Concern Grows Over Drug-Resistant Influenza B Transmission

Widespread use of neuraminidase inhibitors, currently the only available antiviral defense against influenza B, may have led to the emergence of viral variants with reduced sensitivity to the treatment, reported researchers in the April 4 JAMA. The study results indicated that while such variants of influenza B are not as common as resistant forms of influenza A, they can be transmitted within communities and families, thus complicating the management of outbreaks.

The research team examined the development and prevalence of resistant influenza B viruses in Japan, where use of the neuraminidase inhibitor drugs oseltamivir and zanamivir is especially common. Sensitivity of the viruses to these treatments was measured by the concentration of neuraminidase inhibitor required to inhibit 50% of the sialidase activity of the viruses (IC50).

ACTIVE SITE MUTATIONS PREVENT INHIBITOR BINDING

In the first portion of the study, Shuji Hatakeyama, MD, PhD, of the Department of Infectious Diseases at the University of Tokyo, and colleagues analyzed pretreatment and posttreatment nasal or pharyngeal swabs of 74 children to track the appearance of a drug-resistant viral strain. One patient (1.4%) who received a full course of oseltamivir developed a mutated variant, as indicated by 7.1- and 3.9-fold increases in the IC50 values for zanamivir and oseltamivir, respectively, in samples collected three days after therapy was initiated. Cloning of the neuraminidase gene revealed a single amino acid substitution located near the sialidase enzymatic center.

In the second portion of the study, samples from 348 additional treatment-naïve patients were analyzed along with the pretreatment samples from the first portion of the study to establish transmissibility of neuraminidase inhibitor–resistant influenza B. Seven (1.7%) of the total 422 sampled viruses isolated from untreated patients were found to have a reduced sensitivity to zan­am­ivir, oseltamivir, or both. “Each of the seven isolates with reduced sensitivity contained amino acid substitutions in the neuraminidase at the sialidase active center, by comparison with the consensus type B neuraminidase sequence,” reported the authors.

Transmissibility of the neuraminidase inhibitor–resistant viruses between family members was illustrated: Three of the seven study participants infected with neuraminidase inhibitor–resistant influenza B had siblings who had been infected with influenza B six to 10 days earlier. In two cases, the infected siblings were also included in the study, and it was found that the later-infected siblings’ viruses had the same active site mutations as those in their earlier-infected siblings. The remaining four participants with a drug-resistant form of influenza B (including the two earlier-infected siblings) did not report any infected family members before the onset of their own symptoms; therefore, the researchers concluded that that the mutant strains were circulated and transmitted within their respective communities.

POTENT INFECTIONS POSSIBLE WITH MUTATED VIRUSES

There were no “appreciable differences” in the clinical course of infection, duration of fever after antiviral therapy, or the duration and titer of virus shedding between patients infected with drug-resistant or drug-sensitive viruses, reported the researchers. This finding was of particular significance to Anne Moscona, MD, and Jennifer McKimm-Breschkin, PhD, who authored an accompanying editorial calling for the close monitoring of neuraminidase inhibitor–resistant influenza B.

“Part of the complacency about neuraminidase inhibitor–resistant influenza has been fueled by experiments in vitro and in animal models that have generally found neuraminidase inhibitor–resistant influenza viruses to be compromised in infectivity and transmissibility,” they said. “[I]t is no longer possible to be confident that resistant strains will have little effect on epidemic or pandemic influenza.”

Drs. Moscona and McKimm-Breschkin noted that there is another neuraminidase inhibitor, peramivir, that has not yet been licensed for use; however, they said it is unlikely to be of significant benefit, as it shares key structural features with oseltamivir and zanamivir, and therefore the sialidase active site mutations will likely affect its efficacy as well. They recommended continual monitoring of influenza strains over time and frequent rethinking of the policies for use of antiviral drugs.            

—Jessica Dziedzic

Reference
Hatakeyama S, Sugaya N, Ito M, et al. Emergence of influenza B viruses with reduced sensitivity to neura­mini­dase inhibitors. JAMA. 2007;297:1435-1442.
Moscona A, McKimm-Breschkin J. News about influenza B drug resistance that cannot be ignored. JAMA. 2007;
297:1492-1493.

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