【Cochrane简语概要】神经氨酸酶抑制剂用于预防和治疗成人和儿童流感

（图片来源于网络）

在出现可用的与流行病毒相匹配的流感疫苗之前，奥赛他韦和扎那米韦已被许多国家储备用于治疗和预防季节性和大流行性流感。奥司他韦被世界卫生组织列为基本药物。

该综述如何进行 

我们根据制造商向监管机构的报告（临床研究报告）和监管机构的意见，对成人和儿童流感的抗病毒药物扎那米韦和奥司他韦进行了更新和综合评估。我们称这些评论和报告为“监管信息”。临床研究报告为未发表的、有广泛且丰富的细节信息的文件，是构成市场认可的基础，包括方案，方法和结果。直至今日，临床研究报告仍是保密的，只有制造商和监管机构才能看到。

为什么采用这种方法 

在本综述的之前版本中，根据已发表的试验报告提供的数据，我们发现存在无法解决的差异及实质性的发表偏倚。因此，我们选择不使用期刊发表文献中的数据，而是纳入药品许可申请过程中产生的资料。我们已经从英国，美国，欧洲药品管理局，日本监管机构和制造商的临床研究报告（经过长时间的媒体宣传）中获得了这些数据。这使我们能够验证来自成年人或儿童已确诊或疑似暴露于自然流行性感冒中的随机、安慰剂对照试验的信息。

根据我们对监管文件（超过16万页）的评估，得出的结论是，许多试验的设计，实施，报告和信息可及性存在严重问题。

我们发现了什么 

本研究中我们采用了来自46项试验的数据（20项奥司他韦和26项扎那米韦研究）。在纳入的许多研究中存在一些设计问题，这影响了我们对其结果的信心。我们发现两种药物都缩短了流感样症状（未确诊的流感或“流感”）的持续时间，缩短程度少于1天。根据所有参与奥司他韦治疗试验者的数据，奥司他韦对住院人数没有影响。扎那米韦试验没有记录这一结果。对肺炎和其他并发症如支气管炎，中耳感染（中耳炎）和鼻窦炎的影响的报告是不可靠的，因为数据来源于试验资料中的病例报告表。有些记录显示肺炎的诊断标准存在局限性。监管评论指出受试者缺少后续日记卡随访的问题。对哮喘儿童首次症状缓解所需时间无明显影响。

预防性试验表明，奥司他韦和扎那米韦降低了个人和家庭罹患症状性流感的风险。没有证据显示对无症状流感或非流感样或流感样疾病有疗效，但是试验执行中存在的问题也使得无法得出明确的结论。

奥司他韦的使用与恶心，呕吐，头痛，肾脏和精神事件有关，其中后三种是用于预防流行性感冒时出现的（预防）。它对心脏的影响不清楚：它可能会减轻心脏症状，但也可能会引起严重的心律问题。在扎那米韦的成人治疗试验中，没有增加不良事件的记录。关于儿童扎那米韦治疗儿童相的可能危害的证据很少。

与其他发现的一致性 

缺少显示对于并发症影响的良好证据，与美国食品和药物管理局（FDA）提出的关于两种药物的保守结论一致。FDA只认可两种药物用于预防和治疗流行性感冒症状的有效性声明，而不是其他疗效（包括中断流感病毒的人对人之间传播或预防肺炎）。FDA将两种药物的整体效能描述为“适度”。

疗效的作用机制 

这些发现都表明，通过奥司他韦羧酸盐的作用诱导的低水平的促炎细胞因子的低免疫应答可能减轻与抑制流感病毒复制无关的流感症状。奥司他韦作为中枢神经系统抑制剂具有潜在的降温或解热作用，这也可能导致宿主症状的明显减轻。我们能够获得的任何数据不支持奥司他韦在中断病毒传播和减少并发症方面的作用。

制造商提出的作用机制（流感病毒特异性）与临床证据不符，显示多系统与核心作用。

结论:

奥司他韦和扎那米韦对减少成年人流感症状缓时间有很小的非特异性疗效，但对哮喘儿童则没有。使用这两种药物作为预防措施可降低发生症状性流感的风险。由于缺乏诊断定义，奥司他韦或扎那米韦的治疗试验不能解决流感并发症（如肺炎）是否减少的问题。奥司他韦的使用增加了不良效应的风险，如成人的恶心，呕吐，精神影响和肾脏事件以及儿童呕吐。较低的生物利用度可以解释与奥司他韦相比，扎那米韦的毒性较低。在作出有关使用NI预防或治疗流感的决定时，应考虑获益与危害之间的平衡。制造商提出的流感病毒特异性作用机制不符合临床证据。

【Cochrane Plain Language Summary】Regulatory information on trials of oseltamivir (Tamiflu) and zanamivir (Relenza) for influenza in adults and children

Oseltamivir and zanamivir have been stockpiled in many countries to treat and prevent seasonal and pandemic influenza, before an influenza vaccine matched to the circulating virus becomes available. Oseltamivir is classified by the World Health Organization as an essential medicine.

