News about influenza B drug resistance that cannot be ignored.

DURING THE LAST 2 YEARS, THE MEDICAL COMMUnity has been tensely following the emergence of resistance to oseltamivir in strains of influenza A. The clinical relevance and transmissibility of these resistant variants has been unknown, and planning for epidemic and pandemic influenza thus far has ignored the issue due to lack of evidence that it will be of medical consequence. Neuraminidase inhibitors are presently the only reliable antiviral option for treatment of influenza infection: the usefulness of the adamantanes (amantadine and rimantidine) has been virtually eliminated by the development of resistance. Until now, little spontaneous resistance to neuraminidase inhibitors has been documented, and no spontaneously resistant influenza viruses were identified in the world prior to the introduction of the drugs. This may now be changing. In this issue of JAMA, the report from Japan by Hatakeyama and colleagues documenting influenza B viruses with decreased sensitivity to oseltamivir and zanamivir increases concerns about the possibility and clinical significance of resistance. The article describes influenza B viruses partially resistant to neuraminidase inhibitors in individuals who had not been treated with antiviral medications and strongly suggests personto-person transmission of these resistant viruses, either within families or in the community. Japan has the highest use of neuraminidase inhibitors of any country in the world, with more than 90% of the prescriptions being for oseltamivir. While the mutations reported in the resistant isolates in the report are mainly those previously associated with selective pressure from oseltamivir, it is not certain whether the mutated viruses came from other treated individuals in the community or if they emerged spontaneously. The emergence of the variants having low-level resistance discussed in the study is also of concern because influenza B has lower baseline sensitivity to neuraminidase inhibitors compared with influenza A, and the presence of low-level resistance sets the stage for selective pressure for development of high-level resistance. In Australia, 2 influenza viruses with mutations conferring high-level resistance to neuraminidase inhibitors have been isolated from untreated patients. One of these viruses had a mutation in the neuraminidase that is known to confer high-level oseltamivir-specific resistance. Since there is little use of neuraminidase inhibitors in Australia, these viruses likely both arose due to spontaneous mutations. 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. This has led to the belief that significant transmission is unlikely to occur among humans. A 2003 model of the spread of resistant viruses in a pandemic concluded that community spread of such variants would be negligible because of decreases in biological fitness and transmissibility of drug-resistant viruses. However, a recent report predicted that, while use of antiviral drugs could significantly slow or stop transmission in the absence of drug resistance, the emergence of resistance could seriously diminish this benefit, depending on the cost of biological fitness: if there were a modest biological fitness cost and transmissibility were high, the effectiveness of antiviral use would plummet. Even if resistant strains emerge de novo at extremely low frequencies in individuals receiving antiviral drugs for treatment or prophylaxis, these strains may well make a significant contribution in an epidemic or pandemic setting. These concepts, together with the findings reported by Hatakeyama et al suggesting that partiallyresistant influenza B viruses are circulating, mean it is no longer possible to be confident that resistant strains will have little effect on epidemic or pandemic influenza. Resistance to oseltamivir has been predicted by in vitro and structural studies to be more likely to arise than resistance to zanamivir under the selective pressure of drug treatment. Zanamivir is more structurally similar to the natural substrate of neuraminidase and fits directly into the active site. For oseltamivir, a rearrangement of amino acids in the active site is necessary to accommodate the drug’s hydrophobic side chain; mutations that prevent this rearrangement might lead to resistance to oseltamivir but not to zanamivir. It has also