Influenza B viruses with lower antiviral sensitivity reported

Mar 29, 2011 (CIDRAP News) – North Carolina health officials have reported a number of influenza B isolates with reduced sensitivity to oseltamivir (Tamiflu), a rare finding, but they say antivirals remain effective and there is no reason for clinicians to change their prescribing practices.

Out of 92 type B isolates from North Carolina that were tested by the Centers for Disease Control and Prevention (CDC) in recent months, 31 had a mutation associated with reduced sensitivity to oseltamivir, but not actual resistance, the North Carolina Department of Health and Human Services announced yesterday.

"These particular viruses are less sensitive to the drug in the lab, but they are not resistant," Dr. Zack Moore of the state Division of Public Health (DPH), said in a press release. "We want to assure physicians and their patients that antiviral drugs remain an effective treatment for influenza."

The viruses do not show reduced susceptibility to zanamivir (Relenza), the other antiviral in the neuraminidase inhibitor class, state officials said. Neuraminidase inhibitors are the only antivirals useful against type B viruses, which are not affected by the two older antivirals, amantadine and rimantadine.

Most of the patients who were infected with the reduced-sensitivity viruses had typical flu symptoms and recovered after several days, but one patient had "severe underlying immune problems" and died shortly after being diagnosed as having flu, according to the state press release.

"Because the importance of intermediate sensitivity to oseltamivir in these samples is not yet clear, the N.C. Division of Public Health and the CDC are advising physicians to follow existing antiviral guidelines, but to consider this new information when caring for North Carolina patients who are hospitalized with severe influenza B infections," the state press release said.

Reduced antiviral sensitivity in type B viruses is not unknown, according to experts, but resistance is much more commonly associated with influenza A viruses. Oseltamivir resistance in 2009 H1N1 viruses has been reported sporadically ever since that virus emerged almost 2 years ago. And the previous seasonal H1N1 virus became widely resistant to oseltamivir in the 2008-09 flu season, prompting a change in the CDC's antiviral guidance.

The CDC is testing more type B viruses from North Carolina and from neighboring states for the mutation associated with reduced sensitivity, state and CDC officials said. The CDC is also conducting a telephone survey of North Carolinians who had influenza B to gather information about their treatment. No updated numbers or survey results were available today, officials told CIDRAP News.

Julie G. Henry, public information officer with the North Carolina DPH, said the reduced sensitivity was discovered by the CDC after the DPH sent the agency a batch of type B isolates during routine surveillance. After discovering the phenomenon, the CDC asked for more isolates to test, she told CIDRAP News. The CDC had analyzed 92 isolates by mid March.

Alicia Fry, a medical epidemiologist with the CDC's Influenza Division, stressed that the reduced sensitivity was discovered in lab assays and its practical implications are unclear.

"The important thing to understand is that in a lab test we found that the sensitivity was reduced, but it was not resistant," she told CIDRAP News. "Whenever we find this, we sequence the neuraminidase, and this virus had a genetic change in the active site of the neuraminidase, at position 221, an isoleucine to valine change."

"We have no idea of the clinical significance of this," she added. "The release was really just North Caroline trying to be careful."

Fry said there were two things that prompted the CDC to pay attention. One was that the relevant number was "a little elevated," and the mutation was on the active site of the virus's neuraminidase. "And the fact that we found a cluster made us decide to look at it more closely," she said.

"The important thing that North Carolina has been very careful to point out is that this is not a reason not to use antiviral agents," she commented. "At this point we don't have any evidence that oseltamivir doesn't work. . . . . We hope we can learn a little more about this so we can understand it and find out how far it's circulated."

Fry said there have been a few previous reports of reduced antiviral sensitivity in type B viruses. She pointed out a Japanese study in which researchers found 1 reduced-sensitivity isolate among 74 children who had received oseltamivir treatment for influenza B and 7 reduced-sensitivity isolates among 348 patients who had not received the drug. The isolates had different mutations from the one identified in the North Carolina cases. The study was published in the Journal of the American Medical Association in 2007.

Influenza B has co-circulated with H3N2 and 2009 H1N1 in the United States this flu season. The CDC's latest flu surveillance update says that 28% of the flu isolates identified in the week of Mar 13 to 19 were type B. Among 461 type B viruses tested this season, none showed resistance to oseltamivir or zanamivir, the CDC report says.

North Carolina also has seen a mix of influenza B, H3N2, and 2009 H1N1 viruses through most of the season, according to a chart on the DPH Web site. Henry said that as of mid March, 213 (43%) of the 490 flu isolates tested by the state lab were type B.

See also:

Mar 28 North Carolina DPH press release

Mar 25 CDC flu update

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