Two publicly funded studies from the United States and England show that the proportion of seasonal influenza A viruses resistant to two types of antiviral drugs has risen in recent years, and that drug-resistant pandemic influenza A was transmitted person-to-person during one 2009 outbreak.

Both studies, published online Dec. 7 in the Journal of Infectious Diseases, highlight concerns about how easily influenza A/H1N1 viruses can develop mutations for resistance, about the paucity of treatment options available for resistant infections, and the risks of using potentially ineffective agents.

For the first study, Tiffany G. Sheu and Dr. Larisa Gubareva of the Centers for Disease Control and Prevention in Atlanta, and their colleagues, tested seasonal H1N1 viruses collected between 2008 and 2010 for resistance to two types of antivirals: oseltamivir and adamantane drugs. The investigators noted that resistance-conferring mutations in an influenza A virus can occur as a result of drug selection, spontaneous mutation, or genetic reassortment with another drug-resistant influenza A virus (J. Infect. Dis. 2011;203[1]:13-7).

Of the nearly 1,500 virus samples submitted by surveillance programs around the world, 28 viruses from 5 countries in North America, Africa, and Asia, exhibited both adamantane and oseltamivir resistance, the investigators reported. The proportion of resistant viruses increased from .06% (1 of 1,753) of those from 2007-2008, to 1.5% in samples from 2008-2009 (21 of 1,426), and to 28% in a smaller number of samples from the 2009-2010 season (7 of 25), when fewer seasonal A strains were circulating. The dual-resistant viruses represented 4 different genotypes.

“Although dual-resistant viruses are still rare,” the researchers wrote, “the increase in prevalence among seasonal influenza A(H1N1) viruses was notable during the last 3 seasons.” Also, the detection of dual-resistant seasonal A(H1N1) viruses from 5 countries “warrants concern,” they wrote, “because of the limited treatment options currently available for dual-resistant influenza A viruses.”

In the U.K. study, clinical virologist Catherine Moore and Dr. Elori Davies of the Public Health Wales NHS Trust in Cardiff, and their colleagues, described the first molecularly confirmed person-to-person transmission of oseltamivir-resistant pandemic influenza A(H1N1) 2009 virus. After an outbreak of 11 cases in the hematology wing of a public hospital in October and November 2009, 10 were shown by sequencing to be virologically related, 8 were oseltamivir-resistant, and 4 of the 8 infections occurred by direct transmission of resistant virus.

Though the infected patients had considerable underlying disease, including leukemia, multiple myeloma, and lymphoma, influenza symptoms were generally manageable during the outbreak, and none of the patients died as a result of their resistant infections, Moore and colleagues reported (J. Infect. Dis. 2011;203[1]:18-24).

Dual treatment with oseltamivir and zanamivir was used when resistant virus was suspected or confirmed. However, Moore and colleagues noted, “recent data suggest there is possibly no synergy to be gained from this approach,” and “zanamivir alone therefore would be preferable as a frontline treatment in particularly high-risk groups.”

In an editorial comment accompanying the two studies, Dr. Frederick G. Hayden of the University of Virginia, Charlottesville, and Dr. Menno D. de Jong of the University of Amsterdam, the Netherlands, saw cautions in both. “Together, these findings illustrate that single reassortment events or mutations can lead to the emergence of transmissible variants of pandemic 2009 or seasonal A(H1N1) viruses unresponsive to most, if not all, of our currently available drugs. This raises multiple questions regarding patient management and preparations for future influenza outbreaks,” they wrote (J. Infect. Dis. 2011;203[1]6-10).

The study by Ms. Sheu and Dr. Gubareva was funded by the Centers for Disease Control and Prevention. The study by Ms. Moore and Dr. Davies was funded by their public institutions; one coauthors acknowledged funding from the Wellcome Trust for a virus-sequencing pipeline project and another received funding from Roche for an influenza virus shedding study in oseltamivir-treated patients.

Dr. Hayden reported that he has received no research grants or personal honoraria from industry since 2006, but that he has served as an unpaid adviser to multiple companies involved in the development of influenza antivirals since 2008, and is member of the Neuraminidase Inhibitor Susceptibility Network, which has received funds from GlaxoSmithKline and Roche.

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

美国和英国进行的两项公费研究显示，对两类抗病毒药耐药的季节性甲型流感病毒的比例在近几年有所上升，并且在2009年度流感暴发期间耐药的大流行性甲型流感可经人与人之间传播。 

在第一项研究中，亚特兰大疾病预防与控制中心的Tiffany G. Sheu和Larisa Gubareva博士等人检测了2008~2010年间采集的季节性H1N1流感病毒样本对奥司他韦和金刚烷胺类药物这两类抗病毒药的耐药性。检测结果显示，在由全世界各地监测项目组提交的近1,500个病毒样本中， 28种来自北美洲、非洲和亚洲5个国家的病毒表现出对金刚烷和奥司他韦的双重耐药性。耐药病毒的比例由2007~2008年的0.06%(1/1,753)上升至2008~2009年的1.5%，而根据对2009~2010年的较少量流感季节样本的检测结果，该比例又进一步上升至该年度的28%。双重耐药的病毒表现出4中不同的表型。药物选择、自发突变或与另一种耐药的甲型流感病毒发生基因重组均可导致甲型流感病毒发生耐药性突变。 

在英国的这项研究中，加地夫威尔士公共卫生组织国民健康服务(NHS)信托基金会的临床病毒学家Catherine Moore 和Elori Davies博士等人描述了第一个从分子水平证实可经人与人之间传播且对奥司他韦耐药的2009年度大流行性甲型H1N1流感病毒。另外，在2009年10月和11月公立医院血液病科暴发11例流感病例后，有10例先后被查出在病毒学上具有相关性，8例对奥司他韦耐药，其中有4例通过耐药病毒直接传播而发生感染。尽管受感染的病例还患有白血病、多发性骨髓瘤、淋巴瘤等众多基础疾病，但暴发期间的流感症状普遍可以得到控制，无一例患者死于耐药性感染。 

在疑似或确诊为耐药病毒时，一般采用奥司他韦和扎纳米韦双重治疗。但最近有数据显示，这种治疗方案可能不会产生协同作用，因此对于极高危的患者，最好采用扎纳米韦单药治疗作为一线治疗。

这两项研究均在线发表于12月7日的《传染病杂志》中，突出了人们对甲型H1N1流感病毒发生耐药性突变的容易程度、对耐药性病毒感染治疗选择匮乏以及使用潜在无效药物的相关风险的担忧，也在患者处置和应对今后流感暴发的准备工作方面提出了更多的难题(J. Infect. Dis. 2011;203[1]6-10)。

Sheu女士和 Gubareva博士进行的研究由疾病预防与控制中心资助。 Moore 女士和 Davies博士进行的研究由其公共机构资助：一位合著者坦言获得维康信托基金会病毒测序项目的资助，另一位合著者在对接受奥司他韦治疗者进行的流感病毒脱落研究中获得罗氏的资助。 

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