Chinese farmers, acting with the approval and encouragement of government officials, have tried to suppress major bird flu outbreaks among chickens with an antiviral drug meant for humans, animal health experts said. International researchers now conclude that this is why the drug will no longer protect people in case of a worldwide bird flu epidemic.
China's use of the drug amantadine, which violated international livestock guidelines, was widespread years before China acknowledged any infection of its poultry, according to pharmaceutical company executives and veterinarians.
Since January 2004, avian influenza has spread across nine East Asian countries, devastating poultry flocks and killing at least 54 people in Cambodia, Thailand and Vietnam, but none in China. World Health Organization officials warned the virus could easily undergo genetic changes to create a strain capable of killing tens of millions of people worldwide.
Although China did not report an avian influenza outbreak until February 2004, executives at Chinese pharmaceutical companies and veterinarians said farmers were widely using the drug to control the virus in the late 1990s.
The Chinese Agriculture Ministry approved the production and sale of the drug for use in chickens, according to officials from the Chinese pharmaceutical industry and the government, although such use is barred in the United States and many other countries. Local government veterinary stations instructed Chinese farmers on how to use the drug and at times supplied it, animal health experts said.
Amantadine is one of two types of medication for treating human influenza. But researchers determined last year that the H5N1 bird flu strain circulating in Vietnam and Thailand, the two countries hardest hit by the virus, had become resistant, leaving only an alternative drug that is difficult to produce in large amounts and much less affordable, especially for developing countries in Southeast Asia.
"It's definitely an issue if there's a pandemic. Amantadine is off the table," said Richard Webby, an influenza expert at St. Jude Children's Research Hospital in Memphis.
Health experts outside China previously said they suspected the virus's resistance to the medicine was linked to drug use at poultry farms but were unable to confirm the practice inside the country. Influenza researchers at the U.S. Centers for Disease Control and Prevention, in particular, have collected information about amantadine use from Chinese Web sites but have been frustrated in their efforts to learn more on the ground.
China has previously run afoul of international agencies for its response to public and agricultural health crises, notably the SARS epidemic that began in 2002. China's health minister was fired after the government acknowledged it had covered up the extent of the SARS outbreak by preventing state-run media from reporting about the disease for months and by minimizing its seriousness.
In interviews, executives at Chinese pharmaceutical companies confirmed that the drug had been used since the late 1990s, to treat chickens sickened by bird flu and to prevent healthy ones from catching it.
"Amantadine is widely used in the entire country," said Zhang Libin, head of the veterinary medicine division of Northeast General Pharmaceutical Factory in Shenyang. He added, "Many pharmaceutical factories around China produce amantadine, and farmers can buy it easily in veterinary medicine stores."
Zhang and other animal health experts said the drug was used by small, private farms and larger commercial ones. Amantadine sells for about $10 a pound, a fraction of the drug's cost in Europe and the United States, where its price would be prohibitive for all but human consumption.
Two months before China first reported a bird flu outbreak in poultry to the World Animal Health Organization in February 2004, officials had begun a massive campaign to immunize poultry against the virus. They have now used at least 2.6 billion doses of a vaccine.
But researchers in Hong Kong have reported that the H5N1 flu virus has been circulating in mainland China for at least eight years and that Chinese farms suffered major outbreaks in 1997, 2001 and 2003. Scientists have traced the virus that has devastated farms across Southeast Asia in the last two years to a strain isolated from a goose in China's Guangdong province in 1996.
The U.N. Food and Agriculture Organization has long recommended that countries try to eradicate infectious animal diseases by slaughtering infected flocks and increasing safety measures on farms. Last year, the FAO also suggested that countries consider vaccinating their poultry against bird flu. But the guidelines never recommended the use of antiviral drugs such as amantadine, which, unlike vaccination, has been proven to make viruses resistant, officials said.
In 1987, researchers at a U.S. Department of Agriculture laboratory demonstrated that bird flu viruses developed drug resistance within a matter of days when infected chickens received amantadine.
Still, a veterinarian with personal knowledge of livestock practices across China said Chinese farmers responded to the bird flu outbreak by putting the drug into their chickens' drinking water. The veterinarian asked that his name not be published because he feared for his livelihood.
"This would explain why we're seeing such high resistance levels," said Michael T. Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota. While various antibiotics have lost their effectiveness because of overuse, he said, the emergence of resistance to amantadine is unprecedented because it is an antiviral.
"This is the first example of an antiviral drug that was used for animal production that has major implications for human health," Osterholm said.
A popular Chinese handbook, titled Medicine Pamphlet for Animals and Poultry, provides farmers and livestock officials with specific prescriptions for amantadine use to treat chickens and ferrets with respiratory viruses. The manual, written by a professor at the People's Liberation Army Agriculture and Husbandry University and issued by a military-owned publishing company, prescribes 0.025 grams of amantadine for each kilogram of chicken body weight.
Farmers also use the drug to prevent healthy chickens from catching bird flu, giving it to their poultry about once a month or more often when the weather is liable to change and chickens are considered susceptible to illness, veterinary experts said. The antiviral is often mixed with Chinese herbs, vitamins and other medicine.
In the United States, amantadine was approved in 1976 by the Food and Drug Administration for treating influenza in adults. Amantadine and it sister drug, rimantadine, known collectively as amantadines, work by preventing a flu virus from reproducing itself. Both are now ineffective against the H5N1 strain.
International health experts stressed that amantadine could have been vital in stanching the spread of the bird flu virus in the early weeks of an epidemic.
Now, the only alternative is oseltamivir and closely related zanamivir, which stop the flu virus from leaving infected cells and attacking new ones. Oseltamivir is easier to use and has far greater sales.
"Amantadine is the cheapest drug against flu," said Malik Peiris, an influenza expert at the University of Hong Kong. "It is much more affordable for many countries of the region. Now, it is clearly no longer an option."
Special correspondents Ling Jin in Beijing and K.C. Ng in Hong Kong contributed to this report.