Neuraminidase inhibitors for preventing and treating influenza in adults and children

  • Comment
  • Review
  • Intervention

Authors


Abstract

Background

Neuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used clinically worldwide.

Objectives

To describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports of published and unpublished randomised, placebo-controlled trials and regulatory comments.

Search methods

We searched trial registries, electronic databases (to 22 July 2013) and regulatory archives, and corresponded with manufacturers to identify all trials. We also requested clinical study reports. We focused on the primary data sources of manufacturers but we checked that there were no published randomised controlled trials (RCTs) from non-manufacturer sources by running electronic searches in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE (Ovid), EMBASE, Embase.com, PubMed (not MEDLINE), the Database of Reviews of Effects, the NHS Economic Evaluation Database and the Health Economic Evaluations Database.

Selection criteria

Randomised, placebo-controlled trials on adults and children with confirmed or suspected exposure to naturally occurring influenza.

Data collection and analysis

We extracted clinical study reports and assessed risk of bias using purpose-built instruments. We analysed the effects of zanamivir and oseltamivir on time to first alleviation of symptoms, influenza outcomes, complications, hospitalisations and adverse events in the intention-to-treat (ITT) population. All trials were sponsored by the manufacturers.

Main results

We obtained 107 clinical study reports from the European Medicines Agency (EMA), GlaxoSmithKline and Roche. We accessed comments by the US Food and Drug Administration (FDA), EMA and Japanese regulator. We included 53 trials in Stage 1 (a judgement of appropriate study design) and 46 in Stage 2 (formal analysis), including 20 oseltamivir (9623 participants) and 26 zanamivir trials (14,628 participants). Inadequate reporting put most of the zanamivir studies and half of the oseltamivir studies at a high risk of selection bias. There were inadequate measures in place to protect 11 studies of oseltamivir from performance bias due to non-identical presentation of placebo. Attrition bias was high across the oseltamivir studies and there was also evidence of selective reporting for both the zanamivir and oseltamivir studies. The placebo interventions in both sets of trials may have contained active substances.

Time to first symptom alleviation. For the treatment of adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval (CI) 8.4 to 25.1 hours, P < 0.0001). This represents a reduction in the time to first alleviation of symptoms from 7 to 6.3 days. There was no effect in asthmatic children, but in otherwise healthy children there was (reduction by a mean difference of 29 hours, 95% CI 12 to 47 hours, P = 0.001). Zanamivir reduced the time to first alleviation of symptoms in adults by 0.60 days (95% CI 0.39 to 0.81 days, P < 0.00001), equating to a reduction in the mean duration of symptoms from 6.6 to 6.0 days. The effect in children was not significant. In subgroup analysis we found no evidence of a difference in treatment effect for zanamivir on time to first alleviation of symptoms in adults in the influenza-infected and non-influenza-infected subgroups (P = 0.53).

Hospitalisations. Treatment of adults with oseltamivir had no significant effect on hospitalisations: risk difference (RD) 0.15% (95% CI -0.78 to 0.91). There was also no significant effect in children or in prophylaxis. Zanamivir hospitalisation data were unreported.

Serious influenza complications or those leading to study withdrawal. In adult treatment trials, oseltamivir did not significantly reduce those complications classified as serious or those which led to study withdrawal (RD 0.07%, 95% CI -0.78 to 0.44), nor in child treatment trials; neither did zanamivir in the treatment of adults or in prophylaxis. There were insufficient events to compare this outcome for oseltamivir in prophylaxis or zanamivir in the treatment of children.

Pneumonia. Oseltamivir significantly reduced self reported, investigator-mediated, unverified pneumonia (RD 1.00%, 95% CI 0.22 to 1.49); number needed to treat to benefit (NNTB) = 100 (95% CI 67 to 451) in the treated population. The effect was not significant in the five trials that used a more detailed diagnostic form for pneumonia. There were no definitions of pneumonia (or other complications) in any trial. No oseltamivir treatment studies reported effects on radiologically confirmed pneumonia. There was no significant effect on unverified pneumonia in children. There was no significant effect of zanamivir on either self reported or radiologically confirmed pneumonia. In prophylaxis, zanamivir significantly reduced the risk of self reported, investigator-mediated, unverified pneumonia in adults (RD 0.32%, 95% CI 0.09 to 0.41); NNTB = 311 (95% CI 244 to 1086), but not oseltamivir.

