Bird flu drug for humans rendered useless China’s use on chickens has led to resistance in virus

HONG KONG - 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.

Commentary
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Amantadine Resistance in Bird Flu Vietnam and Thailand

Recombinomics Commentary
June 18, 2005

>> 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.

Su Lijian, vice president of Zhejiang Kangyu Pharmaceutical Co. in southeastern China, said amantadine was introduced into China in the 1970s for human use before being extended to poultry in the 1990s.
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 billion doses of a vaccine. 2.6

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 past two years to a strain isolated from a goose in China's Guangdong province in 1996…….

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, work by preventing a flu virus from reproducing itself. Both are now ineffective against the H5N1 strain.
Even before, these drugs had limitations in treating an ongoing human flu outbreak because of the speed at which the virus would become resistant in humans. But 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 work by hampering the flu virus from leaving infected cells and attacking new ones. Of the two, oseltamivir is easier to use and has far greater sales. <<

The genetic trail of Amantadine resistance is a bit more complicated than many realize. The isolates from Vietnam and Thailand actually have two Amantadine resistance markers in the M2 protein. One, L26I, is found only in the isolates from Vietnam and Thailand. It is not in isolates from China or anywhere else, yet is in all Vietnam and Thailand isolates.

The other M2 mutation, S31N, is much more common, but traces back to lab isolates from the 1930's It is in WSN/33 (also found in swine isolates in South Korea) and PR-8 (used to make vaccines worldwide). These may be related to growing these viruses in tissue culture. The mutation is also in a variety of human isolates (including those from New York last year).

In Asia, the first H5N1 isolates were from Hong Kong in 2002, It is also present in isolates from two patients in 2003 and they presumably were infected in Fujian province. There is also an isolate from Shantou Province and Indonesia. However, most of the isolates from each of these areas do not have the mutation (but ALL 2004 isolates from Vietnam and Thailand do).

Earlier bird isolates can be found in China. The earliest H9N2 isolates were in northern China in 1998 (Shanghai and Beijing).

However, the mutation is also found in swine isolates, and the earliest swine isolates are in the US and Europe. The mutation began appearing in Asian swine in 1999 (in Hong Kong).

Thus, one of the markers is probably traced to treating humans or pigs with Amantadine years ago in the west (US and Europe) and the second mutation may well have arisen in Vietnam or Thailand fairly recently

Good News: Tamiflu should still work.

Bad News: "Given the difficulty of rapidly producing an effective vaccine, drugs will be the first line of defense. However, the limited stockpile of the anti-viral drug Tamiflu makes the United States vulnerable to the avian flu threat, panel experts said.

Stockpile purchases of 2.3 million doses, made by the Department of Health and Human Services, would only be enough to treat less than 1 percent of the U.S. population.

"We would need between 60 million to 150 million doses of the drug," said Dr. Andrew T. Pavia of the Infectious Diseases Society of America.

In contrast, other countries such as the United Kingdom, France, Finland, Norway, Switzerland and New Zealand are ordering enough Tamiflu to cover between 20 percent to 40 percent of their populations.

Dominick A. Iacuzio, medical director of Tamiflu's manufacturer Hoffman La-Roche Inc., said he cannot assure an adequate supply of the drug at the outbreak of a pandemic because of production complexities.

"We are greatly concerned that without the United State's commitment to secure the drug, the continually increasing global demand for Tamiflu will force us to export the drug to countries with committed orders," he said."

www.sciencedaily.com/upi/index.php?feed=Science&article=UPI-1-20050526-18290900-bc-us-flu.xml

www.tinyurl.com/agcty

Wrong. Tamiflu is NOT EFFECTIVE against H5N1. Sorry.

Commentary
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Emerging H5N1Tamiflu Resistance in Northern Vietnam

Recombinomics Commentary
May 18, 2005

>> Sequence analysis of NA genes and neuraminidase inhibitor susceptibility testing of H5N1 human 2005 isolates from Viet Nam has also revealed that one virus (A/VN/HN30408/05) has a "mixed" virus population of amino acid residues 274-H (wild-type) and 274-Y (resistant) sequences. Although this virus does not exhibit a fully resistant phenotype, the IC50 value for oseltamivir is shifted upward and consequently this virus is less susceptible to oseltamivir than other H5N1 isolates tested. The patient from whom this virus was isolated had been/was being treated with oseltamivir. The community emergence and spread of viruses resistant to oseltamivir, if it were to occur, would have significant implications for influenza A/H5N1 prevention and control. <<

The emergence of H5N1 Tamiflu-resistance is cause for concern. This "mixed" infection is common and such dual infections generate recombinants. Most of the prior dual infections were in animals. This mixed infection in a recovering patient is cause for concern. Treatment of the patient with Tamiflu will likely select for H274Y. In the hospital setting, this emerging virus will probably not transmit beyond the patient being treated.

However, the cases in northern Vietnam are milder, and treatment of milder cases with Tamiflu may select H274Y, which could then be transmitted. Tamiflu resistance in the small number of confirmed H5N1 cases suggest that H5N1 resistant strains will emerge rapidly, ending hopes of bird flu containment with Tamiflu.

Moreover, since the 2005 H5N1 isolates are more heterogeneous and the isolates in northern Vietnam are distinct from isolates in southern Vietnam, which have a high associated case fatality rate, further recombinants with increase virulence and Tamiflu resistance combined with improved human-to-human transmission are possible.

H5N1 has become endemic to birds in Vietnam and Thailand. The distribution of H5N1 in people is largely unknown. These combinations and potential interactions complicate H5N1 control efforts.

See my # 12. Many more details are posted on that link. Hope the new link helps to untangle some issues for you.

The drug known as "amantadine" was overused by China for their domestic chickens. That type of misapplication violated the standards set by every Western nation. In fact, it violated the standards Beijing had agreed to follow. China's use of a drug designed for humans on its domestic bird flocks was so incredibly stupid it was criminal. Or, it was intentionally criminal and planned so that China could now claim it made "mistake." China's handling of the Avian Flu may show its rogue nation attitudes.

There is a drug known as "oseltamivir" commonly called Tamiflu. In the past few weeks reports coming out of Asia say that Tamiflu may be useless against Avian Flu. There is another drug, "zanamivir," which sold under the trade name Relenza. Tamiflu and Relenza may be nearly identical in their chemical make up.

In my humble opinion, NOW is the time to prevent air travel in and out of China.

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