Influenza Antivirals: Do We Need More Evidence?

COMMENTARY

The American Academy of Pediatrics (AAP), Centers for Disease Control and Prevention (CDC), and the Infectious Disease Society of America (IDSA) recommend prompt antiviral use, regardless of duration of symptoms, in hospitalized children with influenza, those with severe or prolonged illness, and those at high-risk for influenza complications, including children aged younger than 5 years (especially <2 years).^1–3 These guidelines also recommend consideration of antivirals in those with symptoms for less than 48 hours and those with high-risk household contacts. For pediatricians, this often includes patients with pregnant, elderly, or immunocompromised family members or younger siblings. These guidelines are supported by findings from randomized controlled trials (RCTs) in both children and adults, as well as a robust set of observational studies that support their recommended use.^1–3

There are 4 antivirals approved by the Food and Drug Administration (FDA) for use in the outpatient setting: oseltamivir, baloxavir, zanamivir, and peramivir.² Oseltamivir is the most commonly prescribed influenza antiviral, accounting for more than 99% of influenza antiviral use in the pediatric population due to its wide availability, low cost, well-studied safety profile, and approval for use in children aged younger than 5 years.^2,4 The main reported side effect is vomiting, with a number needed to harm of 1 in 17 or approximately 6% compared with the placebo.⁵ There is also an FDA label warning for rare neuropsychiatric events, although growing evidence suggests these events are related to influenza itself and not oseltamivir.^6–8

Targeted interventions designed to increase guideline-concordant antiviral treatment would benefit both individual patients and society at large. Influenza is a common infection with 40 to 80 million illnesses during the 2024 to 2025 influenza season.⁹ The aggregate effect of even modest reductions in symptom duration, viral transmission, missed school/work, antibiotic use, or influenza-related complications, when put in the context of tens of millions of influenza illnesses, is substantial. However, influenza antivirals remain underutilized in the United States, as almost 40% of children at high risk for influenza complications with influenza do not receive antiviral treatment.^10,11

In this issue of Pediatrics, Bassett et al shed light on potential reasons for underuse of influenza antivirals, specifically oseltamivir.¹² The authors performed a vignette-based study surveying outpatient pediatric providers across 7 institutions, creating fictional cases where there was anticipated inconsistency in care. The authors found significant variability in antiviral treatment decisions, which varied by provider specialty, study site, and reported number of influenza cases in the prior year. There was no information on provider awareness of national guidelines available to correlate with treatment decisions. The authors postulated 3 potential reasons for variation in antiviral use: (1) inadequate awareness of national guidelines and clinical evidence for their recommendations, (2) skepticism of the clinical benefits of antivirals, and (3) concern about side effects.

Bassett et al further queried providers on what additional information would be desired to inform treatment decisions. Approximately 85% of respondents indicated additional antiviral RCTs were moderately or extremely important, with over two-thirds reporting hospitalization or duration of symptoms as the primary outcomes of interest. Desired secondary outcomes included missed work/school days, duration of symptoms, and unscheduled outpatient visits, among others.

With this new information from Basset et al, the question arises: do we need more evidence for influenza antivirals or do we need better awareness of and compliance with national guidelines? Clearly, providers desire more data on antiviral effectiveness but indicate they want information on outcomes that are both well-studied and understudied. The AAP, IDSA, and CDC guidelines are supported by findings from RCTs in children with mild to moderate influenza illness in the outpatient setting with primary outcomes of duration of symptoms or time to alleviation of symptoms.^5,13–16 Meta-analyses of these RCTs demonstrate that, among those with laboratory-confirmed influenza, antiviral treatment within 48 hours of symptom onset reduces duration of symptoms by approximately 30 hours in children without asthma,⁵ comparable to the 25-hour reduction in adult trials.¹⁴ It is also notable that antivirals are most effective early in the course of illness. For example, an RCT in children 1 to 3 years of age found that influenza antiviral use within 24 hours of symptom onset reduced duration of symptoms by approximately 3 days compared with the placebo,¹⁷ similar to an adult trial on early antiviral initation.¹⁸

Antiviral RCTs in children also demonstrate benefits outside of symptom duration including reductions in viral load, antibiotic use, absence from daycare, parental work absenteeism, viral transmission, and common influenzarelated complications such as acute otitis media.^{5,15–17,19–21} Although pediatric RCTs were underpowered to assess influenza-related pneumonia,⁵ RCTs in adults¹⁴ and pediatric cohort studies²² support the notion that influenza antivirals prevent lower respiratory tract infections. Reductions in influenza transmission, however, may differ between antivirals.²³ In a large, multinational randomized trial, treatment of the index case with baloxavir reduced household transmission by approximately 30% compared with the placebo.²⁰ A smaller RCT performed in Bangladesh suggests a more modest reduction in viral transmission with oseltamivir treatment.¹⁹

Although influenza and its complications are a common cause of pediatric hospitalization,²⁴ the vast majority of children with influenza illness do not require hospital care. There were too few hospitalizations in pediatric RCTs to evaluate whether antivirals prevent hospitalization.⁵ A clinical trial powered for a primary outcome of hospitalization would require more than 100 000 pediatric participants with influenza illness, raising questions about its feasibility.^25,26 Meta-analyses from adult RCTs were also substantially underpowered to assess associations between oseltamivir and hospitalization.^14,25–27 Well-performed observational studies in children suggest oseltamivir is associated with a reduced risk of influenza-related hospitalization.^22,28

Despite growing evidence supporting the recommended use of influenza antivirals, additional questions remain and are emphasized by Basset et al. What subpopulations of children benefit most from influenza antivirals? Most children have self-limited influenza illness, and not all high-risk conditions are the same. Treating an immunocompromised child with influenza illness is an easy decision, but what about a child with obesity and mild illness on day 4 of symptoms? Are newer agents such as baloxavir more effective than oseltamivir in certain populations? Influenza is unpredictable and can have severe manifestations. The recent 2024 to 2025 influenza season highlighted neurologic complications of influenza, including necrotizing encephalopathy, seizures, and cerebral edema.²⁹ More than half of these life-threatening neurologic complications occur in otherwise healthy children.^29,30 The question remains whether antivirals prevent uncommon but serious influenza complications.²³

Optimal use of antivirals is challenging because of the short incubation period of influenza and rapid rise and fall of viral load in most cases.³¹ Antivirals are most effective when used early in the course of influenza illness, and operationalizing early diagnosis to maximize the benefit of antivirals is critical. Studies focusing on barriers and facilitators of antiviral treatment are needed to inform effective interventions to improve guideline-concordant care. Recent FDA approvals of home influenza testing provide an opportunity to shorten the period between diagnosis and antiviral therapy.³² Pragmatic RCT, quality improvement, and implementation science approaches aimed at reducing time to antiviral treatment could have a significant impact on influenza outcomes.

Antivirals are a crucial tool to complement vaccination in the management of influenza. Despite calls for more RCTs by clinicians on effectiveness of antivirals, many clinically important but rare influenza outcomes are not feasible to assess using RCTs in the general pediatric population or may be unethical in certain populations because of the known benefits of antivirals. Studies are needed on barriers and facilitators to antiviral treatment, shortening time to antiviral treatment, comparative effectiveness of antivirals, and serious influenza-related complications. Given current data on influenza antivirals, providers should follow AAP, CDC, and IDSA recommendations for prompt treatment of influenza in those at high risk for influenza complications.