Thursday, December 22, 2005

News - Tamiflu-resistant avian flu cases raise concerns

Researchers in Vietnam have reported two additional cases of H5N1 avian flu infection in which the virus developed resistance to the antiviral drug Tamiflu, raising concerns the current dosing regimen is inadequate to combat the virulent strain.
While the findings will likely lead to questions over the future efficacy of the No. 1 weapon in the limited pharmaceutical arsenal against pandemic flu, influenza experts were quick to caution against over-interpreting the results.

Dr. Menno de Jong, lead author of the report, said the drug?s performance against the current purely avian virus can?t be used to predict how effective oseltamivir, or Tamiflu, would be if H5N1 adapts to become a strain that can easily spread among humans.

?For the current sporadic infections with this avian virus, it?s bad news,? de Jong said of his team finding resistance in two of eight cases studied from December 2004 through February 2005.

?But we cannot automatically say: `So, this is the end of the world.? ?

Dr. Keiji Fukuda of the World Health Organization agreed.

?It is . . . unhelpful to paint antiviral drugs as the . . . silver bullet. And it is equally unhelpful on the other stream to start wringing one?s hands and saying, `They?re not going to be helpful,?? Fukuda, a leading flu expert, said from Geneva.

?The truth is ? as it is for every other drug out there ? in between.?

De Jong and his co-authors ? from Oxford University?s clinical research unit at the Hospital for Tropical Medicine in Ho Chi Minh City ? published their report in Thursday?s New England Journal of Medicine.

This week?s issue of the influential journal also ran two commentaries exhorting doctors to refuse requests for Tamiflu prescriptions from people looking to stockpile the drug against a possible flu pandemic.

The de Jong paper is the second in which resistance to oseltamivir has been reported. The earlier case also occurred in Vietnam.

It?s the first, however, to report that someone suffering from H5N1 infection who received standard treatment with the drug during the optimal window ? the first 48 hours ? developed resistance to oseltamivir.

The patient, a 13-year-old girl, started Tamiflu treatment a day after she developed symptoms. Many H5N1 patients have started drug therapy well outside the recommended window for commencing treatment.

But flu experts have been speculating for some time that the current dosing regime, which is based on experience with regular human flu strains, is inadequate to combat the infection caused by this virulent avian strain.

Research studies are currently being set up in Southeast Asia to try to determine whether higher doses, for longer periods, are needed to treat H5N1 infections. Antiviral expert Dr. Frederick Hayden of the University of Virginia has just returned from Asia, where he has been working to try to co-ordinate this research.

For Hayden, the study highlights the many questions that need answering.

?Is an alternative dosing regimen ? higher dose, longer treatment, perhaps combination with another antiviral or a different drug entirely ? going to get around the (resistance) problem?? he wondered.

If it turns out the current dose is too low, that could explain the development of resistance. Doses which are too low allow the virus to evade the drug?s mechanisms.

Should the research prove that H5N1 infections require more drug for a longer period, governments which have been rushing to stockpile Tamiflu would face the unwelcome realization that existing national stockpiles will not protect as many people as they had hoped.

?I . . . worry desperately that the timing and dosage of this drug, if it is to be effective, is going to be very different than the current H3N2 (human flu) model,? said infectious disease expert Dr. Michael Osterholm, who has been warning that current stockpiling calculations may be underestimating the amount of drug needed to treat each person.

In addition to pinpointing the optimal dosing regime, flu experts hope the research will create a clearer picture of whether drug-resistant viruses, when they do arise, are capable of transmitting and spreading in the way antibiotic-resistant bacteria do.

In theory and in laboratory testing, flu viruses that find ways to evade Tamiflu lose what scientists call fitness. In essence, they become wimpier viruses that don?t transmit well ? though there is some evidence in animal models that under the right conditions resistant viruses will spread.

Flu specialists would like to see human data ? and much more of it ? before they can feel assured that the prospect of Tamiflu-resistance viruses emerging and spreading is of low probability.

Concerns about the potential spread of drug-resistant strains of flu were behind the calls in two commentaries that strongly urged doctors to refuse requests from people looking to stockpile Tamiflu.

The authors of one of the pieces, Drs. Allan Brett and Abigail Zuger, argued that personal stockpiling exhausts limited supplies of the drug meant for the treatment of people with human flu and could lead to a rise in resistance if people take the drug inappropriately.

As well, without the guidance of a physician, people could end up taking the drug when they don?t actually have flu, they argued.

?It seems to me . . . that the potential for it to be used wrongly is just so great . . . that it would just be a colossal waste, I think,? Brett, an internal medicine specialist and professor of medicine at the University of South Carolina, said in an interview.

Experts agreed with the concerns raised. But at least one noted that urging people to wait to get and take the drug under the guidance of their doctor could be misrepresenting how likely it is they?d be able to do that during the chaos a pandemic could cause.

?I think before we just summarily dismiss personal stockpiles of this drug or any other drug, we need to be honest about that and say: `OK, what?s the likelihood that people can get this drug? And how soon can they get it?,? ? said Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota.

?I think that the authors make a legitimate point. But I think it?s hardly a complete point,? said Osterholm, who favours rationing Tamiflu for health-care and essential workers, to keep hospitals and crucial services operating during a pandemic. - Tamiflu-resistant avian flu cases raise concerns


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