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To date, tests of isolates from eight farms in Canada have yielded a rare neuraminidase (NA) protein mutation known as H275Y that has shown resistance to oseltamivir, according to a new research letter published in the journal Emerging Microbes and Infections. 

Until recently, highly pathogenic avian influenza subtype A(H5N1) viruses sequenced in North America descended from viruses of Eurasian origin, wrote Anthony V. Signore, of the National Centre for Foreign Animal Disease, Winnipeg, Canada, and colleagues.

However, tests of chickens in farms in British Columbia in October 2024 were identified with a NA segment of North American lineage instead of Eurasian, the authors wrote.

Gene sequencing revealed several amino acid substitutions, most notably H275Y, “which has been shown to confer resistance to neuraminidase inhibitors commonly used to treat influenza infections,” the researchers noted. In particular, the H275Y substitution has been associated with strong resistance to oseltamivir, they said.

“As oseltamivir is the most widely used therapeutic and prophylactic against IAV [influenza A virus], the continued circulation of viruses harboring NA-H275Y may necessitate a re-evaluation of influenza treatment strategies in Canada,” the researchers concluded.

Human Implications

The emergency of an oseltamivir-resistant strain of avian flu is rare but not surprising, said Jose A. Lucar, MD, associate professor of medicine in the Division of Infectious Diseases at George Washington University, Washington, DC, in an interview.

“While oseltamivir resistance is rare, it has been documented during previous outbreaks of avian influenza, for example, in human cases in Vietnam in 2005,” he said.

The two major antigens on the surface of influenza viruses are hemagglutinin and NA, and influenza viruses are known for their ability to mutate, Lucar said. One such mutation could be for the NA protein that is the target for oseltamivir, he said. “This could happen, for example, because of two influenza variants exchanging genetic material with each other while in an animal host, a process known as reassortment,” he explained.

“In this report, researchers identified a reassortant influenza A H5N1 virus with a mutated neuraminidase gene segment from a low-pathogenic avian influenza virus conferring oseltamivir resistance in Canadian poultry that has spread rapidly across dozens of poultry farms in British Columbia,” Lucar told Medscape Medical News.

As for implications in humans, “it is important to note that while the ongoing outbreaks of avian influenza in poultry and dairy cows is concerning, the current public health risk is low at this time,” said Lucar. “However, clinicians should continue to consider the possibility of avian influenza infection in persons showing signs or symptoms of acute respiratory illness or conjunctivitis who have relevant exposure history,” he said.

Obtaining a clinical history is essential for persons with influenza to determine any relevant exposures, such as contact with potentially infected sick or dead birds, livestock, or other animals within 10 days before the onset of illness, said Lucar. “Also, clinicians should inquire about contact with or consumption of unpasteurized (raw) milk or unpasteurized dairy products or parts of potentially infected animals,” he added.

“If a human case of avian influenza is suspected, clinicians should isolate the patient and follow the infection control recommendations provided by CDC [Centers for Disease Control and Prevention], start empiric antiviral treatment, and contact their state or local health department immediately to coordinate proper testing,” Lucar noted.

Red flags for drug resistance in human patients include the development of influenza after receiving antiviral prophylaxis with a NA inhibitor, lack of clinical improvement despite treatment with a NA inhibitor in patients with severe influenza, or persistently positive influenza tests for individuals after more than 7 days of treatment, Lucar said. “If a clinician suspects antiviral resistance, a respiratory sample can be sent to the state public health laboratory for resistance testing,” he said.

Treatment Options and Research Gaps

In cases of suspected oseltamivir resistance, zanamivir is the preferred treatment, and the variant described in the current report remained susceptible to zanamivir, Lucar told Medscape Medical News. Clinicians should consult an infectious disease specialist for additional guidance in these cases, he said.

“While previous research suggested that variants with the mutation described in this report (H275Y) appeared to have lower fitness, data in this report indicated that it may not be the case, as the variant has spread rapidly across many poultry farms in British Columbia,” Lucar said. “More research is needed to better understand the clinical and public health implications of finding variants with this mutation, as well as optimal therapeutic and prophylactic approaches in the event of more widespread oseltamivir resistance,” he added.

The researchers had no financial conflicts to disclose. Lucar had no financial conflicts to disclose.