Tuesday, November 26, 2019

Nature MicroB.: Influenza A Variants with Reduced Susceptibility to Baloxavir Are Fit & Transmit Easily

Credit NIAID


The new, one-dose influenza antiviral Baloxavir marboxil (trade name Xofluza®) was approved in the United States just over a year ago (see FDA Approval Of Xofluza : A New Class Of Influenza Antiviral, but has been approved for use in Japan since early 2018.
This new class of antiviral is particularly welcome as the two existing neuraminidase inhibitors - zanamivir and oseltamivir (Tamiflu ®) - have been in use now for 20 years, and there are always concerns over creeping resistance.
In early March of this year, however, we saw several reports - and a Eurosurveillance Rapid Communications - on the detection of a small number of Baloxavir resistant flu viruses among patients in Japan - including three that had not received the antiviral drug.

In August, in EID Journal: H-2-H Transmission Of A(H3N2) with Reduced Susceptibility to Baloxavir, Japan, we looked at a study that reported:
During the 2018–19 influenza season in Japan, we detected 32 mutant influenza A(H3N2) viruses carrying various types of PA I38 substitutions, 4 of which were isolated from children < 12 years of age without prior baloxavir exposure
The researchers concluded:  `These 4 children were probably infected with mutant viruses acquired from hosts previously treated with baloxavir.'

A month later, in J.I.D: Replicative Fitness of Seasonal Influenza A Viruses with Decreased Susceptibility to Baloxavir, we saw a study that evaluated the biological fitness of baloxavir resistant viruses collected last winter, and found them only mildly impaired.

The spontaneous development of resistant viruses in a patient who is already receiving antiviral drugs is a known - but relatively rare (roughly 1%) - complication. Usually, these mutated viruses suffer a fitness penalty' - making them less likely to be transmitted on to others.
Usually, but not always.  
In 2008 we saw the old seasonal H1N1 flu virus go from being nearly 100% sensitive to Oseltamivir to almost 100% resistant (see CIDRAP On the CDC Change Of Advice On Tamiflu) in a matter of months.
It was only the unexpected arrival of a new, oseltamivir-sensitive H1N1 pandemic virus in the spring of 2099 - one which supplanted the newly resistant strain - that salvaged Tamiflu's usefulness against H1N1.
All of which brings us to a new report that characterizes the fitness and transmissibility of one of last winter's baloxivir-resistant viruses, and finds that a single amino acid change was all that was needed to make it fit, and easily transmissible in humans.

While the full report is behind a paywall (link below), we've a press release from the University of Wisconsin-Madison providing more details.

Influenza A variants with reduced susceptibility to baloxavir isolated from Japanese patients are fit and transmit through respiratory droplets
Masaki Imai,Makoto Yamashita, […]
Yoshihiro Kawaoka
Nature Microbiology (2019)
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. 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.

I've only included some excerpts from the press release (bolding mine), so follow the link to read it in its entirety.

New flu drug drives drug resistance in influenza viruses 
November 25, 2019 By Kelly April Tyrrell
On January 31, 2019, an 11-year old boy in Japan went to a medical clinic with a fever. The providers there diagnosed him with influenza, a strain called H3N2, and 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.

An 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 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.

He and 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.

“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.”


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 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 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.”
        (Continue . . . )

So far, these early reports of baloxavir resistance - while concerning - remain highly scattered.  We should get a much better idea of its scope and significance this winter, as enhanced surveillance is planned in both Japan and the United States.

Stay tuned.