How this review has been approached

We have updated and combined our reviews on the antiviral drugs zanamivir and oseltamivir for influenza in adults and children on the basis of the manufacturers' reports to regulators (clinical study reports) and the regulators' comments. We have called these comments and reports 'regulatory information'. Clinical study reports are unpublished, extensive documents with great detail on the trials that formed the basis for market approval. They include the protocols, methods and results. Clinical study reports have until now been confidential, seen only by the manufacturers and regulators.

Why we have taken this approach

In previous versions of this review we identified unresolved discrepancies in the data presented in published trial reports and substantial publication bias. As a consequence, we elected not to use data from journal articles but included the documents generated during licensing processes. We have accessed such data from the UK, USA, European Medicines Agency (EMA), Japanese regulators and clinical study reports from the manufacturers (after a protracted media campaign). This has enabled us to verify information from the randomised, placebo-controlled trials on adults and children with confirmed or suspected exposure to naturally occurring influenza.

Based on our assessments of the regulatory documents (in excess of 160,000 pages), we came to the conclusion that there were substantial problems with the design, conduct, reporting and availability of information from many of the trials.

What we have found

We have used data from 46 trials (20 oseltamivir and 26 zanamivir studies) in this review. We identified problems in the design of many of the studies that we included, which affects our confidence in their results. We found that both drugs shorten the duration of symptoms of influenza-like illness (unconfirmed influenza or 'the flu') by less than a day. Oseltamivir did not affect the number of hospitalisations, based on the data from all the people enrolled in treatment trials of oseltamivir. Zanamivir trials did not record this outcome. The effects on pneumonia and other complications of influenza, such as bronchitis, middle ear infection (otitis media) and sinusitis, were unreliably reported, as shown by the case report form in the trial documents. Some forms showed limitations in the diagnostic criteria for pneumonia. Regulatory comments noted problems with missing follow-up diary cards from participants. In children with asthma there was no clear effect on the time to first alleviation of symptoms.

Prophylaxis trials showed that oseltamivir and zanamivir reduced the risk of symptomatic influenza in individuals and households. There was no evidence of an effect on asymptomatic influenza or on non-influenza, influenza-like illness, but trial conduct problems prevent any definitive conclusion.

Oseltamivir use was associated with nausea, vomiting, headaches, renal and psychiatric events; these last three were when it was used to prevent influenza (prophylaxis). Its effect on the heart is unclear: it may reduce cardiac symptoms, but may induce serious heart rhythm problems. In adult treatment trials of zanamivir there was no increased risk of reported adverse events. The evidence on the possible harms associated with the treatment of children with zanamivir was sparse.

Agreement with other findings

The lack of good evidence demonstrating an effect on complications agrees with the conservative conclusions on both drugs drawn by the US Food and Drug Administration (FDA). The FDA only allowed claims of effectiveness of both drugs for the prevention and treatment of symptoms of influenza and not for other effects (including the interruption of person-to-person spread of the influenza virus or prevention of pneumonia). The FDA described the overall performance of both drugs as 'modest'.

Mechanism of action for beneficial effects

These findings all suggest that the low immune response with low levels of pro-inflammatory cytokines, which is induced by the action of oseltamivir carboxylate, may reduce the symptoms of influenza unrelated to an inhibition of influenza virus replication. The potential hypothermic or antipyretic effect of oseltamivir as a central nervous system depressant may also contribute to the apparent reduction of host symptoms. Statements made on the capacity of oseltamivir to interrupt viral transmission and reduce complications are not supported by any data we have been able to access.

The mechanism of action proposed by the producers (influenza virus-specific) does not fit the clinical evidence which suggests a multi-system and central action.

Authors' conclusions: 

Oseltamivir and zanamivir have small, non-specific effects on reducing the time to alleviation of influenza symptoms in adults, but not in asthmatic children. Using either drug as prophylaxis reduces the risk of developing symptomatic influenza. Treatment trials with oseltamivir or zanamivir do not settle the question of whether the complications of influenza (such as pneumonia) are reduced, because of a lack of diagnostic definitions. The use of oseltamivir increases the risk of adverse effects, such as nausea, vomiting, psychiatric effects and renal events in adults and vomiting in children. The lower bioavailability may explain the lower toxicity of zanamivir compared to oseltamivir. The balance between benefits and harms should be considered when making decisions about use of both NIs for either the prophylaxis or treatment of influenza. The influenza virus-specific mechanism of action proposed by the producers does not fit the clinical evidence.

译者：李文元；审校：梁宁；编辑排版：张晓雯，北京中医药大学循证医学中心

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