Hooker Kyla L, Ganusov Vitaly V
Genome Science and Technology, University of Tennessee, Knoxville, TN, United States.
Department of Microbiology, University of Tennessee, Knoxville, TN, United States.
Front Microbiol. 2021 Mar 1;12:631211. doi: 10.3389/fmicb.2021.631211. eCollection 2021.
Influenza viruses infect millions of humans every year causing an estimated 400,000 deaths globally. Due to continuous virus evolution current vaccines provide only limited protection against the flu. Several antiviral drugs are available to treat influenza infection, and one of the most commonly used drugs is oseltamivir (Tamiflu). While the mechanism of action of oseltamivir as a neuraminidase inhibitor is well-understood, the impact of oseltamivir on influenza virus dynamics in humans has been controversial. Many clinical trials with oseltamivir have been done by pharmaceutical companies such as Roche but the results of these trials until recently have been provided as summary reports or papers. Typically, such reports included median virus shedding curves for placebo and drug-treated influenza virus infected volunteers often indicating high efficacy of the early treatment. However, median shedding curves may be not accurately representing drug impact in individual volunteers. Importantly, due to public pressure clinical trials data testing oseltamivir efficacy has been recently released in the form of redacted PDF documents. We digitized and re-analyzed experimental data on influenza virus shedding in human volunteers from three previously published trials: on influenza A (1 trial) or B viruses (2 trials). Given that not all volunteers exposed to influenza viruses actually start virus shedding we found that impact of oseltamivir on the virus shedding dynamics was dependent on (i) selection of volunteers that were infected with the virus, and (ii) the detection limit in the measurement assay; both of these details were not well-articulated in the published studies. By assuming that any non-zero viral measurement is above the limit of detection we could match previously published data on median influenza A virus (flu A study) shedding but not on influenza B virus shedding (flu B study B) in human volunteers. Additional analyses confirmed that oseltamivir had an impact on the duration of shedding and overall shedding (defined as area under the curve) but this result varied by the trial. Interestingly, treatment had no impact on the rates at which shedding increased or declined with time in individual volunteers. Additional analyses showed that oseltamivir impacted the kinetics of the end of viral shedding, and in about 20-40% of volunteers that shed the virus treatment had no impact on viral shedding duration. Our results suggest an unusual impact of oseltamivir on influenza viruses shedding kinetics and caution about the use of published median data or data from a few individuals for inferences. Furthermore, we call for the need to publish raw data from critical clinical trials that can be independently analyzed.
流感病毒每年感染数百万人，全球估计有40万人死亡。由于病毒不断进化，目前的疫苗对流感的防护作用有限。有几种抗病毒药物可用于治疗流感感染，最常用的药物之一是奥司他韦（达菲）。虽然奥司他韦作为神经氨酸酶抑制剂的作用机制已为人熟知，但它对人类流感病毒动态的影响一直存在争议。罗氏等制药公司已经进行了许多关于奥司他韦的临床试验，但直到最近，这些试验的结果都是以总结报告或论文的形式呈现。通常，此类报告包括安慰剂组和接受药物治疗的流感病毒感染志愿者的病毒排泄中位数曲线，常常表明早期治疗效果显著。然而，中位数排泄曲线可能无法准确反映个体志愿者体内药物的影响。重要的是，由于公众压力，检测奥司他韦疗效的临床试验数据最近以编辑后的PDF文档形式发布。我们对来自三项先前发表的试验的人类志愿者流感病毒排泄实验数据进行了数字化处理和重新分析：一项关于甲型流感病毒（1项试验），两项关于乙型流感病毒（2项试验）。鉴于并非所有接触流感病毒的志愿者都会实际开始病毒排泄，我们发现奥司他韦对病毒排泄动态的影响取决于：（i）选择感染病毒的志愿者，以及（ii）测量检测方法的检测限；而这两个细节在已发表的研究中均未详细说明。通过假设任何非零病毒测量值都高于检测限，我们能够匹配先前发表的关于人类志愿者甲型流感病毒排泄中位数的数据（甲型流感研究），但无法匹配乙型流感病毒排泄的数据（乙型流感研究B）。进一步分析证实，奥司他韦对排泄持续时间和总体排泄量（定义为曲线下面积）有影响，但这一结果因试验而异。有趣的是，治疗对个体志愿者体内排泄随时间增加或减少的速率没有影响。进一步分析表明，奥司他韦影响病毒排泄结束的动力学，在约20%-40%排泄病毒的志愿者中，治疗对病毒排泄持续时间没有影响。我们的结果表明奥司他韦对流感病毒排泄动力学有不同寻常的影响，并提醒人们谨慎使用已发表的中位数数据或少数个体的数据进行推断。此外，我们呼吁有必要公布关键临床试验的原始数据，以便能够进行独立分析。
