Background To support an update of WHO influenza guidelines, we performed a systematic review and network meta-analysis of the evidence on antiviral drugs for prophylaxis of influenza.

Methods We analyzed randomized controlled trials published as of September 2023 on the efficacy and safety of antivirals compared to another antiviral or placebo, standard care, or no prophylaxis for prevention of symptomatic influenza. Paired reviewers independently screened studies, extracted data and assessed the risk of bias. We used frequentist random effects to perform network meta-analyses and assessed the certainty of evidence using the grading of recommendations assessment, development and evaluation (GRADE) methodology.

Findings We included thirty-three trials of six antivirals (zanamivir, oseltamivir, laninamivir, baloxavir, amantadine, and rimantadine) that enrolled 19096 individuals. Zanamivir, oseltamivir, laninamivir and baloxavir probably achieve important reductions in symptomatic influenza in persons at high risk of severe disease (moderate certainty) when given promptly after exposure to seasonal influenza. These antivirals probably do not achieve important reductions in symptomatic influenza in persons at low risk of severe disease when given promptly after exposure to seasonal influenza (moderate certainty). Zanamivir, oseltamivir, laninamivir and baloxavir might achieve important reductions in symptomatic zoonotic influenza in persons exposed to novel influenza A viruses associated with severe disease in infected humans when given promptly after exposure (low certainty). These antivirals do not result in an important incidence of adverse events related to drugs or serious adverse events, with varying certainty of evidence.

Interpretation Post-exposure prophylaxis with zanamivir, oseltamivir, laninamivir or baloxavir probably decreases the risk of symptomatic seasonal influenza in persons at high risk for severe disease after exposure to seasonal influenza viruses. Post-exposure prophylaxis with zanamivir, oseltamivir, laninamivir or baloxavir might reduce the risk of symptomatic zoonotic influenza after exposure to novel influenza A viruses associated with severe disease in infected humans.

Evidence before this study Antivirals can be used to prevent influenza in people who have close contact to sick persons or animals infected with influenza viruses. Although previous reviews have found that antivirals (oseltamivir, zanamivir) are effective in preventing symptomatic influenza, these reviews assessed selected antivirals and did not rate the quality of evidence or consider the importance of effects in their interpretation. Additionally, a randomized controlled trial (RCT) of baloxavir for influenza post-exposure prophylaxis was not included in previous reviews.

Added value of this study This systematic review and network meta-analyses of RCTs addressing antiviral prophylaxis against influenza was performed in support of a World Health Organisation (WHO) guidelines development group panel to formulate recommendations on use of antivirals for influenza. We present our analyses of the efficacy of antiviral prophylaxis to prevent symptomatic influenza for high or low-risk (non-high-risk) populations and for preventing symptomatic zoonotic influenza.

We found moderate certainty evidence that zanamivir, oseltamivir, laninamivir and baloxavir all probably result in an important reduction in the risk of symptomatic seasonal influenza in high-risk persons when given promptly after exposure, but probably have no important effect for low-risk populations. Rimantadine probably has little or no effect on symptomatic seasonal influenza A virus infection (moderate certainty). Zanamivir, oseltamivir, laninamivir and baloxavir may decrease the risk of symptomatic zoonotic influenza (low certainty). The evidence for amantadine to prevent influenza A virus infection is limited. All of these antivirals have no important impact on adverse events.

Implications of the available evidence The findings of this systematic review and network meta-analysis support use of zanamivir, oseltamivir, laninamivir or baloxavir for post-exposure prophylaxis of seasonal influenza in persons at high risk of severe influenza, and also provide some support for the use of these antivirals for post-exposure prophylaxis of zoonotic influenza. The systematic review did not support using these antivirals among low-risk populations for post-exposure prophylaxis of seasonal influenza and did not support the use of amantadine and rimantadine for preventing symptomatic influenza A virus infection.

The authors have declared no competing interest.

https://www.crd.york.ac.uk/prospero/

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EMBASE, MEDLINE, the Cochrane Central Registry of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Global Health, Epistemonikos and ClincalTrials.gov databases

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