Everyone’s Wild About Tami

The outbreak of H5N1, the virus that causes avian influenza, on an English farm last week not only brought bird flu back to the front page, but demonstrated again America’s myopia about the disease. When H5N1 spread rapidly into Europe last winter, appearing in country after country, near-hysteria erupted and poultry sales plummeted. But as international health officials have said all along, the disease is much more easily contained and combated in highly developed countries with advanced veterinary services and laboratory technology. And in fact, the European outbreaks were quickly stamped out. The public then largely forgot about avian flu—especially in the U.S., which was unaffected—even though people in the developing world continued to contract it. Now, dying British turkeys have brought new attention to dying Asian people. But if Americans wait until chickens start dying of H5N1 in Maryland to realize that the battle against avian flu will probably be won or lost in Asia, the Near East, or Africa, it may well be too late.

But we have a national pandemic strategy, don’t we? Ironically, of all the money appropriated in last year’s panic over avian influenza, only a trickle helps fight H5N1 today. Most of it went toward a pharmacological security blanket—much like dealing with the energy crisis by building a Strategic Petroleum Reserve. For our public officials, last year’s favorite strategy was to buy truckloads of Tamiflu, the trade name of the antiviral drug oseltamivir. In fact, of the billions the Bush administration put into its pandemic preparedness plan in November 2005, about 90 percent was for vaccine research and stockpiling Tamiflu. Tamiflu was all the rage.

So, when last month the World Health Organization (WHO) reported that a new, Tamiflu-resistant strain of H5N1 had appeared in Egypt, it was not good news. It threatened to knock out what the New York Times called our “chief weapon” against H5N1. But that was not the full story, or it was at least a misleading way of telling it. Tamiflu is indeed the chief weapon in fighting the flu strain in people who have contracted avian flu from animals, but it is not the main weapon in fighting the battle against the virus itself in the animal kingdom where it currently rages (and where, we hope, it can be contained). As previous articles in this series have discussed, the global strategy pursued by the WHO, the Food and Agriculture Organization of the United Nations (FAO) and other organizations comprises a battery of approaches including early detection, culling, vaccination, isolation of farmed birds from wild species, and “compensation strategies” to pay poor farmers for animals that have to be killed. Tamiflu was the weapon of choice only once one had failed at the main objective: preventing a flu that is mainly an animal disease from infecting people through human-bird contact. It is only by infecting humans that the virus can undergo the process of genetic “reassortment” that would allow it to mutate into a pandemic strain directly passable from human to human.

The Tamiflu story has fallen through the cracks before. When President Bush presented his pandemic preparedness plan in November 2005, the WHO had already reported, earlier in the year, on Tamiflu-resistant strains of H5N1 found in Vietnam. And just a few months later, the WHO issued its “Advice on the use of Oseltamivir” [PDF], in which it stated that “there is no direct clinical trial evidence that shows that oseltamivir is effective in human H5N1 disease because such studies have not yet been conducted. Without such trials, the optimal dose and duration of oseltamivir treatment in H5N1 disease is uncertain and therefore doses of oseltamivir used for seasonal human influenza continue to be recommended.” (It was somewhat odd, then, that President Bush had promised to stockpile enough Tamiflu to treat a quarter of the U.S. population when nobody knew the right dosage.)

The only way to create vaccines and drugs against a specific pandemic-causing virus is to have the pandemic strain available to study—thus, after a pandemic has started. Even more striking, the month after Bush unveiled his plan, Dr. Anne Moscona of Cornell’s Weill Medical College wrote in The New England Journal of Medicine that “it is not surprising that many believe there should be a supply of oseltamivir in every medicine cabinet,” but pointed out that this fever for Tamiflu “is potentially dangerous” because of a vulnerability in the drug itself (not present in another drug of the same family, zanamivir). Among the facts brought forward by Moscona that never made it into the Tamiflu debate was that “several years ago, structural analysis predicted that aspects of the chemical structure of oseltamivir (not present in zanamivir) could facilitate the development of resistance mutations.” The molecular feature that led to this prediction was oseltamivir’s “bulky side chain,” which requires the formation of a “pocket” to allow it to bind to the active site. Several mutations can prevent this pocket from forming. Moscona cited Japanese studies in which 14 to 18 percent of children who had been treated for seasonal flu with oseltamivir showed a drug-resistant mutation. But so far, no patients treated with zanamivir have shown resistance mutations. She provided a fascinating molecular analysis, complete with animation.

No one at a political level seems to have found it interesting, however. Last March—well after Moscona’s article was published—Health and Human Services Secretary Mike Leavitt announced the government was buying 1.75 million courses of zanamivir, and 12.4 million courses of Tamiflu. Now, a Tamiflu-resistant strain of H5N1 has been found—again. But nobody can claim that we didn’t already know that stockpiling Tamiflu might not be enough.