Bronchitis, sinusitis and otitis media. Zanamivir significantly reduced the risk of bronchitis in adult treatment trials (RD 1.80%, 95% CI 0.65 to 2.80); NNTB = 56 (36 to 155), but not oseltamivir. Neither NI significantly reduced the risk of otitis media and sinusitis in both adults and children.

Harms of treatment. Oseltamivir in the treatment of adults increased the risk of nausea (RD 3.66%, 95% CI 0.90 to 7.39); number needed to treat to harm (NNTH) = 28 (95% CI 14 to 112) and vomiting (RD 4.56%, 95% CI 2.39 to 7.58); NNTH = 22 (14 to 42). The proportion of participants with four-fold increases in antibody titre was significantly lower in the treated group compared to the control group (RR 0.92, 95% CI 0.86 to 0.97, I2 statistic = 0%) (5% absolute difference between arms). Oseltamivir significantly decreased the risk of diarrhoea (RD 2.33%, 95% CI 0.14 to 3.81); NNTB = 43 (95% CI 27 to 709) and cardiac events (RD 0.68%, 95% CI 0.04 to 1.0); NNTB = 148 (101 to 2509) compared to placebo during the on-treatment period. There was a dose-response effect on psychiatric events in the two oseltamivir "pivotal" treatment trials, WV15670 and WV15671, at 150 mg (standard dose) and 300 mg daily (high dose) (P = 0.038). In the treatment of children, oseltamivir induced vomiting (RD 5.34%, 95% CI 1.75 to 10.29); NNTH = 19 (95% CI 10 to 57). There was a significantly lower proportion of children on oseltamivir with a four-fold increase in antibodies (RR 0.90, 95% CI 0.80 to 1.00, I2 = 0%).

Prophylaxis. In prophylaxis trials, oseltamivir and zanamivir reduced the risk of symptomatic influenza in individuals (oseltamivir: RD 3.05% (95% CI 1.83 to 3.88); NNTB = 33 (26 to 55); zanamivir: RD 1.98% (95% CI 0.98 to 2.54); NNTB = 51 (40 to 103)) and in households (oseltamivir: RD 13.6% (95% CI 9.52 to 15.47); NNTB = 7 (6 to 11); zanamivir: RD 14.84% (95% CI 12.18 to 16.55); NNTB = 7 (7 to 9)). There was no significant effect on asymptomatic influenza (oseltamivir: RR 1.14 (95% CI 0.39 to 3.33); zanamivir: RR 0.97 (95% CI 0.76 to 1.24)). Non-influenza, influenza-like illness could not be assessed due to data not being fully reported. In oseltamivir prophylaxis studies, psychiatric adverse events were increased in the combined on- and off-treatment periods (RD 1.06%, 95% CI 0.07 to 2.76); NNTH = 94 (95% CI 36 to 1538) in the study treatment population. Oseltamivir increased the risk of headaches whilst on treatment (RD 3.15%, 95% CI 0.88 to 5.78); NNTH = 32 (95% CI 18 to 115), renal events whilst on treatment (RD 0.67%, 95% CI -2.93 to 0.01); NNTH = 150 (NNTH 35 to NNTB > 1000) and nausea whilst on treatment (RD 4.15%, 95% CI 0.86 to 9.51); NNTH = 25 (95% CI 11 to 116).

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.

Resumo

Inibidores da neuraminidase para prevenir e tratar influenza em adultos e crianças saudáveis

Introdução

Os inibidores da neuraminidase são estocados e recomendados por agências de saúde pública para o tratamento e prevenção da influenza sazonal e pandêmica. Eles são utilizados clinicamente no mundo inteiro.

Objetivos

Descrever os benefícios e danos potenciais dos inibidores da neuraminidase para influenza em todas as faixas etárias através da revisão de todos os artigos de ensaios clínicos randomizados e placebo-controlados publicados e não publicados e de comentários regulatórios.

Métodos de busca

Fizemos buscas nas plataformas de registros de ensaios clínicos, em bases de dados eletrônicas (até 22 de julho de 2013) e arquivos regulatórios e nos correspondemos com fabricantes para identificar todos os estudos. Nós também solicitamos os relatórios de estudos clínicos. Nós focamos nas fontes de dados primárias dos fabricantes mas também verificamos se não havia ensaios clínicos randomizados (ECRs) de fontes que não tinham vínculo com os fabricantes através de buscas nas bases de dados eletrônicas: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE (Ovid), EMBASE, Embase.com, PubMed (não MEDLINE), Database of Reviews of Effects, NHS Economic Evaluation Database e Health Economic Evaluations Database.

