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Tamiflu resistance in seasonal influenza could thwart national pandemic plans

The cornerstone of most national pandemic preparedness plans revolves around the use of the antiviral drug Tamiflu, a neuraminidase inhibitor. Nations have been dutifully stockpiling the drug in massive quantities, keeping it in climate-controlled facilities guarded by armed military personnel.

But just as Hitler’s Wehrmacht took a Sunday drive around Belgium’s Maginot Line (pictured) in World War II, influenza appears to be ready to drive around the fixed fortifications of Tamiflu that have been constructed by national governments to combat an eventual influenza pandemic.

The Canadian Press’ Helen Branswell has written an excellent story on the sudden appearance of Tamiflu-resistant H1H1 across the European continent, as well as in Canada. The story appears at the bottom of the blog; but first, a little ru-ru (a punch line to a very, very funny joke).

We have known for years that H5N1 was slowly gaining Tamiflu resistance in some areas, most notably Egypt. We have also known that about 3% of Japanese seasonal Influenza B had shown some Tamiflu resistance.

What I don’t think we knew was that H1N1 was showing a markedly increased resistance to Tamiflu, and we did not know the CDC was actually tracking and cataloguing those resistance markers. Good for them; that is reassuring news. But if we are seeing a measurable, quantifiable increase in Tamiflu resistance in seasonal flu, we are doubtless able now to take a swag at the day that Tamiflu is no longer viable for influenza treatment of most – if not all – Type A influenzas.

Simply put: Tamiflu could go the way of Amantadine and Rimantadine, two antivirals that, once upon a time, went after the M2 protein outercoat of the flu virus, keeping it from dissolving  – until their effectiveness ran out and influenza A viruses became immune to the drugs.

The fact that Influenza A basically no longer responds to amantadine and rimantadine is unknown by a shockingly high number of American doctors, who apparently still get their updates on the effectiveness of medicine from the Saturday Evening Post. An excellent article from CIDRAP News details the unexplained continued mass prescription of M2-class antivirals to treat seasonal influenza by ignorant doctors – despite warnings from the CDC that such prescriptions are worthless. (Edited by me, the complete article can be found at: http://www.cidrap.umn.edu/cidrap/content/influenza/general/news/jan2408antivirals-jw.html

Older flu drugs still used, against CDC advice

Jan 24, 2008 (CIDRAP News) – A recent survey suggests that about a quarter of primary care physicians (PCPs) were still prescribing older antiviral drugs for influenza during the last flu season, despite a federal warning to avoid them because of viral resistance, according to the Centers for Disease Control and Prevention (CDC).

In the survey of 730 physicians in four states, 26.4% reported prescribing amantadine or rimantadine to some patients in the 2006-07 flu season, according to the report in the CDC's Morbidity and Mortality Weekly Report. In January 2006 the CDC recommended that physicians stop using the two drugs because of high rates of resistance in circulating strains of influenza A.

The survey also showed that 69% of physicians ordered influenza tests for patients with influenza-like illness (ILI), and most of those ordered rapid antigen tests. Because rapid tests miss up to 30% of flu cases, the CDC says, physicians should exercise clinical judgment when using them.

Antiviral prescriptions
About 54% of the physicians reported prescribing antiviral drugs to at least some patients, with the rates ranging from 41.7% for pediatricians to 66.4% for family practice.

The most commonly prescribed antiviral by far was oseltamivir (Tamiflu), a neuraminidase inhibitor, used by 87% of the respondents. The two older drugs, amantadine and rimantadine, were prescribed by 17.8% and 8.7%, respectively. Zanamivir (Relenza), the other licensed neuraminidase inhibitor, was prescribed by 5.3% of the physicians.

Amantadine use was highest in New Mexico (43.2% of doctors), followed by Minnesota (16.6%) and New York (14.2%), the report says. Respondents in Connecticut reported the highest use of oseltamivir (94.7%), followed by those in Minnesota (90.2%), New York (85.8%), and New Mexico (70.3%).

In light of the findings on antiviral prescribing, the CDC article calls for more education efforts to make PCPs aware of current treatment recommendations. The report also says that pediatric patients treated with oseltamivir should be watched closely for signs of neuropsychiatric effects, such as hallucinations, delirium, or abnormal behavior. Such effects have been reported in a number of young patients in recent years, mostly in Japan.

