10 July 2020

Antiviral protects against flu, but drug resistance is a worry

Clinical

A pharma-funded Japanese study shows the antiviral baloxavir technically works as a prophylactic, but widespread use of the drug also increases the risk of creating a drug-resistant virus.

In the study, which was funded and designed by baloxavir manufacturer Shionogi and published in the NEJM this week, people were identified as having influenza through a PCR test and then their household was randomly assigned to receive either the antiviral baloxavir as a prophylactic treatment or a placebo.

In general, kids aged around 12 were the infectious agents in the study and their older relatives were the ones receiving the prophylactic protection. The circulating strains of influenza were mostly A(H1N1)pdm09 and A(H3N2).

The trial of around 750 people found that a single dose of baloxavir reduced the risk of a non-infected person catching influenza from an infected household contact by 87% over 10 days compared with placebo. The adverse event rate was similar in the baloxavir and placebo groups.

The study appeared to support the use of baloxavir to suppress influenza outbreaks within households, except for one major problem – the emergence of drug resistant influenza in some study participants.

Mutations that made influenza less susceptible to baloxavir were detected in 15 of 374 participants (4%) in the baloxavir group and transmission could not be ruled out.

“Public health concerns are that viruses with reduced susceptibility to baloxavir can emerge more frequently in baloxavir-treated children and may be associated with prolonged illness, longer viral shedding, and rebound in influenza virus levels in the upper respiratory tract and that limited person-to-person transmission can occur,” said Professor Timothy Uyeki, the chief medical officer at the Influenza Division of the CDC wrote in the accompanying editorial.

Professor Uyeki said the “large benefit of postexposure prophylaxis with single-dose baloxavir in reducing the transmission of influenza should be considered in the context of several issues”, including the fact that this antiviral was not approved for prophylatic use in the US.

Unlike Japanese patients, US patients did not typically seek medical care for influenza early in the disease, which meant there was limited scope for prophylactic treatment of household contacts.

Baloxavir was only recently registered in Australia and is not yet PBS listed.

It’s not approved for use as a prophylactic agent but is indicated for the treatment of uncomplicated influenza in patients aged 12 years of age and older who have been symptomatic for no more than 48 hours and who are otherwise healthy, or at high risk of developing influenza complications.

Dr Trent Yarwood, an infectious diseases physician based in Queensland, said drug resistance wasn’t the primary barrier to use of baloxavir; the real issue was the non-PBS listed drug was “crazy expensive” in Australia.

“Oseltamivir is actually also quite effective in reducing lab-confirmed influenza in contacts (relative risk reduction: 55%) but has the disadvantage of us needing to give a full course, instead of a single dose as in the baloxavir study,” said Dr Yarwood.

Oseltamivir wasn’t PBS listed either, but it wasn’t as expensive as baloxavir, he said. It could be used for prophylaxis in high-risk settings, such as nursing homes, but was not commonly used outside these settings, he said.

“The benefits are lesser in single households than in large institutions full of high-risk patients,” he said.

“If I had significant chronic lung disease or immunosuppression or was pregnant and someone in my house got influenza, I’d take tamiflu.”

NEJM 2020, 8 July (paper, editorial)

Editor’s note: This article was updated on 14 July to include comments from Dr Yarwood.

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