Study suggests drug-resistant strains of influenza B can spread

Apr 13, 2007 (CIDRAP News) – Japanese researchers who identified antiviral-resistant strains of influenza B found that they seemed to circulate in communities and families and to make patients just as sick as their nonresistant counterparts did, contrary to a common assumption that resistant flu viruses are likely to be less transmissible and less virulent.

The report in the Apr 4 Journal of the American Medical Association says that strains with reduced drug sensitivity "appear to be transmitted from person to person" and that the clinical course of influenza B infection "did not appear to be affected by the sensitivity of the virus to neuraminidase inhibitors," though the sample size was small.

Other researchers have documented antiviral-resistant strains of the (influenza A) H5N1 avian flu virus in Egypt and Vietnam, and with the threat of an influenza pandemic in mind, disease experts are eager to learn more about how flu viruses evolve in response to antiviral medications.

The Japanese group, with the goal of detecting and analyzing antiviral resistance in influenza B strains, isolated samples from patients who were diagnosed with influenza B during the 2004-05 season in the pediatric departments of four community hospitals. Their study was conducted during a year when the influenza B virus caused widespread outbreaks in Japan, where the neuraminidase inhibitors oseltamivir and zanamivir are used more extensively than anywhere else in the world.

The investigators, with Shuji Hatakeyama, MD, PhD, of the University of Tokyo as lead author, collected influenza B isolates from 74 children before and after treatment with oseltamivir, along with pretreatment samples from 348 other patients.

After using a sialidase inhibition assay to evaluate the antiviral sensitivity of the samples, the group sequenced the neuraminidase and hemagglutinin genes of those that showed reduced sensitivity to neuraminidase inhibitors to determine if any had mutations associated with antiviral resistance.

In one of the 74 children who received treatment with oseltamivir, researchers identified an influenza B variant with reduced drug sensitivity that had a Gly402Ser neuraminidase substitution. In seven of the pretreatment samples, they found three different influenza B variants associated with reduced drug sensitivity, carrying the mutations labeled Asp198Asn, Ile222Thr, and Ser250Gly.

In reviewing the clinical and viral genetic information from the seven patients whose pretreatment isolates showed drug resistance, the researchers concluded that four were probably infected in the community and three were likely infected by their siblings.

The researchers did not find any difference in the clinical course of illness between patients who had "wild-type" viruses and those who had drug-resistant strains. Also, there was no difference in the extent of virus shedding, though the number of patients with drug-resistant strains was too small to assess statistical significance, the report says.

The authors concluded that frequent Japanese use of oseltamivir—which they said was prescribed 90 times more often than zanamivir during the 2004-05 flu season—could have generated the drug-resistant influenza B strains found in the study.

"Continued surveillance for the emergence or spread of neuraminidase inhibitor-resistant influenza viruses is critically important," the authors write.

In an editorial accompanying the research report, antiviral experts Ann Moscona, MD, of Weill Medical College of Cornell University in New York City, and Jennifer McKimm-Breschkin, PhD, of Molecular and Health Technologies in South Victoria, Australia, write that the Japanese study serves as a wake-up call regarding the emergence of flu viruses resistant to neuraminidase inhibitors.

In vitro and animal studies have found that resistant viruses were less infective and transmissible, they write, which "has led to the belief that significant transmission is unlikely to occur among humans." The Japanese study suggests that such strains are transmissible, they assert.

Though the study raises more questions than it answers about viral evolution, biological fitness, and transmissibility, it establishes that influenza B mutants with reduced neuraminidase inhibitor sensitivity are transmissible and can cause clinical illnesses mirroring those caused by wild-type influenza B strains, according to Moscona and McKimm-Breschkin.

"Contrary to what had been hoped until now, some resistant variants are vigorous pathogens," they write.

"Influenza viruses evolve rapidly and nimbly, which compels ongoing investigation of antiviral therapies that use alternative mechanisms of action and target different points in the viral life cycle," the article states.

Hatakeyama S, Sugaya N, Ito M, et al. Emergence of influenza B viruses with reduced sensitivity to neuraminidase inhibitors. JAMA 2007 Apr;297(13):1435-41 [Abstract]

Moscona A, McKimm-Breschkin J. News about influenza B drug resistance that cannot be ignored (editorial). JAMA 2007 Apr;297(13):1492-93 [Abstract]

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