Neuraminidase Resistance Seen in Influenza B

TOKYO, April 3 -- There are signs that influenza B can develop resistance to two of the main antiviral drugs, according to scientists here.

Influenza B resistance to oseltamivir (Tamiflu) and zanamivir (Relenza) also appears to be transmitted within communities and families, reported Shuji Hatakeyama, M.D., Ph.D., of the University of Tokyo, and colleagues, in the April 4 issue of the Journal of the American Medical Association.

The emerging resistance, although still not at the levels seen in influenza A strains, is worrisome and will require "continued close monitoring," said Dr. Hatakeyama and colleagues.

Equally important, they said, the resistant strains did not appear to differ from other circulating influenza B in terms of duration of symptoms, level of viral shedding, or clinical outcome.

The resistant strains "do not lose virulence even though they have evolved to a status that is less sensitive to the drug," Dr. Hatakeyama and colleagues added.

The neuraminidase inhibitors oseltamivir and zanamivir are used more widely in Japan than anywhere else, the investigators noted, so that an outbreak of influenza B in the winter of 2004-2005 provided an opportunity to evaluate the prevalence and transmissibility of resistant strains.

The researchers evaluated 74 pairs of influenza B isolates in children, taken before and after treatment with oseltamivir at four community hospitals. They also evaluated 348 isolates taken mostly from children at the same hospitals before treatment.

In the first group of isolates, one patient (1.4%) appeared to develop resistance as a result of oseltamivir treatment, the investigators said, which is lower than the rate of emergent resistance - from 5.5% to 18% -- in influenza A strains.

Resistance to neuraminidase inhibitors is measured as an increase in the concentration of drug needed to block 50% of the viral activity against sialic acid -- the so-called IC₅₀.

In the case of the child with the resistant strain, the IC₅₀ after treatment rose 7.1-fold against zanamivir and 3.9-fold against oseltamivir, the researchers reported.

In a second analysis, the researchers tested all 422 pre-treatment isolates for resistance to oseltamivir and found variants with reduced sensitivity in seven patients (1.7%).

In four cases, Dr. Hatakeyama and colleagues said, there was evidence that the resistant strain had been transmitted in a community setting, while the remaining three were probably infected by siblings shedding the mutant viruses.

In one example, an eight-year-old boy was diagnosed with influenza B six days before onset of symptoms in his one-year-old sister. The boy's pretreatment isolate showed resistance to zanamivir and oseltamivir.

When the sister's virus was studied it was identical to her brother's, suggesting he had been infected with a resistant strain and passed it on, the researchers said.

The study should explode the "complacency" that has affected the research community, based on the notion that resistant viruses would be less virulent than the wild type, said Anne Moscona, M.D., of Weill Cornell Medical College in New York and Jennifer McKimm-Breschkin, Ph.D., of Molecular and Health Technologies in Parkville, Australia, in an accompanying editorial.

"It is no longer possible to be confident that resistant strains will have little effect on epidemic or pandemic influenza," they wrote.

The emergence of influenza B strains having low-level resistance to the drugs is worrisome, they said, because the B type is already less susceptible to neuraminidase inhibitors than the A type.

"The presence of low-level resistance sets the stage for selective pressure for development of high-level resistance," they said.

Dr. Moscona reports serving on advisory committees and/or as a consultant to GlaxoSmithKline, Medimmune, and Roche. Dr. McKimm-Breschkin reports receiving basic research funding from GlaxoSmithKline.