Antiviral therapy against influenza always has been plagued by the development of resistance. Unfortunately, as medical management of influenza relies increasingly on antiviral therapy, drug resistance will become more commonplace, and may ultimately render some drugs obsolete.

Resistance Patterns to Date

Resistance to the M2 inhibitors amantadine and rimantidine is widespread among H3N2 influenza A isolates, is universal in the pandemic 2009 H1N1 influenza A strain, and is intrinsic to all influenza B strains. This year, the seasonal H1N1 influenza virus exhibited widespread resistance to the neuraminidase inhibitor oseltamivir. Relatively spared thus far has been the inhaled neuraminidase inhibitor zanamivir, with only one reported instance of clinical resistance in an influenza B strain (zanamivir-resistant H3N2 isolates have been created in the lab). However, a research team from Australia has recently reported1 isolation of H1N1 influenza A zanamivir-resistant viruses that contain a novel mutation.

Nine Strains Exhibited Zanamivir Resistance

Of 391 H1N1 strains isolated between 2006 and 2008 that were selected for detailed resistance testing from the WHO Collaborating Centre for Reference and Research on Influenza in Melbourne, 9 were found to have significant resistance to zanamivir.

Sequence analysis of the resistant viruses revealed a mutation common to all residing in the neuraminidase gene: a substitution of glutamine for lysine at position 136 was found in all isolates (Q136K). Development of this mutation was not associated with exposure to zanamivir.

Cross-Resistance to Peramivir, Not to Oseltamivir, and No Loss in Fitness

The zanamivir resistant isolates also displayed cross-resistance to peramivir; however, sensitivity to oseltamivir was retained. The Q136K mutation did not compromise virus fitness, as the mutant virus grew in vitro at higher rates than those without the mutation, and it was equally transmissible and pathogenic in ferret models. Recombinant versions of the resistant viruses, in which only the Q136K mutation was induced, suggested the possibility that the preserved fitness may be the result of additional compensatory mutations in the hemagglutinin gene.

Will This Mutation Spread?

It is worrisome that viral fitness was not compromised: the Strategic National Stockpile, which is stocked primarily with oseltamivir, is currently being stocked with zanamivir in response to the resistance patterns observed this season. If the Q136K mutation becomes more widespread, it will be impossible to stockpile any antiviral that has assured efficacy—there would be no antiviral to which all influenza A viruses were susceptible. The appearance of these mutations underscores the need to develop both novel antivirals and rapid resistance testing to guide therapy.

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