The good news is that the new Egyptian strain of H5N1 that was resistant to oseltamivir was not resistant to zanamivir or amantadine, another antiviral medicine. But does that mean we are now going to start stockpiling those drugs too? Gargantuan costs and practical problems apart (zanamivir is more expensive and is harder to handle because it has to be inhaled), what the Egyptian cases underscore most is what scientists have said from the beginning: The only way to create vaccines and drugs against a specific pandemic-causing virus is to have the pandemic strain available to study—thus, after a pandemic has started. Meanwhile, in treating human beings who contract the disease directly from animals, medicine must rely on existing antiviral drugs, and work to develop new ones.

But expensive antiviral drugs are not plentiful in the developing world, particularly Asia, where the vast majority of human cases of avian influenza have occurred. A further tragic illustration of that fact came last month, with the death of another victim in Indonesia, a woman who had helped to slaughter sick chickens. Eighty-one people are confirmed to have contracted avian flu in Indonesia, of whom 63 have died. Of the 166 worldwide deaths that the WHO reports as laboratory-confirmed, none have been in a developed country.

It is ironic, then, that on the “Pandemic Planning Toolkit” website created for Tamiflu by Roche, its manufacturer, there is a notice at the foot of the page: “This site is intended for U.S. audiences only.” If you live in the developing world, you probably don’t have a pandemic toolkit. And while the “Pandemic Toolkit” tells U.S. audiences how to protect their organization or business, decide which employees to protect, and so on, it doesn’t say what you will do if the pandemic strain turns out to be immune to the drugs you have in your toolbox. I was unable to find on the website any mention of Tamiflu-resistant strains of H5N1. The section headed “What evidence supports Tamiflu activity against avian flu?” does not raise the issue.

Following a vaccination drive in Vietnam, in the first four months of 2006 there were no human deaths and only one outbreak among animals. The campaign involved 100,000 vaccinators, who were paid $3 a day. Despite what your inner conspiracy theorist may be thinking, there has been no sinister plot to hoodwink the American public into spending billions of dollars on Tamiflu. After all, the WHO has “urged countries with adequate resources to stockpile antiviral drugs nationally for use at the start of a pandemic.” The problem is that the countries currently most affected are precisely those that lack the wherewithal to do so. And in fact, the WHO recognizes that “on present trends, most developing countries will have no access to vaccines and antiviral drugs throughout the duration of a pandemic.” It is not surprising that Indonesia is displeased with providing viral samples that aid in the development of vaccines its poor might well be unable to afford. Will the developing world provide the key for an anti-flu drug that will be “for U.S. audiences only?”

To its credit, “Roche has offered to provide WHO with an international stockpile of oseltamivir… to treat the people in the greatest need at the site of an emerging influenza pandemic in an attempt to contain it.” [PDF] But that is only if and when a pandemic hits (which, of course, may involve a Tamiflu-resistant strain). It doesn’t help victims dying in the struggle against the disease today.

That struggle slipped from the front page last summer as the flu season waned and the pandemic failed to materialize. But it went right on, in places like Vietnam, where there has been heartening success in efforts to contain and beat back H5N1 in birds. In 2004-05, avian flu was rampant in Vietnam. Millions of birds and 42 people died. But following a massive campaign to vaccinate all of the country’s 220 million chickens, in the first four months of 2006 there were no human deaths and only one outbreak among animals. The vaccination campaign involved 100,000 vaccinators, who were paid $3 a day. The money was provided by U.S.AID. Compensation measures and changes to make poultry markets safer are also being pursued. [PDF]

The United States is contributing to the fight against avian flu overseas. At a December 2006 conference in Bamako, Mali, the U.S. pledged $100 million. (Less than the EU, at $131 million, and slightly more than Canada, at $92.5 million.) But these are small amounts compared with what the U.S. government has spent to prepare for a pandemic that hasn’t happened yet—$4 billion on Tamiflu alone. Meanwhile, the government Tamiflu sits in the toolbox and isn’t doing anything to fight avian flu right now. Indeed, H5N1 seems to be off the political agenda for the moment; the President didn’t even mention avian flu or pandemic preparedness in his State of the Union address. But if another spike in animal outbreaks, emergence of Tamiflu-resistance strains, or rising human deaths occur, I bet the message from Washington will be loud and clear: Buy zanamivir.

The legacy of last year’s furor over avian flu and the rush to show that the government had a plan is perhaps a widespread misperception that a pandemic strategy and drug stockpiles are protecting us from H5N1. In fact, of course, there is no human-to-human pandemic strain of that virus—yet. Preparing for its existence is not the same as trying to prevent its emergence. And although all the experts agree that a pandemic based on some virus, sometime, is inevitable, and preparedness is therefore important (and hence more zanamivir is a good idea), we really don’t want that virus to be H5N1. With a fatality rate of over 50 percent (70 percent in Indonesia) last year, avian flu was more than ten times as deadly as the 1918 flu. Thus, unglamorous as animal health programs and giving money to poor farmers in distant countries may be, U.S. lawmakers would be wise to send greater resources to the front now, if they want to avoid a more gruesome battle at home.