Influenza testing
A large majority—69%—of the responding doctors reported using a flu test during the flu season. The use of testing ranged from 87.1% of the Minnesota doctors to 55.0% of those in New Mexico. Of those who ordered tests, 88.0% used rapid antigen testing, 18.8% ordered viral culture, and 6.3% ordered serologic tests.

The CDC says many rapid antigen tests for flu can be handled by nonlaboratorians in office settings, which may explain why many physicians choose them. "However, the benefit of obtaining results quickly must be weighed against the low sensitivities of the tests (70%-75%)," the report says. Consequently, "PCPs should use clinical judgment and check reports of weekly influenza activity from CDC and their individual state health departments to guide their clinical decisions."

OK, so we know we need to slap some New Mexican doctors silly, plus a few in New York and Minnesota. We also know that only 69% of doctors everywhere are actually testing patients for influenza. Most of the 69% served up the rapid test, which is only 70% effective at diagnosis. So what that means is that out of every 100 people who suffer flu-like symptoms, only 69 are tested, and of those, only 48 have reliable test results. Someone in statistics test me on this, please.

It also means there are gaping holes in surveillance in this nation, when it comes to – well, when it comes to everything. We’re not testing properly for influenza. We’re not testing for MRSA. We’re not testing for adenovirus, especially Ad14. No wonder, then, that a Tamiflu-resistant H1N1 might crop up without anyone noticing!

There has always been a hunch among flu researchers that, in exchange for Tamiflu resistance, there might be a corresponding drop in a Tamiflu-resistant flu virus’s ability to transmit person-to-person. A quid pro quo, a “You scratch my nose and I’ll scratch yours,” a get-along-to-go-along virus mutation.

But as Lee Corso would say, “Not so fast, my friend!” The study, reported so well by Ms. Branswell, suggests that Tamiflu-resistant H1N1 is just as virulent and just as communicable as regular H1N1. So throw that theory out the window!

It is also quite interesting that while Tamiflu is encountering resistance via the position H274Y genetic marker (on the HA strand of RNA), Relenza, another neuraminidase inhibitor, is not suffering resistance. We know Relenza is essentially worthless as a treatment for severe H5N1, because you cannot inhale the drug deeply enough into the lungs to be effective. But as I have maintained over and over again, Relenza will make a dang skippy prophylactic against bird flu!

Nations, therefore, would do well to try and determine the prophylactic Relenza dosage for first responders and law enforcement types, and think seriously about expanding their Relenza strategery, as well as using Tamiflu to treat ill essential workers.

Tamiflu and Relenza are the only arrows in the quiver today to fight an eventual influenza pandemic. Other antiviral trials have failed recently (Bio-Cryst). Despite suggestions that science and medicine look to other strands in the flu’s RNA nucleus for disruption of the virus, precious little research has been done on that topic to date.

It is abundantly clear that Tamiflu’s life expectancy as an Influenza A inhibitor is finite. How finite that is requires extensive research and extensive data-gathering. It also means extensive surveillance and sample-collecting. So those county and state health departments need to be ready to gear up for a pretty huge swabbing effort.

All this points back to a quote that Dr. C. Everett Koop, former Surgeon General of the US, said last year.  He said: "We're fighting today's pandemic with the same tools we had 100 years ago." 

How about we drop this pretense of finding magic bullets, and just get on with the task of teaching hundreds of millions of people how to wash their hands correctly, how to cough or sneeze into their arm or sleeve or tissue, and how to keep a respectable distance from strangers?  Teaching these simple items is the absolute most cost-effective thing we can do  today.  Vaccines will be late to the dance and not reproducable until we have ID'ed the pandemic strain.  Antivirals will be iffy, depending upon when the pandemic strikes and whether the virus might have reassorted with a Tamiflu-resistant strain of existing Influenza A (although Egypt's Tamiflu-resistant H5N1 hasn't reassorted with a human strain that we are aware of, yet we know it is being given Tamiflu resistance from somewhere). 

