Hussain Mazhar, Galvin Henry D, Haw Tatt Y, Nutsford Ashley N, Husain Matloob
Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
Infect Drug Resist. 2017 Apr 20;10:121-134. doi: 10.2147/IDR.S105473. eCollection 2017.
Influenza A virus (IAV) is the sole cause of the unpredictable influenza pandemics and deadly zoonotic outbreaks and constitutes at least half of the cause of regular annual influenza epidemics in humans. Two classes of anti-IAV drugs, adamantanes and neuraminidase (NA) inhibitors (NAIs) targeting the viral components M2 ion channel and NA, respectively, have been approved to treat IAV infections. However, IAV rapidly acquired resistance against both classes of drugs by mutating these viral components. The adamantane-resistant IAV has established itself in nature, and a majority of the IAV subtypes, especially the most common H1N1 and H3N2, circulating globally are resistant to adamantanes. Consequently, adamantanes have become practically obsolete as anti-IAV drugs. Similarly, up to 100% of the globally circulating IAV H1N1 subtypes were resistant to oseltamivir, the most commonly used NAI, until 2009. However, the 2009 pandemic IAV H1N1 subtype, which was sensitive to NAIs and has now become one of the dominant seasonal influenza virus strains, has replaced the pre-2009 oseltamivir-resistant H1N1 variants. This review traces the epidemiology of both adamantane- and NAI-resistant IAV subtypes since the approval of these drugs and highlights the susceptibility status of currently circulating IAV subtypes to NAIs. Further, it provides an overview of currently and soon to be available control measures to manage current and emerging drug-resistant IAV. Finally, this review outlines the research directions that should be undertaken to manage the circulation of IAV in intermediate hosts and develop effective and alternative anti-IAV therapies.
甲型流感病毒（IAV）是不可预测的流感大流行和致命人畜共患病爆发的唯一原因，并且在人类每年定期发生的流感流行病因中至少占一半。两类抗IAV药物，即金刚烷类药物和分别靶向病毒成分M2离子通道和神经氨酸酶（NA）的神经氨酸酶抑制剂（NAIs），已被批准用于治疗IAV感染。然而，IAV通过使这些病毒成分发生突变，迅速对这两类药物产生了抗性。对金刚烷耐药的IAV已在自然界中确立了自身地位，全球流行的大多数IAV亚型，尤其是最常见的H1N1和H3N2，对金刚烷类药物具有抗性。因此，金刚烷类药物实际上已不再作为抗IAV药物使用。同样，直到2009年，全球流行的IAV H1N1亚型中高达100%对最常用的NAI药物奥司他韦耐药。然而，2009年大流行的IAV H1N1亚型对NAIs敏感，现已成为主要的季节性流感病毒株之一，取代了2009年前对奥司他韦耐药的H1N1变体。本综述追溯了自这些药物获批以来对金刚烷和NAI耐药的IAV亚型的流行病学情况，并强调了当前流行的IAV亚型对NAIs的敏感性状况。此外，它概述了目前以及即将采用的控制措施，以应对当前和新出现的耐药IAV。最后，本综述概述了为控制IAV在中间宿主中的传播以及开发有效和替代的抗IAV疗法应开展的研究方向。
