Europeans find Tamiflu resistance in seasonal flu virus

Jan 29, 2008 (CIDRAP News) – An early report on the seasonal influenza strains circulating in Europe reveals that some H1N1 viruses show signs of resistance to the antiviral drug oseltamivir, the European Centre for Disease Prevention and Control (ECDC) reported this week.

Of 148 influenza influenza A H1N1 samples collected in November and December in 10 European countries, 19 tested positive for resistance to oseltamivir, the ECDC said in a Jan 27 press release. Twelve of the resistant virus isolates were from Norway; the rest included one from Denmark, four from France, and two from the United Kingdom.

According to ECDC's full interim report, the oseltamivir-resistant variant, H1N1 (H274Y), is a new development this winter. (H274Y is the term for a mutation associated with resistance to the drug.) The strain is sensitive to other antivirals, which include zanamivir, amantadine, and rimantadine.

The overall proportion of the oseltamivir-resistant strain among European isolates is 13%, but if the Norwegian samples are excluded from the total, the proportion for Europe falls to 5%, the report said.

Though the ECDC cautioned that the findings are preliminary, it said Norway is still seeing the oseltamivir-resistant H1N1 this month and that the same mutation is being seen in other countries, including those in North America.

"There are some indications that some of the same oseltamivir-resistant A H1N1 viruses are being observed at low levels in the United States," the report said.

Experts from the ECDC, the European Commission, and the World Health Organization (WHO) are assessing the significance of the findings and will release an interim joint assessment soon, based on the initial surveillance findings, the ECDC said.

The WHO today held a virtual meeting of experts to discuss the findings. WHO spokesman Gregory Hartl told CIDRAP News the group agreed that more studies are needed to answer the many questions raised by the ECDC's initial report. For example, he said experts would like to determine why antiviral resistance rates in the study vary so widely between countries and why the resistant H1N1 strain surfaced so early in the flu season.

The findings need to be fleshed out, and experts are just now looking at isolates collected in January, Hartl said. "Theses are small numbers, so this is a work in progress," he commented.

Joe Bresee, MD, chief of epidemiology and prevention for the US Centers for Disease Control and Prevention's (CDC's) immunization services division, told CIDRAP News today that of 204 influenza samples tested by the CDC so far this season, six (2.9%) were resistant to oseltamivir. The resistant samples accounted for 5.5% of the 109 H1N1 viruses the CDC isolated, he said.

"It's interesting. Last year we wouldn't have expected this level of resistance," Bresee said. The CDC is continuing to monitor patterns with the oseltamivir-resistant H1N1 variant, but he said the numbers were low enough that the agency is not changing its recommendations for the treatment of seasonal influenza.

The CDC has urged clinicians to stop using amantadine or rimantadine to treat influenza because circulating influenza A strains have high rates of resistance to the two drugs.

Martina Rupp, a spokeswoman for Roche, the maker of Tamiflu, said the preliminary results are a contrast to previous years, when experts found little or no oseltamivir resistance, according to a Bloomberg News report. She said more surveillance is needed to establish the prevalence and geographic distribution of the resistant H1N1 variants and to gauge the impact on the drug's efficacy.

Frederick Hayden, MD, an antiviral expert with the WHO, said the change in the virus's resistance pattern warrants concern, the Canadian Press (CP) reported yesterday. "This is not only interesting, it's unusual and would not have necessarily been predicted by the necessary information. So it's certainly something we're taking seriously and trying to gather additional information [on]," he said.

Though the source of the H1N1 variant is not known, ECDC experts reported that they don't believe its emergence is related to antiviral use in Europe, because the drugs are rarely used there. They wrote that the Norwegian patients who had the resistant strain had not taken antiviral medications.

The ECDC report said it's not clear if the variant virus will be overwhelmed by more fit and oseltamivir-susceptible viruses as the influenza season progresses. "Equally, however, the resistant virus could come to spread and predominate. We simply do not know at present," the authors reported.

Evidence on the effect of the resistance mutation on viral fitness is contradictory, they noted. Some studies have shown the mutation reduces the virus's capacity to replicate and spread, while others have shown the variant's fitness is similar to that of viruses lacking the mutation.

"People who become ill with the oseltamivir-resistant strain of A(H1N1) do not appear to become any more sick than people infected with 'normal' seasonal influenza," the ECDC said in its press release.

In addition, the ECDC report stated, "It also needs to be remembered that antiviral resistant is a relative not absolute term. Patients ill with viruses that are deemed resistant in the laboratory often still seem to benefit when they take antivirals."

See also:

Jan 24 CIDRAP News story "Older flu drugs still used, against CDC advice"

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