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    Avian flu gaining drug resistance in China

    Resistance to the antiviral drug amantadine is spreading significantly more rapidly among avian influenza viruses of H5N1 subtype in Southeast Asia than in North America, according to a study done by investigators at St. Jude Children’s Research Hospital.

    The St. Jude team reached this conclusion by studying mutations in the so-called M2 protein of avian influenza viruses of different H5N1 subtypes isolated in North America and Southeast Asia during 1991-2004; and by evaluating the frequency of drug-resistant strains. A properly functioning M2 protein is key to the virus’s ability to replicate. The St. Jude researchers demonstrated that the largest proportion of Asian drug-resistant H5 and H9 avian influenza viruses occurred in China. A report on these findings appears in the October 10, 2005, edition of Virology.

    “We were able to determine how frequently amantadine resistance occurs in avian influenza A subtypes isolated in various parts of the world—especially among those subtypes that had the potential to cause a pandemic,” said Natalia Ilyushina, PhD, a postdoctoral fellow in Infectious Diseases. Iluyshina is the first author of the Virology paper and did much of the work on this project.

    H5 influenza viruses concern world health officials because the H5N1 subtype has been spreading throughout chicken flocks and wild birds in Southeast Asia since it emerged in 1997. Furthermore, between late 2003 and early 2004, outbreaks of highly pathogenic avian H5N1 influenza occurred among poultry in eight Asian countries, causing the death of or the need for culling many tens of millions of birds. In addition, as of August 5, 2005, 112 cases of human H5N1 infection had been confirmed in Indonesia, Vietnam, Thailand and Cambodia, of which 57 were fatal, according to the World Health Organization.

    Humans contract H5N1 only from close contact with infected birds, especially chickens, and only one probable human-to-human transmission was reported in Vietnam. This has so far prevented H5N1 from becoming a major threat to humans.

     “However, if H5N1 variants acquire the capacity for sustained human-to-human transmission, the world will face the threat of a serious pandemic,” said Robert Webster, PhD, of Infectious Diseases and holder of the Rose Marie Thomas Chair.

    “We now have solid proof that in Southeast Asia, and especially in China, these mutations are undergoing strong selective pressure,” said Elena Govorkova, PhD, staff scientist in Infectious Diseases and co-author of the paper.

    The high rate of M2 mutations in China probably arises from some human activity that encourages selection of such changes, such as treating chickens with amantadine to prevent infection with H5N1, the researchers say.

    “H5N1 is now endemic—a permanent resident—in Southeast Asia, including China,” Webster said. “Therefore, any selective pressure on this virus ensures plenty of opportunity for H5N1 to acquire amantadine resistance, which would bring additional difficulties in controlling the pandemic.”

    This concern over activities in China that might increase selective pressure for amantadine resistance in H5N1 has been voiced on the postings of ProMED during the past several months. ProMED (Program for Monitoring Emerging Diseases) is an electronic outbreak reporting system established by the International Society for Infectious Diseases to permit rapid and accurate monitoring of infectious disease outbreaks globally; and to serve as a central location for news, updates and discussions of infectious disease outbreaks that threaten humans. For example, a ProMED transmission on July 6, 2005, noted that Joseph Domenech, the chief veterinary officer for the United Nations Food and Agriculture Organization commented that the use of human flu drugs by Chinese farmers is “a big concern.”