Researchers Discover New Roche Flu Drug, Xofluza Can Drive Resistance In Influenza Viruses
In January this year, an 11-year old boy in Japan went to a medical clinic with a fever and was diagnosed with influenza
, a strain called H3N2, and was sent him 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. She, too, was diagnosed with H3N2 influenza
on February 8.
A detailed analysis of flu
samples collected from her and her brother show she was sickened by a strain of H3N2
harboring a new kind of mutation, one that Dr Yoshihiro Kawaoka, University of Wisconsin-Madison Professor of pathobiological sciences, says is resistant to baloxavir
, is just as capable of making people sick as the non-mutated version, and is capable of passing from person to person.
Dr Yoshihiro Kawaoka and his colleagues describe this in a study published today [Nov. 25, 2019] in Nature Microbiology
that examined the effects of baloxavir
treatment on influenza
virus samples collected from patients before and after treatment.
Dr Yoshihiro Kawaoka told Thailand Medical
News, "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. Out of 13,133 nucleotides, there was only one nucleotide difference between the two."
That means what distinguished the virus collected from the brother before treatment and the virus collected from the sister later was a single mutation, a single change in just one letter among the more than 13,000 found in the genetic code of the virus.
Dr Yoshihiro Kawaoka added, "It tells you the virus acquired resistance during treatment and transmitted from brother to sister."
) 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 percent 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 says.
He and his co-authors note 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, part of the virus's machinery that is targeted by the drug. 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.
Kawaoka explains, "
;Although the new drug was safe, it went through phase three and was approved safety-wise, 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.
Dr Kawaoka, also a professor of virology at the University of Tokyo added, "Baloxavir
-resistant viruses emerge with a relatively high rate in kids."
With these findings, Kawaoka and his research team in Japan were interested in understanding the properties of H3N2
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.
Initially, 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 percent of patients.
Whereas 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.
Many times, 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.
The team then tested the mutant H1N1
viruses in hamsters and learned that once the virus mutates, that mutation continues to be copied as new virus grows.
The researchers 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.
Although it's unlikely the mutation will lead to widespread resistance
around the world, Kawaoka says 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 says. And, he explains, patients with H1N1
that do develop resistance to baloxavir with treatment still do respond to other virus-fighting drugs.
Dr Yoshihiro Kawaoka added, "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. The vast majority remain drug sensitive."
Reference : Masaki Imai, Makoto Yamashita, Yuko Sakai-Tagawa, Kiyoko Iwatsuki-Horimoto, Maki Kiso, Jurika Murakami, Atsuhiro Yasuhara, Kosuke Takada, Mutsumi Ito, Noriko Nakajima, Kenta Takahashi, Tiago J. S. Lopes, Jayeeta Dutta, Zenab Khan, Divya Kriti, Harm van Bakel, Akifumi Tokita, Haruhisa Hagiwara, Naomi Izumida, Haruo Kuroki, Tamon Nishino, Noriyuki Wada, Michiko Koga, Eisuke Adachi, Daisuke Jubishi, Hideki Hasegawa, Yoshihiro Kawaoka. Influenza A variants with reduced susceptibility to baloxavir isolated from Japanese patients are fit and transmit through respiratory droplets. Nature Microbiology, 2019; DOI: 10.1038/s41564-019-0609-0