Antiviral Resistance in Influenza Viruses: Clinical and Epidemiological Aspects

There are three classes of antiviral drugs approved for the treatment of influenza: the M2 ion channel inhibitors (amantadine, rimantadine), neuraminidase (NA) inhibitors (laninamivir, oseltamivir, peramivir, zanamivir), and the protease inhibitor (favipiravir); some of the agents are only available in selected countries [1, 2]. These agents are effective at treating the signs and symptoms of influenza in patients infected with susceptible viruses. Clinical failure has been demonstrated in patients infected with viruses with primary resistance, i.e., antivirals can be present in the virus initially infecting the patient, or resistance may emerge during the course of therapy [3–5]. NA inhibitors are active against all nine NA subtypes recognized in nature [6], including highly pathogenic avian influenza A/H5N1 and recent low-pathogenic avian influenza A/H7N9 viruses [7]. Since seasonal influenza is usually an acute, self-limited illness in which viral clearance usually occurs rapidly due to innate and adaptive host immune responses, the emergence of drug-resistant variants would be anticipated to have limited effect on clinical recovery in otherwise healthy patients, as has been demonstrated clinically [3, 8, 9]. Unfortunately, immunocompromised or immunologically naïve hosts, such as young children and infants or those exposed to novel strains, are more likely to have mutations that confer resistance emergence during therapy; such resistant variants may also result in clinically significant adverse outcomes [10–13].