 4 more; low certainty); all other drugs may have little or uncertain effect. For time to alleviation of symptoms, baloxavir probably reduces symptom duration (mean difference (MD) 1.02 days lower, 95% CI 1.41 lower to 0.63 lower; moderate certainty); umifenovir may reduce symptom duration (MD 1.10 days lower, 95% CI 1.57 lower to 0.63 lower; low certainty); oseltamivir probably has no important effect (MD 0.75 days lower, 95% CI 0.93 lower to 0.57 lower, moderate certainty) and other drugs may have no important or little effect. For adverse events related to treatment, baloxavir (RD 32 fewer per 1000, 95% CI 52 fewer to 6 fewer; high certainty) has few or no such events; oseltamivir (RD 28 more per 1000, 95% CI 12 more to 48 more; moderate certainty) probably increases such events; other drugs may have little or no effect, or uncertain effect. Interpretation: Baloxavir may reduce the risk of hospital admission for high-risk patients and probably reduces time to alleviation of symptoms, without increasing adverse events related to treatment in patients with non-severe influenza. All other antivirals either probably have little or no effect, or uncertain effects on patient-important outcomes.