A continuous 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. Figure 1. Potential pathways and origins of antiviral drug-resistant viruses through environmental waters. 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 (e.g., 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. The unprecedented mass use of antiviral drugs is looming as global researchers race to develop them for COVID-19 applications, alongside vaccine development. In March 2020, U.S. health officials estimated that it may take 12–18 months for production and delivery of effective vaccines for COVID-19,(12) with many hurdles to overcome, placing greater pressure on antiviral drug development. The urgent question to understand is to what extent wild animal reservoirs could be exposed to antiviral drug residues in environmental waters, and how that may induce antiviral drug-resistant viruses in the future that then challenge the existing treatments for COVID-19-like pandemic diseases. Presumptive actions are required to study the occurrence, behavior and fate of various antiviral drugs and their metabolites during wastewater treatment and into receiving waters during pandemic events. In addition, the susceptibility of SARS-CoV-2 to antiviral drugs needs an urgent evaluation of potential antiviral drug resistance development in wild animal reservoirs. Perhaps this current COVID-19 crisis may become an opportunity to invest in upgrading WWTPs with advanced treatment capabilities such as ozonation for the enhanced removal of pharmaceuticals, including antiviral drugs.(1,5) Lack of proper sanitation infrastructure in less developed countries is also a challenge in terms of antiviral spread control in the environment, and thus additional investments in this area is needed as a global responsibility to maintain the efficacy of antiviral drugs. We believe that significant research is required to safeguard the efficacy and longevity of antiviral treatments. By responsibly understanding their environmental fate in WWTPs and environmental settings, accelerated antiviral resistance may be avoided, and treatment tools for future viral pandemics preserved. The authors declare no competing financial interest. This article references 12 other publications.

中文翻译：

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通过动物水库的环境药物暴露可能产生抗病毒的大流行性病毒。

我们初步的最坏情况（仅通过活性污泥法处理）估计表明，江河和湖泊接受了430–2120 ng / L的非维拉韦氢氧化物，这是流感药物favipiravir（Avigan）的主要代谢产物，或54–270 ng / L GS-441524如果每天向使用该药物治疗的现有患者中增加100名新患者/每100万人，则是WWTP废水中的活性形式埃博拉药物remdesivir（根据Singer等人2008（2）和Azuma等人的估计。 2012（5））。然后，可能会将天然存在病毒的动物（包括蝙蝠，骆驼，猫，穿山甲和猪）暴露于含有抗病毒药的河水中（图1），从而诱导抗病毒选择压力和病毒突变，从而导致产生抗病毒药抵抗性。图1。通过环境水域的抗病毒耐药性病毒的潜在途径和来源。已知病毒会快速发生基因突变并连续复制，从而增加了对现有抗病毒治疗的抵抗力。（7）迄今为止，据报道，人类病毒性疾病的抗病毒耐药性包括艾滋病，乙型和丙型肝炎，疱疹和流感。（7）同样，通过将动物水库暴露于含有抗病毒药的环境水中，可以加快抗病毒药的耐药性。例如，对于流感病毒，多项研究（1,2,5）都警告了水禽体内抗流感药物耐药性的风险，水禽体内被称为流感病毒的天然贮藏库。（8）在流感大流行期间，水禽，例如鸭子，可能会在环境水域中摄入抗流感药物和代谢物。在日本，过去一次新型流感大流行期间，在河水中检测到了奥司他韦（Tamiflu）的活性代谢产物oseltamivir羧酸盐，其浓度高达864.8 ng / L（6），超过了抑制50％体外生长的浓度（我知道了₅₀）的A型流感病毒（97-210 ng / L）。（9）这表明，在大流行抗病毒药物使用率的大流行期间，被污染的天然水可能在动物水库中引发抗病毒选择压力。同样，如果在COVID-19大流行期间暴露于受抗病毒药物污染的地表水，SARS-CoV-2可能能够在其动物蓄水池（例如蝙蝠和穿山甲）中获得抗病毒药物耐药性（10）。截至2020年5月14日，SARS-CoV-2的平均突变率为每年25.3个替换，约等于14天中的一个。（11）考虑到该突变率和众多的野生动物水库，在当前的COVID-19浪潮中，对SARS-CoV-2的抗病毒药物耐药性的出现可能给COVID-19大流行人类后的人类治疗带来挑战。随着全球研究人员竞相开发抗COVID-19应用的抗病毒药物，以及疫苗的开发，抗病毒药物的前所未有的大规模使用正在迫近。到2020年3月，美国卫生官员估计，生产和交付有效的COVID-19疫苗所需的时间可能为12至18个月，[12]尚需克服许多障碍，这给抗病毒药物的开发带来了更大的压力。迫切需要了解的问题是，野生动物水库在多大程度上可以暴露于环境水中的抗病毒药物残留，以及将来如何诱发抗病毒耐药性病毒，从而挑战现有的治疗COVID-19样大流行疾病的方法。需要采取推定行动来研究各种抗病毒药物及其代谢产物在废水处理过程中以及大流行事件期间进入接收水中的发生，行为和命运。此外，SARS-CoV-2对抗病毒药物的敏感性需要紧急评估野生动物库中潜在抗病毒药物耐药性的发展。也许当前的COVID-19危机可能会成为一个投资机会，以投资升级具有先进治疗能力的污水处理厂，如臭氧处理以增强对包括抗病毒药在内的药物的清除。（1，5）在欠发达国家，缺乏适当的卫生基础设施也是对环境中抗病毒传播控制的挑战，因此，作为保持抗病毒药物效力的全球责任，需要在这一领域进行额外投资。我们认为需要大量研究来保证抗病毒治疗的有效性和寿命。通过负责任地了解其在污水处理厂和环境中的环境命运，可以避免加速的抗病毒耐药性，并保留用于未来病毒性大流行的治疗工具。作者宣称没有竞争性的经济利益。本文引用了其他12个出版物。我们认为需要大量研究来保证抗病毒治疗的有效性和寿命。通过负责任地了解其在污水处理厂和环境中的环境命运，可以避免加速的抗病毒耐药性，并保留用于未来病毒性大流行的治疗工具。作者宣称没有竞争性的经济利益。本文引用了其他12个出版物。我们认为需要大量研究来保证抗病毒治疗的有效性和寿命。通过负责任地了解其在污水处理厂和环境中的环境命运，可以避免加速的抗病毒耐药性，并保留用于未来病毒性大流行的治疗工具。作者宣称没有竞争性的经济利益。本文引用了其他12个出版物。