Division of Infectious Diseases, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada.
WHO Collaborating Centre for Reference and Research on Influenza, VIDRL, Peter Doherty Institute, Melbourne, Australia.
Curr Opin Infect Dis. 2018 Dec;31(6):520-526. doi: 10.1097/QCO.0000000000000498.
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.
神经氨酸酶抑制剂（NAI），包括奥司他韦、扎那米韦和帕拉米韦，是临床应用的主要抗病毒药物类别。因此，这些药物的耐药性发展是一个重大的临床和公共卫生问题。
目前，循环病毒中的 NAI 耐药性仍然罕见（奥司他韦<3.5%，扎那米韦<1%）。A(H1N1)比 A(H3N2)和 B 病毒的耐药风险略高。耐药性可能在药物暴露期间出现，特别是在幼儿（<5 岁）、免疫功能低下者和接受预防方案的个体中。具有高水平奥司他韦耐药性的 H275Y A(H1N1)变异株能够引起暴发。R294K A(H7N9)变异株对所有 NAI 的抑制作用均降低。免疫功能低下者中报告了多 NAI 耐药性。
这些发现强调了持续监测的重要性，以及评估耐药病毒株的病毒适应性和传染性。检测可能具有挑战性，尤其是在耐药和野生型病毒混合的情况下。最近分子技术（例如靶向突变 PCR、iART、ddPCR、焦磷酸测序、下一代测序）的进展提高了检测水平，并加深了我们对病毒动力学的理解。针对奥司他韦耐药病毒的治疗选择有限，可能需要进行其他 NAI 的药敏试验，但针对这些耐药病毒有效的非 NAI 抗病毒药物（例如聚合酶抑制剂）处于临床开发后期。