Critério de seleção

Incluímos ensaios clínicos randomizados ou placebo-controlados em adultos e crianças com exposição confirmada ou suspeita à influenza de ocorrência natural.

Coleta dos dados e análises

Nós extraímos dados e avaliamos o risco de viés dos usando instrumentos criados especificamente para esta revisão. Nós analisamos os efeitos do zanamivir e oseltamivir sobre os seguintes desfechos: tempo até o alívio dos sintomas, desfechos da influenza, complicações, internação e eventos adversos. As análises foram feitas segundo a intenção de tratar (ITT). Todos os estudos foram patrocinados pelos fabricantes dos medicamentos.

Principais resultados

Nós obtivemos 107 relatórios de ensaios clínicos da European Medicines Agency (EMA), Glaxo Smith Kline e Roche. Tivemos acesso aos comentários do US Food and Drug Administration (FDA), EMA e da agência regulatória do Japão. Nós incluímos 53 estudos em Fase 1 (avaliação da adequação do desenho do estudo) e 46 estudos em Fase 2 (análise formal), incluindo 20 estudos sobre oseltamivir (9.623 participantes) e 26 estudos sobre zanamivir (14.628 participantes). Devido a falhas na descrição dos estudos, a maioria dos estudos com zanamivir e metade dos estudos com oseltamivir foram classificadas como tendo alto risco de viés de seleção. Em 11 estudos com oseltamivir houve risco de viés de performance porque os placebos não tinham aparência idêntica. O viés de atrito (perda) foi alto nos estudos com oseltamivir e também houve evidência de viés de relato seletivo nos estudos com zanamivir e oseltamivir. As intervenções com placebo dos estudos com ambas as drogas podem ter contido substâncias ativas.

Tempo até o primeiro alívio de sintoma.O oseltamivir reduziu o tempo para o alívio de sintoma em 16.8 horas (intervalo de confiança de 95%, 95% CI, de 8,4 a 25,1 horas; P < 0,0001) nos adultos. Isso representa redução no tempo de alívio de sintoma de 7 para 6,3 dias. Não houve efeito nas crianças asmáticas. Nas crianças saudáveis, o oseltamivir reduziu esse tempo em média 29 horas, (95% CI de 12 a 47 horas, P = 0,001). Nos adultos, o zanamivir reduziu o tempo para o alívio de sintoma em 0,60 dias (95% CI 0,39 a 0,81 dias; P < 0,00001), equivalendo a uma redução na duração média dos sintomas de 6,6 para 6,0 dias. O efeito em crianças não foi significante. Não houve diferença no tempo para o alívio dos sintomas na análise dos subgrupos de adultos infectados e não infectatos por influenza que usaram zanamivir (P = 0,53).

Hospitalizações.Nos adultos, o uso do oseltamivir não modificou significativamente o risco de internação hospitalar: diferença de risco (DR) 0,15% (95% CI de -0,78 a 0,91). Não houve efeito significativo em crianças ou quanto o medicamento foi usado profilaticamente. Os efeitos do zanamivir sobre o risco de internação não foram relatados.

Complicações graves da influenza ou complicações que levaram ao abandono do estudo.Em estudos com adultos, o oseltamivir não reduziu significantemente as complicações classificadas como graves ou aquelas que levaram ao abandono do estudo (DR 0,07%, 95% CI -0,78 a 0,44), nem em estudos com crianças. O mesmo ocorreu com o zanamivir usado para o tratamento ou a profilaxia de adultos. Não houve eventos suficientes para comparar esse desfecho com uso profilático de oseltamivir ou com zanamivir para o tratamento em crianças.