Tamiflu-resistant flu viruses found in Canada

Provided by: Canadian Press
Written by: Helen Branswell, Medical Reporter, THE CANADIAN PRESS
Jan. 29, 2008

TORONTO - Canada's National Microbiology Laboratory is reporting a high level of Tamiflu resistance among H1N1 viruses circulating so far this flu season in this country, one of a number of labs to see a phenomenon that is unsettling influenza experts.

Nearly 10 per cent of H1N1 viruses tested so far this year by the Winnipeg lab are resistant to the drug, a cornerstone of pandemic planning for many countries around the globe. In the past, fewer than one per cent of circulating human flu viruses were thought to be resistant to Tamiflu.

"That's quite a surprise," the lab's scientific director, Dr. Frank Plummer, said, noting the resistance mutation spotted in the Winnipeg testing is the same one that has been reported over the past few days from Norway, several other European countries and the United States.

Eight of 81 H1N1 viruses tested carry the H274Y mutation - one each from British Columbia and Newfoundland and Labrador, and six from Ontario. Plummer said that total includes one virus (from British Columbia) recovered from a child who is believed to have been infected in Sudan.

His surprise is shared by experts with the World Health Organization's Global Influenza Program, which convened a teleconference of about 50 scientists from leading influenza laboratories around the world Tuesday to try to get a handle on how far this virus has spread, how common it is in places where it is being found and what is driving the spread.

Dr. Frederick Hayden, a leading antiviral expert working at the WHO, said the resistance virus has been reported over a broad geographic range, both in terms of countries and within countries themselves.

"We do know that again within the countries that have the information, it's not just focal pockets. There are multiple sites, for example, within France or within Norway where this has been detected," he said from Geneva.

The United States has reported that 5.5 per cent of tested H1N1 viruses there are resistant to the drug. European countries known to have found resistant viruses include Norway, Denmark, France and the United Kingdom. Hayden suggested more countries have found these viruses, but said he wasn't at liberty to name names.

Perplexingly, Japan - the country that uses more Tamiflu by far than any other in the world - has not found any of these resistant viruses this flu season, Hayden said.

Reports worldwide still number in the "few dozens." But that is enough to send up red flags, especially given that in all of the cases where details are known, people who caught the virus hadn't taken Tamiflu.

It wouldn't be startling to see people who've used the drug shedding viruses that are resistant to it. Like antibiotic resistance, resistance to antiviral drugs can develop in people who use them, though rates of drug-triggered resistance are low with Tamiflu.

But it had been thought that viruses that acquired this H274Y resistance mutation would pay for that gain with a corresponding loss in their ability to transmit. The belief was that if they developed in someone using Tamiflu, they would be unlikely to infect contacts of that person and start to circulate more widely - in essence, that they would be too weak to compete with regular flu viruses in the race to infect human respiratory tracts.

These recent findings suggest the drug is more vulnerable to the development of drug resistance than had been previously thought, experts fear.

"This mutation is not going to affect the fitness of the viruses as much as we thought," said Jennifer McKimm-Breschkin, a virologist with Australia's Commonwealth Science and Industrial Research Organization in Melbourne.

McKimm-Breschkin was one of the scientists involved in the discovery of Tamiflu's competitor, Relenza. Though the two drugs are in the same class, Relenza is still effective against viruses with the H274Y mutation.

"We're now seeing the ability of this virus that we thought would not have the ability to compete (with unmutated viruses) spreading globally," she said, suggesting that doesn't bode well if H5N1 avian flu starts a pandemic. The same mutation creates Tamiflu resistance in H5N1 viruses.

Hayden said the appearance of resistant H1N1 viruses across such a broad expanse "does raise a lot of questions."

Dr. Joe Bresee, chief of flu epidemiology and prevention at the U.S. Centers for Disease Control, questioned Monday whether there was a true rise in the number of resistant viruses.

Bresee cautioned that increased influenza surveillance prompted by concerns over the H5N1 virus may be turning a spotlight on something that always existed but went unnoticed in the past.

Hayden disagreed, saying an international network of antiviral experts has been watching for this resistance pattern but it has only been found rarely.

"Basically it was present at very low frequencies, less than a half per cent. In most studies, (it was) not even detected. So I think this is a new phenomenon and one that we need to understand better."

He said work is already underway to try to catalogue cases and to sequence resistant viruses to see if their genomes hold clues to how the resistance arose.