Neuraminidase inhibitor resistance in influenza: a clinical perspective

Neuraminidase inhibitors (NAIs), including oseltamivir, zanamivir, and peramivir, is the main class of antiviral available for clinical use. As such, development of resistance toward these agents is of great clinical and public health concern.

At present, NAI resistance remains uncommon among the circulating viruses (oseltamivir <3.5%, zanamivir <1%). Resistance risk is slightly higher in A(H1N1) than A(H3N2) and B viruses. Resistance may emerge during drug exposure, particularly among young children (<5 years), the immunocompromised, and individuals receiving prophylactic regimens. H275Y A(H1N1) variant, showing high-level oseltamivir resistance, is capable of causing outbreaks. R294K A(H7N9) variant shows reduced inhibition across NAIs. Multi-NAI resistance has been reported in the immunocompromised.

These findings highlight the importance of continuous surveillance, and assessment of viral fitness and transmissibility of resistant virus strains. Detection can be challenging, especially in a mix of resistant and wild-type viruses. Recent advances in molecular techniques (e.g. targeted mutation PCR, iART, ddPCR, pyrosequencing, next-generation sequencing) have improved detection and our understanding of viral dynamics. Treatment options available for oseltamivir-resistant viruses are limited, and susceptibility testing of other NAIs may be required, but non-NAI antivirals (e.g. polymerase inhibitors) that are active against these resistant viruses are in late-stage clinical development.