Pneumonia.O oseltamivir reduziu significantemente a pneumonia auto-relatada, relatada pelo investigador e não comprovada (DR 1,00%, 95% CI 0,22 a 1,49); com número necessário para tratar para beneficiar (NNTB) = 100 (95% CI 67 a 451) na população tratada. Nos cinco estudos que utilizaram uma forma de diagnóstico mais detalhada para pneumonia, o efeito não foi significativo. Nenhum dos estudos definiu pneumonia (ou outras complicações). Nenhum dos estudos com oseltamivir relatou efeitos em pneumonia que fossem confirmados radiologicamente. Não houve efeito significante em pneumonia não comprovada em crianças. Não houve efeito significante de zanamivir sobre pneumonia auto-relatada ou confirmada radiologicamente. O uso profiláticos do zanamivir reduziu significantemente o risco de pneumonia auto-relatada, informada pelo investigador ou não verificada em adultos (DR 0,32%, 95% CI 0,09 a 0,41); NNTB = 311 (95% CI 244 a 1.086), mas não o oseltamivir.

Bronquite, sinusite e otite média.O zanamivir reduziu significantemente o risco de bronquite nos estudos que trataram adultos (DR 1,80%, 95% CI 0,65 a 2,80); NNTB = 56 (36 a 155), mas o oseltamivir não teve esse efeito. Nenhum inibidores da neuraminidase reduziu significantemente o risco de otite média e sinusite em adultos ou crianças.

Danos do tratamento.O oseltamivir para o tratamento em adultos aumentou o risco de náusea (DR 3,66%, 95% CI 0,90 a 7,39); o número necessário para tratar para danos (NNTH) = 28 (95% CI 14 a 112) e vômitos (DR 5,56%, 95% CI 2,39 a 7,58); NNTH = 22 (14 a 42). A proporção de participantes que aumentou em quatro vezes o título de anticorpos foi significantemente menor para o grupo tratado comparado com o grupo controle (RR 0,92, 95% CI 0,86 a 0,97, I2 = 0%; diferença absoluta de 5% entre os braços). O oseltamivir diminuiu significantemente o risco de diarreia (DR 2,33%, 95% CI 0,14 a 3,81); NNTB = 43 (95% CI 27 a 709) e eventos cardíacos (DR 0,68%, 95% CI 0,04 a 1,0); NNTB = 148 (101 a 2509) comparado com placebo, durante o período de tratamento. Houve um efeito de dose-resposta para eventos psiquiátricos nos dois estudos principais de tratamento com o oseltamivir, WV15670 e WV 15671, com 150 mg (dose padrão) e 300 mg (dose alta) ao dia (P = 0,038). O tratamento de crianças com oseltamivir induziu o vômito (DR 5,34%, 95% CI 1,75 a 10,29; NNTH = 19; 95% CI 10 a 57). Uma proporção significativamente menor de crianças usando oseltamivir teve aumento de quatro vezes nos títulos de anticorpos (RR 0,90, 95% CI 0,80 a 1,00, I2 = 0%).

Profilaxia.Nos estudos de profilaxia, o oseltamivir e o zanamivir reduziram o risco de influenza sintomática em indivíduos [oseltamivir: DR 3,05% (95% CI 1.83 a 3.88); NNTB = 33 (26 a 55); zanamivir: RD 1,98% (95% CI 0,98 a 2,54); NNTB = 51 (40 a 103)] e em famílias (oseltamivir: DR 13,6; 95% CI 9,52 a 15,47; NNTB = 7; 6 a 11; zanamivir: DR 14,84%; 95% CI 12,18 a 16,55; NNTB = 7; 7 a 9). Não houve efeito significante sobre influenza assintomática (oseltamivir: RR 1.14; 95% CI 0,39 a 3,33; zanamivir: RR 0,97; 95% CI 0,76 a 1.24). Devido à falta de informações completas, não foi possível avaliar as doenças não influenza e parecidas com influenza ("influenza-like"). Nos estudos profiláticos com oseltamivir, houve aumento nos eventos adversos psiquiátricos durante o tempo que incluía os períodos de tratamento e não tratamento (DR 1,06%, 95% CI 0,07 a 2,76; NNTH = 94; 95% CI 36 a 1.538) na população em tratamento. O oseltamivir aumentou o risco de cefaleia durante o seu uso (DR 3,15%, 95% CI 0,88 a 5,78; NNTH = 32; 95% CI 18 a 115), de eventos renais durante o uso (DR 0,67%, 95% CI -2,93 a 0,01; NNTH = 150; NNTH 35 a NNTB > 1000) e náusea durante o uso (DR 4,15%, 95% CI 0,86 a 9,51; NNTH = 25; 95% CI 11 a 116).

