J.I.D.: Antivirals for Novel Influenza A Virus Infections

 

#18,914

During the opening months of the 2020 COVID pandemic we found ourselves with few pharmaceutical options, since no coronavirus vaccine had previously been developed, and no antivirals had been proven to work against the SARS-CoV-2 virus. 

As a result, treatment was mainly supportive (ventilation, O2, IV fluids, etc.) with a few desperate attempts to incorporate `off-label' drugs, many of which proved to be of little value (see WHO Solidarity Therapeutics Trial: Remdesivir, HCQ, Lopinar/Ritonavir & Interferon Disappoint).

While we will hopefully have better options going into a novel influenza pandemic, a strain-specific vaccine could 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), and we've seen recent warnings that our current arsenal of antivirals may be lacking.

St. Jude Researchers: Current Antivirals Likely Less Effective Against Severe Infection Caused by Bird Flu in Cows’ Milk

We've also seen sporadic reports of antiviral resistance turning up in HPAI H5 outbreaks in poultry (see Emerg. Microbes & Inf: Oseltamivir Resistant H5N1 (Genotype D1.1) found On 8 Canadian Poultry Farms), and in a recent EID Journal: Antiviral Susceptibility of Influenza A(H5N1) Clade 2.3.2.1c and 2.3.4.4b Viruses from Humans, 2023–2024, the authors advised:

". . . higher antiviral dosing and combination antiviral treatment (e.g., oseltamivir and baloxavir) should be considered, in particular for patients with H5N1 who are hospitalized or immunocompromised." 

All of which brings us to a narrative evidence review article by the CDC's Dr. Timothy M. Uyeki, MD, MPH, MPP  and Dr. Jessica A. Belser, PhD, which looks at the available literature on use of antivirals in humans with novel influenza A virus infections of avian A(H5N1), A(H5N6), A(H7N7), and A(H7N9). 

Since randomized trials are both impossible and unethical, nearly all evidence comes from observational studies and case reports. Purists may object, but sometimes that is the only type of evidence available. 

The main takeaways from this 19-page article are:

• 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.

I've only posted some excerpts from this information-dense report, so you'll want to follow the link to read it in its entirety.  I'll have a postscript when you return. 

Antivirals for Novel Influenza A Virus Infections  
Timothy M Uyeki, Jessica A Belser
 
The Journal of Infectious Diseases, Volume 232, Issue Supplement_3, 15 October 2025, Pages S191–S209, https://doi.org/10.1093/infdis/jiaf296
Published: 17 October 2025

PDF

Abstract

Influenza A viruses of animal origin (such as avian or swine influenza A viruses), which are antigenically and genetically distinct from seasonal influenza A viruses and have infected humans, are referred to as novel influenza A viruses. Sporadic human infections with highly pathogenic avian influenza A(H5N1) viruses of a wide spectrum of illness severity in the United States and worldwide have highlighted the need for evidence-based recommendations on the use of antivirals for novel influenza A virus infections. 

We review the available published data on use of antivirals for humans with novel influenza A virus infections of avian [A(H5N1), A(H5N6), A(H7N7), and A(H7N9) viruses associated with severe human disease] or swine origin, and data from in vivo antiviral studies. We summarize the available evidence on the effectiveness of antiviral treatment and antiviral postexposure prophylaxis of novel influenza A virus infections, discuss considerations for use of combination therapy with antivirals of different mechanisms of action, and identify important questions to improve the evidence base and to further guide use of antivirals for treatment and postexposure prophylaxis of novel influenza A virus infections.

(SNIP)

Taken together, available data from observational studies of patients infected with older clades of HPAI A(H5N1) viruses and from animal studies suggest that early initiation of oseltamivir treatment shortly after symptom onset has the greatest clinical benefit.

There are no data on baloxavir treatment effectiveness for A(H5N1) patients or optimal dosing and duration to achieve clinical benefit and to reduce emergence of resistant viruses, although animal data suggest clinical benefit of early initiation of baloxavir treatment.

        (SNIP)

The detection of oseltamivir-resistant HPAI A(H5N1) virus with H274Y in NA circulating among poultry in British Columbia, Canada [106], is notable because if unprotected exposure to oseltamivir-resistant novel influenza A virus is known or suspected, then use of other antivirals that have activity against such oseltamivir-resistant viruses, such as inhaled zanamivir or baloxavir, for postexposure prophylaxis is indicated.

       (SNIP)

Optimal dosing and duration of antiviral treatment in outpatients and hospitalized patients with novel influenza A virus infections remain to be determined. 

Availability of assays in clinical settings or rapid sequencing of target genes that can detect antiviral resistance to NAIs, polymerase inhibitors, adamantanes, and other antivirals in respiratory specimens and provide timely results, can help guide specific treatment. 

Because of the ongoing, unpredictable evolution of influenza A viruses among birds and other animals, susceptibility to antivirals in the past or now does not necessarily inform susceptibility to antivirals in the future, and antiviral treatment decisions for patients with novel influenza A virus infections may vary on a case-by-case basis, depending upon antiviral susceptibility data and what antivirals are available. 

Therefore, ongoing, rapid sharing of data on antiviral susceptibility of novel influenza A viruses currently circulating in animals and infecting humans is important to guide public health and clinical recommendations for use of antivirals and for pandemic influenza preparedness. 

       (Continue . . . )

While the United States and other countries have tens of millions of courses (of mostly oseltamivir) stockpiled, there isn't nearly enough to treat everyone during a pandemic, particularly when the optimum dose and duration have not been established.  

Even during moderately severe flu seasons, we've seen spot shortages and 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).  

While I wouldn't hesitate to take antivirals for pandemic flu infection, their effectiveness and availability are not guaranteed. Which means our initial response  - once again - must focus heavily on preventing infection. 

That means the use of NPIs (non-pharmaceutical interventions); like face masks, hand washing, improved indoor ventilation, staying home while sick, and avoiding crowds. 

Which is why I'm recommending that people consider now (see #Natlprep 2025: Personal Pandemic Preparedness) exactly what they will do if pandemic flu should embark on another world tour.