Newly introduced flu drug baloxavir contributing to rising threat of antiviral resistance, say health experts

The rate of emergence of baloxavir-resistant viruses is high and the resistant viruses transmit and cause disease in humans, warns the research team


                            Newly introduced flu drug baloxavir contributing to rising threat of antiviral resistance, say health experts

The most recent influenza drug to enter the US market -- baloxavir -- is no longer effective in treating a certain population of flu viruses. The drug is already contributing to the rising threat of antiviral resistance, claim scientists from the University of Wisconsin-Madison. The viruses resistant to the drug is as dangerous as the sensitive ones, and are capable of passing infection from person to person, they add.

Developed and licensed in Japan, baloxavir is considered to be a highly effective drug: it can kill the virus faster than the current crop of medications. The US Food and Drug Administration (FDA) had approved the drug on October 24, 2018. Baloxavir, which goes by the brand name Xofluza in Japan, was shown to alleviate flu symptoms in 54 hours.

"The new drug is safe, it went through phase three and was approved safety-wise, but even during clinical trials, the emergence of drug resistance was identified," Yoshihiro Kawaoka, the lead author explains.

The resistance is driven by the virus, which is known to constantly change its form, say experts. The flu virus is capricious: they change so much that they sometimes no longer respond to antivirals, including baloxavir. An earlier study has provided evidence that some patients do not respond to the treatment, after the virus grew resistant to the medication.

"The rate of emergence of baloxavir-resistant viruses is high and the resistant viruses transmit and cause disease in humans," Kawaoka told MEA WorldWide (MEAWW).

Known to changing its form constantly, the flu virus is capricious, say experts. They change so much that sometimes they become resistant or no longer respond to antivirals, including baloxavir. (CDC/Michael Shaw, Doug Jordan)

In the US, baloxavir is the latest tool to fight flu infections and it is in this context that resistance to drug is worrying. This year the flu season in the US has had an earlier start than usual. So far, the Centers for Disease Control and Prevention (CDC) has reported a total of 393 influenza-associated hospitalizations between October 1, 2019 and November 16, 2019.

As of Friday, the CDC reported widespread flu in five states: Alabama, California, Louisiana, Nevada and South Carolina. High levels of flu were reported in seven states — Alabama, Arkansas, Georgia, Mississippi, Nevada, South Carolina and Texas — plus Puerto Rico.

To understand how the resistant virus fares, Kawoka and team studied two patients in Japan. They report that an 11-year old boy who was diagnosed with influenza, a strain called H3N2, was prescribed baloxavir. Though he initially felt better, his fever returned after a few days. And two days later, his 3-year-old sister was also diagnosed with H3N2 influenza.

Upon further analysis, the team found that the boy had a different version of the virus before and after treatment with the drug. The difference was that post treatment, the virus showed a mutation, becoming resistant to baloxavir. The same version was also found in the sister. "It tells you the virus acquired resistance during treatment and transmitted from brother to sister," Kawaoka explains.

A previous study evaluating the drug in pediatric patients also showed the same mutation in the samples collected from nearly one in four of the 77 children enrolled who were also treated with baloxavir.

"Baloxavir-resistant viruses emerge with a relatively high rate in kids," says Kawaoka. When the team studied patients before and after they received the new drug during the 2018-2019 flu season, they found similar results, implying that the drug was driving resistance in influenza viruses.

In the US, the flu season has had an earlier start than usual, being more prominent in the South and in the West, according to the Centers for Disease Control and Prevention (CDC). So far, the CDC has reported a total of 393 influenza-associated hospitalizations between October 1, 2019 and November 16, 2019. (Getty Images)

Gaining resistance does give the virus an edge but there are costs to this too. For instance, the virus could lose its ability to survive or spread well among hosts. Their tests showed that the resistant version grew just as well as their sensitive counterparts. Further tests revealed that the resistant virus was capable of transmitting from infected animals to healthy ones, showing similar severity of illness.

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.

Patients who develop resistance to baloxavir should not lose hopes soon as they can still 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. The vast majority remain drug sensitive." says Kawaoka. 

"Because baloxavir inhibits virus growth by a different mechanism than that used by the other approved influenza drugs (e.g., Tamiflu), combination therapy with baloxavir and Tamiflu should be explored for these patients," Kawaoka told MEAWW. 

The findings were published in Nature Microbiology.

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