TORONTO - As flu season approaches, public health authorities will be keeping an anxious eye on one family of flu viruses to see if an unwelcome phenomenon that cropped up last winter will stage a repeat performance.
To the surprise and dismay of scientists and governments, H1N1 viruses that were resistant to Tamiflu suddenly appeared in high numbers in Northern Europe.
Testing elsewhere has since shown viruses resistant to the key drug -- whose generic name is oseltamivir -- have spread to North and South America, the Caribbean, Africa, parts of Asia, Australia and New Zealand.
North American officials say they will quickly test for resistance once the northern hemisphere flu season begins and H1N1 viruses start to spread. And in the U.S. at least, authorities are entertaining the possibility they may have to tweak the advice they give doctors on which flu drugs to use should -- as most expect -- the problem recur.
"We are thinking about the various sorts of scenarios that might occur," says Dr. Tony Fiori, who develops antiviral drug and vaccine policy in the influenza division of the U.S. Centers for Disease Control in Atlanta, Ga.
"It's hard to imagine we'd be at a point of telling people not to use oseltamivir. We might look at possibilities like pushing people towards using zanamivir when they can, since there hasn't been resistance seen to that."
Zanamivir is the generic name for GlaxoSmithKline's Relenza, which, like Tamiflu, belongs to a class of drugs called neuraminidase inhibitors.
Both drugs block the ability of flu viruses to spread from infected cells to healthy ones, making symptoms less severe and speeding recovery.
Tamiflu producer Hoffman-La Roche intends to get into the surveillance effort, mounting a multi-country study to figure out how much resistance is out there, whether the resistant viruses cause milder disease and what happens clinically to people infected with the resistant viruses who take Tamiflu.
"So in a very short space of time we hope to get a picture on the frequency, if the strain does re-emerge in the northern hemisphere," says Dr. David Reddy, Roche's pandemic influenza task force leader.
"We don't know what the northern hemisphere will bring," he said, expressing an optimism not supported by the resistance pattern seen in H1N1 viruses during the southern hemisphere flu season.
Canada too will be testing early so it can inform the medical community of which kinds of flu viruses are causing the most disease and whether they are resistant to Tamiflu.
But the Public Health Agency of Canada is unlikely to issue across-the-board recommendations, because the drug still works against two other types of flu viruses -- the other influenza A subtype, H3N2 as well as influenza B viruses -- and because it's unlikely there will be one single pattern of illness across the entire country.
"This season's going to be a little bit more complicated than previous seasons. And I think one is going to have to . . . at the local and provincial level take more of a risk-assessment, risk-management approach based on what strains of flu are circulating," says Dr. John Spika, acting director general of the centre for immunization and respiratory infectious diseases.
"Are they H1N1 predominantly or are they H3N2? And, based on the available information, then decide whether or not it is appropriate to use the oseltamivir or potentially adamantane drugs. And how zanamivir fits in with that as well."
The adamantane drugs are older flu drugs that have their own resistance problem. In early 2006 both the CDC and the Public Health Agency told doctors not to use the drugs when it was found over 90 per cent of H3N2 viruses were resistant to them.
As for Tamiflu and Relenza, neither drug has done remarkably well in the seasonal flu market except in Japan, where Tamiflu is widely used.
So in some ways, the resistance problem isn't likely to have a huge impact on how doctors treat their patients who contract influenza -- so long as resistance doesn't also emerge in either or both of H3N2 and influenza B viruses, experts say.
"That's what everybody's holding their breath on," says Dr. Allison McGeer, an influenza expert at Toronto's Mount Sinai Hospital.
"If we see H3N2 resistance at significant levels, that's the catastrophic bridge."
But Roche has sold vast quantities of Tamiflu to governments and corporations for pandemic influenza stockpiles. Discovering the vulnerability of the main drug weapon in pandemic arsenals has unsettled governments, public health officials and flu researchers.
"The bigger issue is loss of confidence overall and how it will shape the stockpiling," says McGeer, who says governments may be less willing to lay in stockpiles when the next generation of flu drugs hit the market for fear the Tamiflu phenomenon will repeat itself.
It is a fact of nature that bacteria and viruses will eventually evolve to become resistant to drugs. But research had suggested that the changes flu viruses would have to undergo to become resistant to Tamiflu would so weaken them that they would lose the capacity to spread from person to person.
Last winter nature delivered a double whammy: Not only had resistance emerged -- and emerged in places where it was clear misuse wasn't responsible -- but the resistant viruses spread easily.
That demolished the theory that resistant viruses were less biologically fit viruses, at least so far as H1N1 viruses are concerned.
"I am really staggered that this H1N1 virus has been able to spread as it has," says Jennifer McKimm-Breschkin, a flu antiviral expert at Australia's Commonwealth Scientific and Industrial Research Organization and a member of the team that developed Relenza.
McKimm-Breschkin, who receives no royalties from sales of the drug, thinks in light of the resistance problem, public health agencies should be telling doctors to use Relenza this flu season.
"The drugs are expensive. So if you have one drug that you know is effective against all (flu) strains, surely the logical prescribing pattern is to prescribe that drug."
But she thinks officials would be reluctant to issue that kind of recommendation, because of the lion's share position Tamiflu holds in most pandemic drug stockpiles.
"It is a politically sensitive issue because of the stockpiling. And governments don't want to alarm people that the stockpiles may not be useful because the bird flu still remains sensitive," McKimm-Breschkin says, referring to the dangerous H5N1 strain killing poultry and occasionally people in parts of Asia and Africa.
Other experts say the Tamiflu situation doesn't merit the same response as the adamantane drug resistance problem did. For one thing, at least in North America, the Tamiflu resistance rates were lower last winter -- 26 per cent in Canada, and 11 per cent in the U.S. And for another thing, H1N1 viruses generally cause milder flu than H3N2 viruses.
Fiori says there is another important distinction between the two situations.
"I think what makes it somewhat different from the adamantane situation of a couple of years ago is that we had a good drug -- perhaps even a better drug -- in reserve at that point," he says, referring to Tamiflu."And we don't at this point. We don't really have that sort of option here."
