Every year influenza season rolls around.

Every year we need to discuss oseltamivir.

However, in 2025, it is no longer solely oseltamivir available for consideration and misuse.  We now have the next generation of influenza antivirals, including peramivir and baloxavir, not to mention potential antiviral candidates from around the world.  Unfortunately, despite the ubiquity and predictability of influenza season, the millions of prescriptions for these medications annually, and this parade of options, the evidence underpinning their use remains poor.

There have  been many individual studies published testing these influenza antivirals.  Further, there have been various systematic reviews, focussing primarily on oseltamivir.  Each of these types of evidence tells one specific type of story, but an interesting tool called a “network meta-analysis” provides scaffolding for a more expansive look.¹

The underlying principle behind a network meta-analysis allows it to perform indirect comparisons where direct, head-to-head trials may not have been performed.  Additionally, it can use information from these indirect comparisons to strengthen or attenuate findings from other, direct comparisons.  Such a tool can potentially integrate the entire landscape of influenza antivirals, assuming such antivirals were tested against each other, or placebo, in trials enrolling similar types of patients.

The network meta-analysis in question looks across the entire landscape of influenza antiviralsinvolving primarily, the aforementioned oseltamivir, peramivir, and baloxavir, but also gives mention to laninamivir, favipiravir, umifenovir, zanamivir, and amantadine.  The scope of this review involves only patients with “non-severe influenza” — i.e.  the ambulatory, outpatient population representing most emergency department patients, rather than those sick enough to require hopsital admission .

In approaching influenza, the United States Center for Disease Control and Prevention, echoing the World Health Organization, makes a distinction between “low risk” and “high risk” patients.² “High risk” patients are considered to be those who are pregnant, aged greater than 65 or younger than 2, those with lung disease, morbid obesity, and other types of serious chronic diseases.  Current recommendations consider treatment appropriate primarily in the “high risk” cohort, while leaving treatment in the “low risk” to individual clinician discretion.  In this network meta-analysis, where data were available, the authors perform the same mortality, hospitalization, and adverse effects comparisons for both these cohorts.

The total population for analysis consisted of 65 trials published between 1971 and 2023, comprised of 34,332 patients.  The largest body of evidence exists for oseltamivir, followed by zanamivir, and most comparisons were with placebo, rather than each other.  The first important descriptive finding these authors report is the risk of bias across the included trials.  Out of the 65 included, only 9 were at “low” or “probably low” risk of bias across all reported outcomes.  The most frequent threats to study validity were inadequate allocation concealment, lack of blinding, and in data analysis.