CDC Influenza Antiviral Medications: Summary for Clinicians - Jan 2026
#19,029
While there are other options (see below), Oseltamivir (aka `Tamiflu') remains the default antiviral for hospitalized or severe influenza worldwide, and has been stockpiled by many countries for use during a pandemic.
Although Baloxavir was approved by the U.S. in 2018, the CDC expressly states that: `There are no data for baloxavir treatment of patients with HPAI A(H5N1) virus infection or avian influenza A(H7N9) virus infection.'
Peramivir is only administered by IV, and Zanamivir is an inhaled powder, which is often not tolerated by those with respiratory symptoms. Additionally, oseltamivir is not only far more available - it is a fraction of the cost of the alternatives.
Which is why oseltamivir makes up > 90% of all stockpiled influenza antivirals, and is the drug of choice for treatment of influenza A.
There's only one problem; increasingly we've seen concerns expressed over the ability of oseltamivir to effectively treat severe novel flu infections. From Feb 2025's St. Jude Researchers: Current Antivirals Likely Less Effective Against Severe Infection Caused by Bird Flu in Cows’ Milk:
Our evidence suggests that it is likely going to be hard to treat people severely infected with this bovine H5N1 bird flu strain,” said corresponding author Richard Webby, PhD, St. Jude Department of Host-Microbe Interactions. “Instead, reducing infection risk by not drinking raw milk and reducing dairy farm workers’ exposures, for example, may be the most effective interventions.”
“In general, baloxavir [Xofluza] caused a greater reduction in viral levels than oseltamivir [Tamiflu], but neither was always effective,” said first author Jeremy Jones, PhD, St. Jude Department of Host-Microbe Interactions.
There is also the matter of antiviral resistance - which is relatively low right now - but appears to be increasing in both seasonal and novel flu strains (see Emerg. Microbes & Inf: Oseltamivir Resistant H5N1 (Genotype D1.1) found On 8 Canadian Poultry Farms).
While we've not seen any reports of H275Y in D1.1 samples collected in the United States, the CDC did report finding a far-less impactful mutation (NA-S247N) in 3 poultry workers from Washington State, which they stated may slightly reduce the virus's susceptibility to antivirals.
Regardless of the antiviral used, it must be administered within 24-48 hours of onset of symptoms to have the most impact, and that presents a difficult logistic problem as well (see Sporadic Tamiflu (Oseltamivir) Shortages Reported In U.S. & Canada).
All of which brings us to a report from researchers at the CDC's Influenza Division, published today in Nature Comms, which looks at both mono and combination therapy with oseltamivir and baloxavir in ferrets infected with H5N1 (genotype D1.1).
Ferrets are a good, but not perfect, proxy for humans in influenza research, so these results may not be 100% applicable to humans.
In short, they found that:
- Ferrets infected with H5N1 D1.1 and treated with oseltamivir saw little or no clinical or virologic benefit compared to no treatment, with persistent high fevers, weight loss, and systemic viral replication.
- Ferrets treated with Baloxavir saw significantly less fever, weight loss, and viral replication. Some ferrets, however, saw a late rise in fever (after 4 days) and viral shedding, suggesting a viral rebound.
- Ferrets treated with both drugs saw similar clinical protection to baloxavir alone, but did not show signs of rebound.
I've only reproduced the abstract below, and a snippet from the conclusion. Follow the link to read the study in its entirety. I'll have a postscript after the break.
Oseltamivir and baloxavir monotherapy and combination therapy efficacy against clade 2.3.4.4b A(H5N1) influenza virus infection in ferrets
Communications Biology , Article number: (2026) Cite this article
We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.
Abstract
Neuraminidase inhibitors (NAIs) and cap-dependent endonuclease inhibitors (CENIs) represent two classes of antiviral drugs recommended for early treatment of patients with seasonal influenza A virus (IAV) infections. However, only limited human data, particularly on combination antiviral treatment, are available to inform optimal dosing regimens against novel IAVs, including highly pathogenic avian influenza A(H5N1) virus, associated with severe disease. Clade 2.3.4.4b A(H5N1) viruses have caused outbreaks in avian and mammalian species worldwide, highlighting the need to assess antiviral drug efficacy against these strains.
We challenged ferrets with a D1.1 genotype A(H5N1) virus and treated infected animals with the NAI oseltamivir phosphate (OST) and the CENI baloxavir acid (BXA), alone or in combination, with treatment onset commencing pre- or post-symptom onset (24- or 48-hours post-inoculation (p.i.), respectively).
When administered pre- or post-illness onset, BXA, but not OST, monotherapy provided significant reduction of clinical signs and significantly decreased infectious viral levels (in both respiratory and extrapulmonary specimens) compared with mock-treated animals.
Combination OST/BXA treatment, when administered pre- or post-symptom onset, resulted in significant improvements in both metrics versus OST monotherapy. These data support continued investigation of antiviral treatment modalities that include both NAI and CENI for patients with mild and severe A(H5N1) disease.(SNIP)
There is a paucity of studies evaluating BXA in combination with NAIs to mitigate clinical signs and viral levels following IAV inoculation compared with monotherapy in animal models, with even fewer studies using novel IAV s.
Our study found when administered at 24 or 48 hours p.i., combination OST/BXA treatment offered generally minimal improvements in reduction of clinical signs and viral levels relative to BXA monotherapy, but substantial improvements in both metrics relative to OST monotherapy .Current recommendations specify prompt oseltamivir treatment of patients with A(H5N1), 2 and consideration of combination antiviral therapy for immunocompromised outpatients and hospitalized patients. Our data support continued investigation of BXA monotherapy and combination OST/BXA therapy in patients with A(H5N1). Further investigations of antiviral treatment modalities are needed, including combination NAI and CENI, in vivo and in patients with mild and severe illness due to A(H5N1) virus infection, due to clade 2.3.4.4b and other virus clades.
Since randomized trials are both impossible and unethical, nearly all evidence comes from observational studies and case reports.
The main takeaways from that 19-page article were:
- Most of our observational data comes from the treatment of H5N1 and H7N9 infections
- Early treatment with neuraminidase inhibitors (NAIs), particularly oseltamivir, within 48 hours dramatically improves survival.
- Delayed treatment (>5–7 days) correlates with higher mortality, longer viral shedding, and increased respiratory failure.
- Post-Exposure Prophylaxis (PEP) evidence exists only for H7N7, but that dataset was small, and confidence is fairly low.
- Antiviral resistance can emerge, particularly with oseltamivir and baloxavir, reinforcing the need for combination therapy trials.
Even during moderately severe flu seasons, we've seen difficulties getting antivirals to patients who need them in the crucial first 48 hours of infection (see CDC HAN #0482: Prioritizing Antiviral Treatment of Influenza in the Setting of Reduced Availability of Oseltamivir).Furthermore, a strain-specific vaccine could easily take 6 - 12 months to reach the masses (see Maggie Fox's SCI AM - A Bird Flu Vaccine Might Come Too Late to Save Us from H5N1).
While I wouldn't hesitate to take antivirals or a vaccine during a flu pandemic if they were offered, their availability and effectiveness are far from guaranteed.
Which means our initial response will once again have to rely heavily on preventing infection; wearing face masks, hand washing, improved indoor ventilation, staying home while sick, and avoiding crowds.
Which is why I've already got my supply of masks, hand sanitizer, and OTC meds in the hall closet, and have stayed current with all of my vaccines.
If you aren't similarly prepared, you may want to revisit:
