The flu virus could quickly become resistant to a drug developed to fight a possible pandemic, according to experts.
They warned that it would have to evolve just two genetic mutations for the antiviral to fail.
During the last century worldwide outbreaks have claimed a million lives or more – and the next one is due, say experts.
Favipiravir is an experimental medication approved in Japan for treatment of flu which is among a class of viruses that use genetic material called RNA, rather than DNA.
Now lab studies by a team at Imperial College London and Public Health England suggest it is not foolproof.
Study leader Professor Wendy Barclay, from the Department of Medicine and Action Medical Research Chair in Virology at Imperial, said: “We are alerting the world to the fact RNA viruses, like influenza, can readily adapt to their environment and evolve.”
She added: “While favipiravir could be a potentially important drug in a pandemic situation, resistance can emerge.”
Favipiravir is not currently licensed in the UK for the treatment of flu but has shown to be effective in clinical trials to date. It has the potential to be used if Tamiflu or other drugs became ineffective.
The findings, published in the journal PNAS, highlight how flu and other viruses could overcome these medications in the event of an outbreak.
It was previously believed this was impossible with laboratory, animal and clinical studies showing little evidence of resistance.
Favipiravir acts by targeting an enzyme called RNA polymerase with which flu makes copies of genes.
Clinical trials have shown the drug to be effective in treating flu in humans. It has also been tested against other RNA viruses, like ebola and chikungunya, which rely on the same type of enzyme to replicate, showing promise in animals.
So Prof Barclay and colleagues explored how flu might potentially develop to counter the drug.
Growing it with favipiravir in cell cultures uncovering a combination of two key mutations that enabled the virus to become resistant to the drug.
The first of the mutations caused a change in the RNA polymerase enzyme itself, blocking the drug’s effect.
It came at a cost for the virus and affected its ability to reproduce. But this loss of fitness was countered by the second mutation, which restored its ability to thrive and spread.
According to the researchers, it is unclear whether this combination of mutations could occur readily in viruses in the wild.
But their findings are the first to show a clear genetic mechanism by which resistance to the drug could potentially come about in flu strains around the world.
They add that while their work focused on flu, other research groups have reported the same mutation in chikungunya – another RNA virus which uses the same enzyme to replicate.
This suggests there may be a general mechanism by which other RNA viruses could become resistant to the drug.
Prof Barclay said: “Favipiravir is still an important drug and should be in the pipeline to be used in the event we need it, but we now know that viruses can develop resistance to it.
“We need to look out for these mutations and monitor for them, particularly if we are using this drug in outbreak situations and in patients that might have prolonged disease, as those are conditions where you might see resistance emerging.”
In the 20th century there were several serious flu pandemics. The Spanish Flu of 1918 was an unprecedented catastrophe. It is estimated up to 40 percent of the world became ill and more than 50 million people died.
Forty years later, the Asian flu of 1958 and 1959 had a global death toll as high as 2 million. In 1968, as many as a million people died from the Hong Kong flu.
Dr Maria Zambon, of Public Health England, said: “We have shown that resistance can emerge to this antiviral, which has not been shown previously and we need to factor this in to our pandemic preparedness.
“However, pandemic planning is multifaceted and includes vaccines, antivirals and good hygiene messaging.”
With pandemic flu, we cannot solely rely on our bodies’ ability to fight. A vaccine is our only real hope.
It could mean the difference between 20,000 people dying in the next one – or more than 20 million. Favipiravir is manufactured by Toyama Chemical Co.