Potential Emergence of Antiviral-Resistant Pandemic Viruses via Environmental Drug Exposure of Animal Reservoirs
Potential Emergence of Antiviral-Resistant Pandemic Viruses via Environmental Drug Exposure of Animal Reservoirs
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DOI：
10.1021/acs.est.0c03105
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发表时间：
2020-07-21
影响因子：
11.4
通讯作者：
Kitajima, Masaaki
中科院分区：
文献类型：
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作者：
Kumar, Manish;Kuroda, Keisuke;Kitajima, Masaaki
抗病毒药物不断泄漏到环境中导致抗病毒药物耐药性，从而危及人类病毒性疾病的治疗。1,2随着全球范围内对新型冠状病毒（SARS-CoV-2）有效药物的深入研究，几种抗病毒和抗寄生虫药物，包括埃博拉（瑞德西韦）、流感（法匹拉韦、奥司他韦）、艾滋病毒（洛匹那韦/利托那韦）和疟疾（氯喹）药物，已在COVID-19患者身上进行了临床试验。3,4由于这些药物及其代谢物大多随尿液排出，因此根据废水处理厂（WWTPs）的去除效率，有可能排放到环境中。1,2,5,6例如，我们初步的最坏情况（仅通过活性污泥法处理）估计显示，河流和湖泊接收到430 - 2120 ng/L的favipiravir氢氧化物（流感药物favipiravir （Avigan）的主要代谢物）或54 - 270 ng/L的GS-441524（埃博拉药物remdesivir的活性形式）。如果在现有接受药物治疗的患者基础上，每100万人均每天增加100名新患者，则从污水处理厂排出的污水中获得的收益（根据Singer等人，2008年2和Azuma等人，2012年5估算）。作为病毒天然储存库的动物，包括蝙蝠、骆驼、猫、穿山甲和猪，随后可能暴露于含有抗病毒药物的河水中（图1），从而在病毒中诱导抗病毒选择压力和突变，导致抗病毒药物耐药性。众所周知，病毒在连续复制的过程中迅速经历基因组突变，增加了对现有抗病毒治疗的耐药性。7迄今为止，已报道了人类病毒性疾病的抗病毒药物耐药性，包括艾滋病、乙型和丙型肝炎、疱疹和流感。7同样，将动物水库暴露于含有抗病毒药物的环境水中可能会加速抗病毒药物的耐药性。例如，就流感病毒而言，多项研究1、2、5对水禽体内抗流感药物耐药性的风险提出了警告，水禽被认为是流感病毒的天然宿主。8 .在流感大流行期间，水禽，如鸭子，可能在环境水中摄入抗流感药物和代谢物。在日本，在过去的新型流感大流行期间，在河水中检测到奥司他韦（达菲）的活性代谢物羧酸奥司他韦，浓度高达864.8 ng/ l6，超过了抑制流感a型病毒50%体外生长（IC50）的浓度（97−210 ng/L）。这表明，在抗病毒药物使用率高的大流行期间，受污染的天然水可能在动物宿主中引发抗病毒药物的选择性压力。同样，如果在COVID-19大流行期间暴露于被抗病毒药物污染的地表水，SARS-CoV-2可能会在其动物宿主（例如蝙蝠和穿山甲）中获得抗病毒药物耐药性。截至2020年5月14日，SARS-CoV-2的平均突变率为每年25.3次，约为14天一次。考虑到这一突变率和众多野生动物宿主种群，在当前的COVID-19浪潮中出现对SARS-CoV-2的抗病毒药物耐药性，可能会给COVID-19大流行后的人类世带来挑战。
Acontinuous leak of antiviral drugs into the environment leads to antiviral drug resistance which compromises the treatment of human viral diseases. 1, 2 As the intense search for effective drugs against the novel coronavirus (SARS-CoV-2) is progressing worldwide, several antiviral and antiparasitic drugs, including those for Ebola (remdesivir), influenza (favipiravir, oseltamivir), HIV (lopinavir/ritonavir), and malaria (chloroquine), have undergone clinical trials on COVID-19 patients. 3, 4 Since these drugs and their metabolites are mostly excreted in urine, there is the potential for discharge to the environment depending on removal efficiency at wastewater treatment plants (WWTPs). 1, 2, 5, 6 For example, our preliminary worst-case (treatment by activated sludge process only) estimation shows that rivers and lakes receive 430− 2120 ng/L favipiravir hydroxide, the major metabolite of influenza drug favipiravir (Avigan), or 54− 270 ng/L GS-441524, the active form of ebola drug remdesivir, from WWTP effluents if 100 new patients per 1 milllion capita are added every day to existing patients who are treated with the drugs (estimated based on Singer et al. 2008 2 and Azuma et al. 2012 5). Animals that are a natural reservoir of viruses, including bats, camels, cats, pangolins, and pigs, may then be exposed to the river water containing antiviral drugs (Figure 1), inducing antiviral selective pressures and mutations in the virus leading to antiviral drug resistance.Viruses are known to rapidly undergo genome mutations with successive replications, increasing the chances of resistance to existing antiviral treatments. 7 To date, antiviral drug resistance has been reported for human viral diseases including AIDS, hepatitis B and C, herpes, and influenza. 7 Likewise, antiviral drug resistance could be accelerated by exposure of animal reservoirs to environmental waters containing antiviral drugs. For example, for influenza viruses, multiple studies 1, 2, 5 have alarmed the risk of anti-influenza drug resistance in the body of water fowls, which are known as natural reservoirs of influenza virus. 8 During influenza pandemic, water fowls, such as ducks, may ingest anti-influenza drugs and metabolites in environmental waters. In Japan, oseltamivir carboxylate, the active metabolite of oseltamivir (Tamiflu), was detected in river water at concentrations up to 864.8 ng/L 6 during the past pandemic of novel influenza, exceeding the concentration that inhibits 50% of in vitro growth (IC50) of influenza-A virus (97− 210 ng/L). 9 This suggests contaminated natural waters could initiate antiviral selective pressure in animal reservoirs during a pandemic with high rates of antiviral drug use. Similarly, SARS-CoV-2 is potentially capable of acquiring antiviral drug resistance in its animal reservoirs (eg, bats and pangolins) 10 in the event of exposure to surface waters contaminated with antiviral drugs during the COVID-19 pandemic. As of May 14, 2020, the average mutation rate of SARS-CoV-2 is 25.3 substitutions per year, which equals approximately one in 14 days. 11 Considering this mutation rate and the numerous populations of wild animal reservoirs, the emergence of antiviral drug resistance to SARS-CoV-2 during the current waves of COVID-19 could generate challenges for human treatment in the post COVID-19-pandemic Anthropocene.