Conclusão dos autores

O oseltamivir e o zanamivir têm efeitos pequenos e não específicos na redução do tempo para alívio dos sintomas da influenza em adultos, mas não houve efeito em crianças asmáticas. O uso profilático de qualquer dessas drogas diminui o risco de desenvolver influenza sintomática. Devido à falta de definições diagnósticas, os estudos de tratamento com oseltamivir ou zanamivir não responderam à questão se esses medicamentos reduzem as complicações da influenza (como a pneumonia). O uso de oseltamivir aumenta o risco de eventos adversos como náuseas, vômitos, efeitos psiquiátricos e eventos renais em adultos e o risco de vômito em crianças. A baixa biodisponibilidade do zanamivir pode explicar a baixa toxicidade desse medicamento em comparação com o oseltamivir. O equilíbrio entre os benefícios e danos deve ser considerado na tomada de decisão do uso dos dois inibidores da neuraminidase tanto para profilaxia quanto para o tratamento da influenza. O mecanismo de ação específico desses medicamentos sobre o vírus da influenza proposto pelos fabricantes não se enquadra nas evidências clínicas.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Maíra Tristão Parra).

摘要

預防與治療成人及兒童流感之神經胺酸酶抑制劑

背景

神經胺酸酶抑制劑(NIs),為公共衛生單位對於治療與預防季節性及傳染性流感之儲備與建議用藥,它們在世界各地臨床上皆被使用。

目的

為了描述NIs對於流感在各年齡族群中潛在的效益與危害,回顧所有包含已發表與未發表的隨機安慰劑對照試驗與法規評論的臨床研究報告。

搜尋策略

我們搜尋了試驗記錄、電子資料庫(直至2013年7月22日)與法規檔案庫並與製造商連繫,以確認所有的試驗,也要求提供臨床研究報告。我們著重於製造商的原始資料,在下列資料庫做了電子搜尋後,發現在已發表的隨機對照試驗(RCTs)中,沒有來自非製造商的:Cochrane Central Register of Controlled Trials (CENTRAL)、MEDLINE、MEDLINE (Ovid)、EMBASE、Embase.com、PubMed (非MEDLINE)、Database of Reviews of Effects、NHS Economic Evaluation Database以及Health Economic Evaluations Database等資料庫。

選擇標準

對於已確診或疑似暴露在自然產生的流感中之成人及兒童的隨機安慰劑對照試驗。

資料收集與分析

我們摘錄臨床研究報告,並以特殊目地為導向的工具來評估偏誤風險。我們分析了zanamivir與oseltamivir在到初次症狀緩解所需時間、流感結果、併發症、住院治療與不良事件上,對於治療意向人數的效應。所有的試驗皆由製造商贊助。

主要結果

我們由歐洲藥物管理局(EMA)、GlaxoSmithKline及Roche公司取得107份臨床研究報告,且獲取美國食品藥物管理局(FDA)、EMA以及日本管理機關所做的評論。收錄了53個在第一階段的試驗(合適的研究設計之判斷)以及46個在第二階段的試驗(正式分析),包含20個oseltamivir(9,623位受試者)與26個zanamivir(14,628位受試者)的試驗。不合適的報告讓大部分的zanamivir研究與一半的oseltamivir研究有高選擇偏誤風險。為避免11個oseltamivir研究出現因安慰劑呈現方式不同而產生的表現性偏誤,因此執行了一些不合適的措施。損耗性偏差在oseltamivir研究中為高,且zanamivir及oseltamivir研究皆有選擇性報告的證據。安慰劑干預在兩階段的試驗中皆可能含有活性物質。

到初次症狀緩解所需時間。對於成人的治療,oseltamivir將到初次症狀緩解所需時間減少了16.8小時(95% 信賴區間(CI) 8.4至25.1小時, P < 0.0001),這代表到初次症狀緩解所需時間由7天減少至6.3天。對於有氣喘的兒童沒有影響,相反的,對健康的兒童則有(減少了29小時的平均差, 95% CI 12至47小時, P = 0.001)。Zanamivir在成人上將到初次症狀緩解所需時間減少了0.60天(95% CI 0.39至0.81天, P < 0.00001),等於將症狀的平均持續期由6.6天減少至6.0天,對於兒童的影響則不顯著。在次群組分析中我們發現,zanamivir在次群組中對於已受流感感染及未受流感感染(P = 0.53)的成人,到初次症狀緩解所需時間的治療效果沒有證據顯示差異。

