Amy L. Becker  Staff Writer

Jun 20, 2005 (CIDRAP News) – International health agencies are questioning China about a report that the country has used a human antiviral drug in poultry for years, thereby causing the H5N1 influenza virus to become resistant to the drug.

The United Nations"e; World Health Organization (WHO) and Food and Agriculture Organization (FAO) are seeking more information from China about its reported use of amantadine in poultry, according to reports today by the Associated Press (AP) and Agence France-Presse (AFP).

The Washington Post reported on Jun 18 that Chinese farmers, with the knowledge and support of government officials, used amantadine on chickens as long ago as the late 1990s. The report called the drug use a violation of international livestock guidelines.

Researchers found last year that the strain of H5N1 found in Vietnam and Thailand had become resistant to amantadine. The Post story quoted health experts outside China as saying they had suspected the link between resistance and use in poultry. The story said international researchers now believe the Chinese use of the drug is to blame.

Amantadine and rimantadine make up an older class of antiviral medications used to reduce the impact of influenza. Some nations have made stockpiling amantadine part of their flu pandemic preparedness plans. A newer and more costly class of antiviral drugs, the neuraminidase inhibitors (oseltamivir and zanamivir), is also used against flu.

According to the Post, pharmaceutical executives in China confirmed that amantadine had been used since the late 1990s to treat or prevent avian flu in chickens. China first reported an outbreak of avian flu to the World Organization for Animal Health (OIE) on Feb 2, 2004, according to the OIE listing of H5N1 outbreaks.

However, the story said researchers in Hong Kong found outbreaks in China in 1997, 2001, and 2003.

Use of amantadine in livestock is banned in the United States and other countries, the newspaper reported. Yet veterinarians explained to Chinese farmers how to use the drug and even supplied it, the story said.

"Amantadine is widely used in the entire country," the Post quoted Zhang Libin, head of the veterinary medicine division of Northeast General Pharmaceutical Factory in Shenyang, as saying. "Many pharmaceutical factories around China produce amantadine, and farmers can buy it easily in veterinary medicine stores."

The FAO"e;s Beijing office was seeking information from China"e;s agriculture ministry, AFP reported today.

Chinese authorities denied the report.

The government has never allowed farmers to use amantadine, said Xu Shixin, director of the agriculture ministry"e;s veterinary bureau, as quoted today in the newspaper China Daily. He added that the government will take action soon to curb illicit use. He also said avian flu in China was under control.

The impact of the amantadine treatment isn"e;t clear. One FAO official quoted by AFP said it"e;s important to find out whether China had found a safe way to deliver the drug to animals, but warned that underdosing causes resistance.

Roy Wadia, a WHO spokesman in Beijing, said it"e;s premature to blame China for spurring resistance to amantadine, AFP reported. The drug dates back to 1976, and human resistance has been a problem. But Wadia added that China"e;s use might have hastened the development of resistance.

Dave Halvorson, DVM, a veterinarian in avian health at the University of Minnesota in S. Paul, registered little surprise at the news today.

"People who thought about it must have figured out they were using amantadine in poultry," he said. "The resistance is not new information."

Halvorson could have predicted that resistance would arise if the drug were used in poultry. He worked on research with amantadine in turkeys about 20 years ago. "We found that resistance occurred quite quickly," he said.

If the H5N1 virus gives rise to a pandemic strain of flu, the resistance to amantadine might not necessarily carry through to the new strain, according to infectious disease expert Michael T. Osterholm, PhD, MPH. It would depend on the process that produced the pandemic strain.

Amantadine targets the "M" protein of flu viruses, explained Osterholm, who is director of the University of Minnesota Center for Infectious Disease Research and Policy, publisher of this Web site. If a pandemic virus arose through the combination, or reassortment, of the H5N1 avian virus with a human flu virus, the M gene would come from the human virus, he said. As a result, "That [new virus] should still be relatively susceptible to amantadine," he said.

However, if the H5N1 virus adapted to humans gradually through a series of mutations, rather than through reassortment, it could remain resistant to amantadine. "If it continues to mutate, and we see a pandemic strain arise through slow human adaptation, that could mean amantadine is all but done," Osterholm said.

However, "Either way it"e;s bad," because even if a pandemic virus is susceptible to amantadine, the drug will be in short supply, he added.

Halvorson emphasized that flu outbreaks in poultry must be addressed on a country-by-country basis because of national laws. He said the international community needs to reach out to those countries willing to get help.

"These other countries are just overwhelmed," he said. "Just finding avian flu is a big enough problem, let alone getting rid of it."

News out of Vietnam today served to underscore his point. Veterinary officials there announced that another 6,000 chickens were infected with H5N1, the first outbreak there in 2 months, according to AFP. The outbreak occurred in the southern province of Ben Tre, southwest of Ho Chi Minh City, the story said.

Bui Quang Anh, animal health director in Vietnam"e;s agriculture ministry, called for "very high vigilance" against avian flu and said that some provinces were not taking the problem seriously, AFP reported. But he said there were no plans for mass poultry vaccinations.

News Editor Robert Roos contributed to this article.