Antiviral resistance and the control of pandemic influenza.
Antiviral resistance and the control of pandemic influenza.
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DOI：
10.1371/journal.pmed.0040015
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发表时间：
2007-01
期刊：
影响因子：
15.8
通讯作者：
Levin BR
中科院分区：
文献类型：
--
作者：
Lipsitch M;Cohen T;Murray M;Levin BR
应对下一次流感大流行的措施可能包括广泛使用抗病毒药物（主要是奥司他韦），并结合其他减少传播的措施。动物和体外研究表明，某些流感毒株可能对奥司他韦产生耐药性，同时保持传染性（适应性）。为控制大流行性流感而预期大规模使用抗病毒药物，将对这些毒株的出现和传播造成前所未有的选择性压力。然而，在评估这些计划时，抗病毒药物耐药性很少受到关注。我们设计并分析了大流行期间奥司他韦敏感和耐药流感感染传播的确定性区室模型。该模型预测，即使抗病毒治疗或预防导致在接受治疗的5万分之一和接受预防的50万分之一的人群中出现可传播的耐药菌株，广泛使用抗病毒药物也可能在人群一级强烈促进耐药菌株的传播，导致在大流行结束时流行率达到10%。另一方面，即使在耐药菌株广泛传播的情况下，使用抗病毒药物也可能大大延缓和/或减少大流行的总规模。如果耐药菌株具有一定的适应性成本，那么，尽管耐药性广泛出现，抗病毒药物可能会将大流行的传播减缓数月或更长时间，并为疫苗开发争取时间；减少传播的非药物控制措施（如保持社会距离）或使用储存的次优疫苗会延长这种延迟。令人惊讶的是，该模型表明，这种非药物控制措施将增加由耐药菌株引起的流行病的比例。使用抗病毒药物控制流感大流行的好处可能会因病毒的耐药性而减少，尽管不是完全抵消。因此，在大流行规划中应考虑耐药性风险，并在大流行期间密切监测。如果广泛使用奥司他韦，在大流行期间很可能出现对奥司他韦具有耐药性的流感毒株，因为选择压力增大。Marc Lipsitch和他的同事认为，耐药性会减少但不会完全抵消这种药物在控制流行病方面的好处。世界各国政府和卫生当局正在规划如何最好地防范和应对未来的流感大流行。据认为，季节性流感每年影响全球5%至15%的人口。大多数感染流感的人在几周内康复，没有持久的影响，但一小部分患者，主要是幼儿和老年人，会出现严重的并发症，可能是致命的。当流感病毒的新变种出现时，一般人群对其几乎没有免疫力，就会发生流感大流行。大流行性流感病毒株的传播速度比季节性流感病毒株要快，经常横扫几个国家或大洲，使更多的人患病。有一些药物可以治疗和预防流感。其中，奥司他韦（达菲）是一种抗病毒药物，通过阻止病毒颗粒从受感染的人体细胞中释放出来而起作用。储存大量奥司他韦和相关药物，目的是治疗很大一部分人口，这是许多国家防备大流行病的一个关键部分。然而，众所周知，流感病毒会对这些药物产生耐药性。目前尚不清楚奥司他韦耐药流感毒株的出现将如何影响未来任何流感大流行的进程。这一领域的许多研究都集中在新菌株出现的可能性上，而不是在它们出现后如何传播。在流感大流行的背景下，抗病毒药物将在很大一部分人群中使用，可能会推动耐药病毒的选择和传播。在这项研究中，研究人员想要估计在流感大流行期间耐药菌株可能产生的影响。这些研究人员建立了一个数学模型（即在计算机上进行的模拟）来模拟流感的传播。然后，他们将一组假设输入计算机。这些信息包括流感在人与人之间传播的速度；有多少人会接受抗病毒药物的预防或治疗？这些药物成功治疗或预防感染的可能性有多大；以及在多大比例的人群中，病毒可能会对药物产生抗药性。该模型得出了三个主要预测。首先，它预测广泛使用诸如奥司他韦之类的抗病毒药物可能很快导致耐药病毒的传播，即使耐药菌株很少出现。其次，即使有耐药菌株在流通，奥司他韦的预防和治疗仍将延缓大流行的传播，并减少其总体规模。第三，非药物干预措施（如社会隔离和学校关闭）将进一步减少病例数，但如果采用这些控制措施，耐药菌株造成的病例比例将更高。这些发现表明，如果未来发生使用抗病毒药物的流感大流行，就有出现耐药性和耐药菌株导致大量人群患病的风险。这将抵消抗病毒药物的好处，但不会完全消除这些好处。像所有的建模研究一样，这一研究依赖于模型中输入的现实假设，在了解实际大流行毒株的特性之前，很难确切地知道模型是否会模拟现实情况。包括本研究在内的大多数研究表明，在发生大流行的情况下，抗病毒药物将对降低死亡率和不良健康后果产生总体有益影响。然而，鉴于此处提出的耐药性的巨大影响，应在大流行规划中考虑其作用。这包括监测能够发现耐药菌株的出现和传播。请通过本摘要的在线版本http://dx.doi.org/doi:10.1371/journal.pmed.0040015访问这些网站。世界卫生组织：流感概况介绍英国卫生防护署关于大流行性流感的资料美国政府网站关于大流行性流感和禽流感的资料（资料由美国卫生及公众服务部提供）
The response to the next influenza pandemic will likely include extensive use of antiviral drugs (mainly oseltamivir), combined with other transmission-reducing measures. Animal and in vitro studies suggest that some strains of influenza may become resistant to oseltamivir while maintaining infectiousness (fitness). Use of antiviral agents on the scale anticipated for the control of pandemic influenza will create an unprecedented selective pressure for the emergence and spread of these strains. Nonetheless, antiviral resistance has received little attention when evaluating these plans. We designed and analyzed a deterministic compartmental model of the transmission of oseltamivir-sensitive and -resistant influenza infections during a pandemic. The model predicts that even if antiviral treatment or prophylaxis leads to the emergence of a transmissible resistant strain in as few as 1 in 50,000 treated persons and 1 in 500,000 prophylaxed persons, widespread use of antivirals may strongly promote the spread of resistant strains at the population level, leading to a prevalence of tens of percent by the end of a pandemic. On the other hand, even in circumstances in which a resistant strain spreads widely, the use of antivirals may significantly delay and/or reduce the total size of the pandemic. If resistant strains carry some fitness cost, then, despite widespread emergence of resistance, antivirals could slow pandemic spread by months or more, and buy time for vaccine development; this delay would be prolonged by nondrug control measures (e.g., social distancing) that reduce transmission, or use of a stockpiled suboptimal vaccine. Surprisingly, the model suggests that such nondrug control measures would increase the proportion of the epidemic caused by resistant strains. The benefits of antiviral drug use to control an influenza pandemic may be reduced, although not completely offset, by drug resistance in the virus. Therefore, the risk of resistance should be considered in pandemic planning and monitored closely during a pandemic. Emergence of oseltamivir-resistant influenza strains during a pandemic is likely given the heightened selective pressure if the drug is widely used. Marc Lipsitch and colleagues suggest that resistance would reduce but not completely offset the drug's benefits for pandemic control. Governments and health authorities worldwide are planning how they would best prepare for and deal with a future influenza pandemic. Seasonal influenza is