Baloxavir, an antiviral medication for treatment of influenza A and influenza B, can prompt the development of a baloxavir-resistant version of the flu. Unfortunately, the baloxavir-resistant flu virus spreads from host to host just as readily as the nonresistant flu virus. And that’s not all the bad news. The baloxavir-resistant flu virus can replicate just as competently, and it can cause illness that is just as severe.

These findings come from a study led by Yoshihiro Kawaoka, PhD, a professor of pathobiological sciences at the University of Wisconsin-Madison and a professor of virology at the University of Tokyo. Kawaoka and his colleagues in Japan were interested in understanding the properties of H3N2 and H1N1 viruses—commonly circulating strains that cause illness in people—before and after treatment with baloxavir.

During the 2018–2019 flu season, they set up a system to collect respiratory samples from patients before and after they received the new drug. When the scientists analyzed these samples, they isolated a drug-resistant form of the flu, one that differed from the drug-susceptible form by only one nucleotide in the flu virus’ 13,133-nucleotide genome.

Additional details appeared November 25 in Nature Microbiology, in an article entitled, “Influenza A variants with reduced susceptibility to baloxavir isolated from Japanese patients are fit and transmit through respiratory droplets.” According to the article’s authors, the genomic mutation they found corresponds to a mutation in a protein that is part of the virus’s machinery targeted by the drug.

“Here we report the isolation of the influenza A/H1N1 2009 pandemic (A/H1N1pdm) and A/H3N2 viruses carrying an I38T mutation in the polymerase acidic protein—a mutation that confers reduced susceptibility to baloxavir marboxil—from patients before and after treatment with baloxavir marboxil in Japan,” wrote the article’s authors. “These variants showed replicative abilities and pathogenicity that is similar to those of wild-type isolates in hamsters; they also transmitted efficiently between ferrets by respiratory droplets.”

For H1N1 influenza, the researchers 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). There were no instances of mutation in any of the samples before treatment, but there were mutations in one adult and four children after, or in about 23% of patients.

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

The younger patients included a brother and sister. On January 31, 2019, the 11-year old boy had visited a medical clinic with a fever. He had been suffering a fever, and the clinic’s healthcare providers had diagnosed him with influenza, a strain called H3N2.

The boy was sent home with a new medication called baloxavir. For a few days, he felt better, but on February 5, despite taking the medication, his fever returned. Two days later, his 3-year-old sister also came down with a fever. The next day, on February 8, she was also diagnosed with H3N2 influenza.

An analysis of flu samples collected from her and her brother show she was sickened by a strain of H3N2 harboring the I38T mutation cited in the Nature Microbiology paper. As the paper’s authors point out, the I38T mutation is a new kind of mutation—one that gives rise to baloxavir-resistant flu virus.

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

Baloxavir is part of a new class of antiviral drugs that targets the machinery flu viruses use to copy their genetic material inside their human or animal hosts. It was first licensed in Japan, the United States, and in Hong Kong in 2018 and 2019. In fact, baloxavir represented 40% of the market share of influenza drugs in Japan during the 2018–2019 flu season. It will soon be licensed in 20 more countries, Kawaoka noted.

However, as he and his co-authors noted in the paper, clinical trial data on the drug revealed that some patients infected with either H3N2 or H1N1 influenza who took baloxavir developed a mutation at position 38 of the polymerase acidic protein. A previous study by another group showed that the particular mutation had not been described among 17,000 H3N2 virus samples catalogued prior to December 2018.

“The new drug went through Phase III and was approved safety-wise,” stressed Kawaoka, “but even during clinical trials, the emergence of drug resistance was identified.” In fact, a previous study in pediatric patients showed the mutation appeared in the samples collected from nearly 1 in 4 of the 77 children enrolled who were also treated with baloxavir.

“Baloxavir-resistant viruses emerge with a relatively high rate in kids,” Kawaoka added.

Often, viruses that gain mutations such as drug resistance sacrifice their ability to survive and spread well among their hosts. To understand whether this was true of the baloxavir-driven mutation, the researchers grew the mutant viruses in cell culture and learned it grows just as well as the non-mutated form.

They then tested the mutant H1N1 and H3N2 viruses in hamsters and learned that once the virus mutates, that mutation continues to be copied as new virus grows.

The team also tested the mutated viruses in ferrets and found the mutated form was capable of transmitting from infected animals to healthy ones. The severity of their illness from flu was also similar to the non-mutated form.

While it’s unlikely the mutation will lead to widespread resistance around the world, Kawaoka said it could become a problem among family members in close proximity, and in facilities like hospitals and nursing homes. And, while children seem particularly prone to viral mutation with baloxavir treatment, it appears to occur less frequently in adults. It also quickly reduces the amount of virus in the systems of treated patients. “It’s a good drug for adults,” Kawaoka pointed out.

And, he explained, 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, Kawaoka said. “Only a small population will be treated with this drug. The vast majority remain drug sensitive.”

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