Europe says Tamiflu-resistant virus seen in 9 countries

Feb 1, 2008 (CIDRAP News) – European officials yesterday reported more evidence that one of the three types of seasonal influenza viruses is showing resistance to oseltamivir (Tamiflu) and said this represents the first clear sign that the resistant variant can spread.

A report published yesterday by the European Centre for Disease Prevention and Control (ECDC) says the resistant variant of the influenza A/H1N1 virus accounted for 59 (14%) of 437 European H1N1 isolates from 19 countries tested so far. The variant has been seen in nine of the 19 countries, according to the report in Eurosurveillance.

The new report suggests the resistant variant is more widespread than indicated by the initial report from the ECDC on Jan 27. That report said the resistant virus was found in four countries and made up 19 of 148 isolates tested.

Increased H1N1 resistance to oseltamvir was also reported in the United States and Canada this week. US officials said about 5% of tested isolates showed resistance, and Canada reported that about 10% were resistant.

European report: Norway most affected
The resistant virus has a mutation called H274Y, which confers approximately a 400-fold reduction in susceptibility to oseltamivir, according to the Eurosurveillance report. Oseltamivir is recommended by the World Health Organization (WHO) as the drug of choice for human patients with H5N1 avian influenza, and many countries have stockpiled it in case the H5N1 virus evolves into a pandemic strain.

From the tests so far, resistance is most common in Norway, where 26 of 37 H1N1 isolates (72%) were resistant, according to Eurosurveillance. Other countries most affected are France, 15 of 87 isolates (17%); Germany, 3 of 43 (7%); and the United Kingdom, 8 of 162 (5%). A few resistant isolates were also reported in Denmark, Finland the Netherlands, Portugal, and Sweden.

The resistant viruses have come from both adults and children, and there is no indication that any of the patients had been treated with oseltamivir or been in contact with others so treated, the report says. It is not unusual for resistance to emerge in patients receiving oseltamivir treatment for H1N1 infections, according to the WHO.

"We therefore conclude that the identification of these oseltamivir-resistant viruses as a substantial proportion of circulating viruses, particularly in Norway, is the first clear evidence that influenza A(H1N1) virus with the H274Y mutation can readily transmit between individuals," the Eurosurveillance report states.

An accompanying Eurosurveillance editorial says resistant viruses with the same mutation were seen in previous flu seasons but "were few in number, 'unfit,' and transmitted poorly. . . . These [current] A/H1N1 isolates with the H274Y mutation are fitter. They are in several countries and are transmitting in the community.

"The specimens tested to date are from early in the season, and it may be that as the season progresses ordinary A/H1N1s [will] predominate," the editorial continues. "Equally, the resistant viruses may come to predominate," as influenza A viruses resistant to two older drugs, amantadine and rimantadine, did in North America 2 years ago. Officials have said the oseltamivir-resistant H1N1 viruses remain susceptible to amantadine and rimantadine.

WHO report: Increased resistance unexpected
The WHO, in a statement yesterday, said the increased drug resistance is unexpected and so far unexplained, especially since few of the patients are known to have taken oseltamivir. "Influenza viruses are continuously changing, and it is possible that a resistant strain has emerged spontaneously," said the statement, released in a question-and-answer format.

While noting that the resistance problem is not limited to Europe, the WHO said no H1N1 isolates from Japan, where oseltamivir is used far more commonly than in most other countries, have shown the resistance mutation so far this season. The same was true for Hong Kong.

The WHO said H1N1 is the predominant flu virus in many European countries and other parts of the northern hemisphere so far this season. The increased oseltamivir resistance has not been found in the other two seasonal flu viruses, A/H3N2 and B.

The agency said the implications of the resistance problem for the treatment of H5N1 cases are uncertain. "The neuraminidase protein in human H1N1 viruses is different from that in avian H5N1 viruses. Until we learn why the unexpected increase in oseltamivir resistance has occurred in H1N1 viruses, it is too early to know what, if any, potential there might be for a similar increase to occur in H5N1 viruses."

The WHO added that it has not changed any of its H5N1 treatment recommendations.

In other observations, the WHO said:

  • So far, the evidence for most of the patients infected with the resistant virus is that they were not linked in any way.
  • There is no evidence that the resistant viruses are causing more severe illness than other flu viruses.
  • There is no sign that the resistant viruses are more transmissible than nonresistant viruses.
  • The drug resistance does not affect the effectiveness of flu vaccines, and the H1N1 strain used in this year's vaccine is well-matched to the circulating H1N1 strains.

See also:

Eursurveillance report
http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=8026

Eurosurveillance editorial
http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=8025

WHO statement
http://www.who.int/influenza/patient_care/antivirals/oseltamivir_faqs/en/index.html

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