Worrying Signals Emerge As Bird Flu Gains Resistance Mutation
Two new studies released in 2025 provide a mixed picture of how well our current antivirals are holding up against H5N1, the highly pathogenic bird flu virus that continues to spill over into mammals and humans. The good news: H5N1 viruses from recent human cases remain susceptible to frontline antiviral drugs. More concerning is a resistance mutation that emerged and spread rapidly during a poultry outbreak in Canada, raising flags about the virus's potential to evolve past our defenses.
The antiviral oseltamivir (commonly known as Tamiflu) is currently recommended for treating and preventing H5N1 infections. It works by inhibiting neuraminidase, a surface protein the virus uses to release itself from infected cells and spread through the body. But this treatment only works if the virus remains sensitive to the drug.
Tamiflu, the same antiviral used to treat ordinary seasonal influenza, is the front line medication ... More recommended for treating highly pathogenic bird flu (Photo by Rui Vieira/PA Images via Getty Images)
In a study published in the CDC's journal Emerging Infectious Diseases, researchers tested H5N1 viruses from human infections reported in Cambodia, Chile, and the United States during 2023–2024. These viruses belonged to two clades (genetic lineages): 2.3.2.1c and 2.3.4.4b. All tested viruses were susceptible to oseltamivir and other neuraminidase inhibitors, including zanamivir and peramivir, as well as baloxavir, a newer drug that targets a different viral protein. Most also remained sensitive to older M2-blocking antivirals—except for two viruses isolated in Cambodia. These results support continued use of oseltamivir as the first-line treatment and for post-exposure prophylaxis in close contacts of infected individuals.
Computer generated 3D model, showing a cross-section of the green RNP spirals, blue hemagglutinin, ... More red neuraminidase, and purple m2 ion channels that constitute the structure of the Influenza A Virus (Orthomyxovirus family) image courtesy CDC/Douglas Jordan, 2009. (Photo by Smith Collection/Gado/Getty Images)
However, not all recent developments are reassuring. A separate study published in Emerging Microbes & Infections documented a large outbreak of H5N1 in poultry in British Columbia, Canada. Genetic sequencing of the virus revealed the presence of the H275Y mutation in the neuraminidase gene—well-known to confer resistance to oseltamivir. This mutation had previously rendered the majority of seasonal H1N1 viruses resistant to the drug during the 2008–2009 flu season.
What makes the Canadian case notable is how quickly the resistant virus spread. Within 27 days of detection, it had jumped across 44 farms. While resistance mutations like H275Y are often associated with reduced viral fitness, the Canadian outbreak strain spread quickly between farms, suggesting that this particular virus was able to transmit efficiently despite carrying the mutation. The mutation appears to have arisen through reassortment, a genetic mixing process that occurs when influenza viruses exchange segments. In this case, the virus acquired its neuraminidase segment from a different influenza lineage circulating in North American birds.
These findings illustrate how resistance can arise in animal populations, well before human outbreaks begin. They also highlight the importance of genomic surveillance—not only in people but also in poultry and wild birds, where the virus continues to evolve.
Combination therapies may offer a way to slow resistance. Studies in animals have shown that using multiple drugs with different mechanisms simultaneously can reduce viral load more effectively and lower the chances of resistance emerging. But in the real world, access to such treatments remains limited.
For now, Tamiflu still works—but the virus is changing. Our response must keep pace.
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