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

Summary 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. Funding WHO. Research in context Evidence before this study Antiviral drugs may play a role in reducing illness duration, preventing serious complications, and lowering morbidity, particularly in high-risk populations. Previous systematic reviews and network meta-analyses have assessed the effects of antiviral drugs for treating influenza, but none assessed all approved antivirals for influenza or addressed patient-important outcomes of mortality and admission to hospital. The effect of many antiviral drugs for treating patients with non-severe influenza remains uncertain. Added value of this study This systematic review and network meta-analysis represents the most comprehensive assessment of the benefits and harms of antivirals in treating patients with non-severe influenza and demonstrates that baloxavir may reduce the risk of admission to hospital for high-risk patients and probably reduces time to alleviation of symptoms, does not increase adverse events related to treatment, but may increase emergence of resistance. Oseltamivir has little or no effect on mortality and admission to hospital, probably has no important effect on time to alleviation of symptoms, and probably increases adverse events related to treatments. Other antivirals probably have little or no effect on mortality and admission to hospital and may have no important effect on time to alleviation of symptoms. Implications of all the available evidence Our study provides evidence that baloxavir may be superior to standard care or placebo in reducing the risk of admission to hospital for high-risk patients and probably decreases time to alleviation of symptoms with few or no adverse effects. These findings support the use of baloxavir for treatment of high-risk non-severe influenza patients.

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