thought to affect between 5% and 15% of the population worldwide each year. Most people who get influenza recover within a couple of weeks without lasting effects, but a small proportion of patients, mostly young children and elderly people, experience serious complications that can be fatal. An influenza pandemic happens when new variants of the influenza virus emerge against which little immunity exists in the general population. Pandemic influenza strains are transmitted more rapidly than seasonal strains, often sweep across several countries or continents, and make more people ill. There are drugs that can treat and prevent influenza. One of them, oseltamivir (Tamiflu) is an antiviral drug that works by preventing viral particles from being released by infected human cells. Stockpiling large amounts of oseltamivir and related drugs with the intent to treat a large fraction of the population is a key part of pandemic preparedness of many countries. However, it is known that influenza viruses can develop resistance to these drugs. It is not clear how the emergence of oseltamivir-resistant influenza strains would affect the course of any future influenza pandemic. Much research in this area has focused on how likely the new strains are to emerge in the first place, rather than on how they might spread once they had emerged. In the context of an influenza pandemic, antiviral drugs would be used in a large proportion of the population, likely driving the selection and spread of resistant viruses. For this study, the researchers wanted to estimate the likely impact of resistant strains during an influenza pandemic. These researchers set up a mathematical model (i.e., simulations done on a computer) to mimic the spread of influenza. They then fed a set of assumptions into the computer. These included information about the rate of transmission of influenza from one person to another; what proportion of people would receive antiviral drugs for prophylaxis or treatment; how likely the drugs would be to successfully treat or prevent infection; and in what proportion of people the virus might become resistant to drugs. The modeling led to three main predictions. First, it predicted that widespread use of antiviral drugs such as oseltamivir could quickly lead to the spread of resistant viruses, even if resistant strains emerged only rarely. Second, even with resistant strains circulating, prophylaxis and treatment with oseltamivir would still delay the spread of the pandemic and reduce its total size. Third, nondrug interventions (such as social isolation and school closures) would further reduce the number of cases, but a higher proportion of cases would be caused by resistant strains if these control measures were used. These findings suggest that, in the event of a future influenza pandemic for which antiviral drugs are used, there is a risk of resistance emerging and resistant strains causing illness in a substantial number of people. This would counteract the benefits of antiviral drugs but not eliminate those benefits entirely. Like all modeling studies, this one relies on realistic assumptions being entered into the model, and it is hard to know closely the model will mimic a real-life situation until the properties of an actual pandemic strain are known. Most studies, including this one, suggest that in the event of a pandemic, antiviral drugs will have an overall beneficial impact on reducing death rates and adverse health outcomes. However, given the sizeable effects of resistance suggested here, its role should be considered in pandemic planning. This includes surveillance that can detect emergence and spread of resistant strains. Please access these Web sites via the online version of this summary at http://dx.doi.org/doi:10.1371/journal.pmed.0040015. World Health Organization: information on pandemic preparedness World Health Organization: fact sheets on influenza Information from the UK Health Protection Agency on pandemic influenza US government website on both pandemic flu and avian flu (information provided by the US Department of Health and Human Services)
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影响因子：
168.9
作者：
Cissé, B;Sokhna, C;Trape, JF
通讯作者：
Trape, JF
影响因子：
7.6
作者：
Ilyushina, Natalia A.;Bovin, Nicolai V.;Govorkova, Elena A.
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影响因子：
168.9
作者：
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通讯作者：
Kawaoka, Y
DOI：
10.1073/pnas.0600349103
发表时间：
2006-05-02
影响因子：
11.1
作者：
Cohen, T;Lipsitch, M;Murray, M
通讯作者：
Murray, M
DOI：
10.1001/jama.295.8.joc60020
发表时间：
2006-02-22
影响因子：
120.7
作者：
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通讯作者：
Klimov, AI