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New flu drug drives drug resistance in influenza viruses

A case in Japan in January 2019 involved an 11 year old boy who went to a medical clinic presenting a fever. The boy was diagnosed with influenza – the strain H3N2 – and was sent home with baloxavir, a new medication used to treat the flu.

After 5 days of feeling better, the boy’s fever returned, despite taking the medication. Two days later, his 3 year old sister also came down with a fever, and was diagnosed with the H3N2 influenza just 8 days after the boy’s initial diagnosis.

Flu samples were collected from both children, and upon analysis it was discovered that the girl had a strain of H3N2 which harboured a new type of mutation. Scientist Yoshihiro Kawaoka, University of Wisconsin–Madison professor of pathobiological sciences, says that this strain is resistant to baloxavir, can be passed between people, and can make people just as sick as the non-mutated strain.

Kawaoka and his colleagues have explained this in a study published November 25, 2019, in the journal Nature Microbiology. The study examined the effects of baloxavir treatment on influenza virus samples that were collected from patients both before and after treatment.

“We sequenced the entire viral genome of the 11-year-old boy with drug sensitive influenza virus (before treatment) and the sample from the girl that is drug resistant,” says Kawaoka. “Out of 13,133 nucleotides, there was only one nucleotide difference between the two.”

To summarise, the virus collected from the girl was differentiated from her brother by a single mutation – one change in one letter among over 13,000 within the genetic code of the virus.

“It tells you the virus acquired resistance during treatment and transmitted from brother to sister,” Kawaoka explains. 

Baloxavir is a type of antiviral drug that targets the system flu viruses use to copy their genetic material inside the host. Japan, Hong Kong, and the United States first licensed the drug in 2018 and 2019, and it represents 40% of the market share of influenza drugs in Japan. It will soon be licensed in 20 more countries.

Kawaoka noted that clinical trial data on the drug showed that although it is safe, the emergence of drug resistance was identified even at that early stage.

A previous study in paediatric patients revealed that the mutation appeared in samples collected from almost 1 in 4 of the 77 participants who were treated with baloxavir. 

“Baloxavir-resistant viruses emerge with a relatively high rate in kids” says Kawaoka, also a professor of virology at the University of Tokyo. 

The team were interested in understanding the properties of H3N2 and H1N1 viruses both before and after treatment with baloxavir. They set up a system to collect respiratory samples from patients both before and after they were treated with the drug during the flu season of 2018-2019.

For H1N1 influenza, the team tested 74 samples from patients before treatment (10 adults and 64 children), and 22 samples from patients both before and after treatment (7 adults and 15 children). No instances of mutation were found in any of the samples provided before the treatment, but after the treatment the mutation was found in one adult and four children – around 23% of patients.

For H3N2, 141 patient samples were tested before treatment (40 adults and 101 children), and from those samples two children possessed the mutation. 16 patient samples were taken before and after treatment (4 adults and 12 children), and there were no mutations found in adult samples, but four of the child samples had the mutation.

Viruses that gain mutations such as drug resistance may often sacrifice their ability to survive and spread among their hosts. The researchers grew mutant viruses in cell culture in order to see if this was the case with the baloxavir-driven mutation, and found that it grows just as well as the non-mutated form.

The mutated viruses were then tested in hamsters, and the researchers discovered that once the virus mutates, that mutation continues to be copied as the new virus grows.

When the viruses were tested in ferrets, the team found that the mutated form was capable of spreading from infected animals to healthy ones. Not only that, but the severity of the illness was similar to the non-mutated form.

Although the mutation is unlikely to lead to widespread resistance, Kawaoka believes that it could become a problem among family members and in facilities such as hospitals and nursing homes. Although children are particularly prone to viral mutation with baloxavir treatment, it appears to occur less frequently in adults, and quickly reduces the amount of virus in the systems of treated patients. Kawaoka believes that baloxavir is a good drug for adults.

And, he explains, patients with H1N1 or H3N2 that do develop resistance to baloxavir with treatment still do respond to other virus-fighting drugs. 

“The drug resistant virus does transmit but there are so many influenza viruses worldwide and only a small population will be treated with this drug,” Kawaoka says. “The vast majority remain drug sensitive.”

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