Tamiflu resistance prompts Canada to change drugs in pandemic stockpile

Canada will adjust the mix of antiviral drugs in an emergency pandemic stockpile this year, a response to concerns over the vulnerability of the main drug in the arsenal, Tamiflu, to the development of viral resistance.

Supplies of the drug zanamivir sold as Relenza by GlaxoSmithKline will be beefed up in the national emergency stockpile, says Dr. Arlene King, the senior official responsible for pandemic influenza planning at the Public Health Agency of Canada.

As well, some stocks of an older flu drug, amantadine, will be added to the mix as an inexpensive extra. Scientists are studying whether using Tamiflu in combination with amantadine or a sister drug, rimantadine, will lower the likelihood flu strains will develop resistance to the few drugs currently marketed to treat influenza.

"I think the general view is that from a scientific perspective, greater diversification [of stockpiles] would be desirable," says King, director general of the public health agency's centre for immunization and respiratory infectious diseases.

"And as I've said, we've made that decision at a federal level."

King says discussions are still underway with provincial and territorial partners about whether to diversify the holdings of another stockpile, known as the national antiviral stockpile, where the bulk of Canada's pandemic flu drugs are held. The cost of building up and maintaining this stockpile is shared by the federal, provincial and territorial governments.

The national antiviral stockpile contains 55.7 million doses, enough to treat nearly 5.6 million people. Tamiflu, which is sold by Hoffman-La Roche, makes up 90 per cent of the holdings. Relenza accounts for the remaining 10 per cent.

Over the past five years a number of countries have stockpiled antiviral drugs mainly Tamiflu as a hedge against a feared flu pandemic. Tamiflu seemed to be a safe bet. Resistance to the drug was rarely seen. And laboratory studies suggested viruses that acquired resistance would be weakened and less able to spread from person to person.

To widespread dismay that theory was proven to be wrong in the winter of 2008. A resistant strain of influenza A virus of the H1N1 variety emerged in Northern Europe. The strain took off, rapidly spreading around the world.

U.S. weighs stockpile change

It is now the dominant strain of H1N1 viruses circulating. Almost 100 per cent of all H1N1 viruses tested in North America this winter were resistant to Tamiflu.

While other flu viruses including the worrisome H5N1 avian flu strain have not followed suit, the demonstrated vulnerability of the drug has prompted a number of governments to rethink how heavily their pandemic response plans lean on Tamiflu.

The U.S. Department of Health and Human Services is considering altering the composition of its national pandemic stockpile, which is 80 per cent Tamiflu to 20 per cent Relenza, according to Dr. Robin Robinson, director of the department's biomedical advanced research and development authority, which oversees pandemic preparedness.

And earlier this year Britain bought more than 10 million additional doses of Relenza, which to date hasn't developed the resistance problem seen with Tamiflu.

In Canada, Tamiflu makes up the lion's share of both the national emergency stockpile, which is maintained by the federal government, and the national antiviral stockpile.

The two stockpiles combined, along with other stores of flu antivirals held by governments, are estimated to contain enough antivirals to treat about a quarter of the population during a pandemic, King says.

That is within the range of the holdings of a number of similar countries, though Britain has stockpiled enough of the drugs to treat half its population.

Expiring drugs

Canada's national emergency stockpile, which is meant to act as a backup to the larger stockpile, currently contains 14 million doses, enough to treat about 1.4 million people. Relenza makes up just under 30 per cent of those supplies. King says an additional two million doses of antivirals will be added this year.

"This upcoming year we'll be purchasing a little bit more zanamivir and a little bit more amantadine," she says.

As well as adding drugs, authorities are now facing decisions about what to do with expiring drugs. Some of the supplies in the stockpiles have reached their expiration date or will do so this year and next.

"The replacement strategies right now are being considered and acted on by each of the jurisdictions that have expiring stock," King says.

In the national emergency stockpile alone, enough drugs to treat roughly 275,000 people will have reached their expiration date by 2010-2011. King says the federal government is looking at a variety of strategies, including approving an extension of Tamiflu's shelf-life.

Tamiflu was originally sold with a five-year shelf-life, but Roche has data showing the drug is still active at seven years.

As well, the company has offered governments the opportunity to reprocess expiring supplies of Tamiflu.

In an interview last year, Roche's Dr. David Reddy said the company could extract the active ingredient, insure its quality and purity and reformulate it into capsules.

That process is the equivalent of "resetting the clock on the drug," said Reddy, the company's pandemic influenza task force leader. He would not say what the process costs, but said it provides significant savings over the cost of buying new supplies of the drug.