住院治療。Oseltamivir治療對成人住院治療沒有顯著的影響:風險差(RD) 0.15% (95% CI -0.78至0.91),對於兒童或預防也沒有顯著的影響。沒有zanamivir的住院治療資料記錄。

嚴重或導致研究中止的流感併發症。成人治療試驗中,oseltamivir並無顯著減少那些被歸類為嚴重或是導致研究中止的併發症(RD 0.07%, 95% CI -0.78至0.44),在兒童治療試驗中也沒有影響;而zanamivir對成人治療或預防也皆無影響。沒有足夠的事件能將此結果與oseltamivir對於預防或zanamivir對於兒童治療做比較。

肺炎。Oseltamivir顯著地減少了自覺性、經檢查發現以及未確診的肺炎(RD 1.00%, 95% CI 0.22至1.49);被治療的人口中,益一需治數(NNTB)為100。在5個使用更詳盡的形式來診斷肺炎的試驗中,效應並不顯著。任一試驗中皆無對於肺炎(或其他併發症)的定義。Oseltamivir的治療研究沒有記錄對於經放射確診的肺炎之影響,對於兒童未確診肺炎則沒有顯著影響。Zanamivir對自覺性或經放射確診的肺炎皆無顯著的影響。在預防上,zanamivir顯著地降低成人罹患自覺性、經檢查發現或未確診的肺炎風險(RD 0.32%, 95% CI 0.09至0.41);NNTB=311(95% CI 244至1086),但oseltamivir則無。

支氣管炎、鼻竇炎及中耳炎。Zanamivir在成人治療試驗中,顯著地降低罹患支氣管炎的風險(RD 1.80%, 95% CI 0.65至2.80);NNTB = 56 (36 to 155),但oseltamivir則無。NI在成人及兒童中,皆無顯著降低罹患中耳炎與鼻竇炎的風險。

治療的危害。Oseltamivir在成人治療中,增加噁心(RD 3.66%, 95% CI 0.90至7.39);害一需治數(NNTH)為28 (95% CI 14至112)與嘔吐(RD 4.56%, 95% CI 2.39至7.58);NNTH = 22 (14至42)的風險。實驗組中,抗體力價增加四倍的受試者比例明顯低於對照組(RR 0.92, 95% CI 0.86至0.97, I2 statistic = 0%) (5% 雙臂間的絕對差量)。在治療期間,oseltamivir較安慰劑顯著地降低了腹瀉(RD 2.33%, 95% CI 0.14至3.81); NNTB = 43 (95% CI 27至709)及心臟相關疾病(RD 0.68%, 95% CI 0.04至1.0);NNTB = 148 (101至2509)的風險。在2個oseltamivir核心治療試驗WV15670及WV15671中,每日150 mg (標準劑量)與300 mg (高劑量) (P = 0.038),在精神病症狀上有劑量效應。在兒童治療中,oseltamivir導致嘔吐(RD 5.34%, 95% CI 1.75至10.29);NNTH = 19 (95% CI 10至57);使用oseltamivir的兒童中,抗體增加四倍的比例顯著較少(RR 0.90, 95% CI 0.80至1.00, I2 = 0%)。

預防。在預防試驗中,oseltamivir與zanamivir降低了個人症狀性流感(oseltamivir:RD 3.05% (95% CI 1.83至3.88);NNTB = 33 (26至55);zanamivir:RD 1.98% (95% CI 0.98至2.54);NNTB = 51 (40至103))與居家流感(oseltamivir:RD 13.6% (95% CI 9.52至15.47);NNTB = 7 (6至11);zanamivir:RD 14.84% (95% CI 12.18至16.55);NNTB = 7 (7至9))的風險。在無症狀流感上則無顯著的影響(oseltamivir:RR 1.14 (95% CI 0.39至3.33); zanamivir:RR 0.97 (95% CI 0.76至1.24))。由於資料沒有完全地記錄下來,無法評估非流感、類流感疾病。在oseltamivir預防研究中,研究治療群體的精神不良事件在治療與非治療期中皆增加(RD 1.06%, 95% CI 0.07至2.76); NNTH = 94 (95% CI 36至1538)。Oseltamivir在治療期中增加了頭痛(RD 3.15%, 95% CI 0.88至5.78);NNTH = 32 (95% CI 18至115)、腎臟相關事件(RD 0.67%, 95% CI -2.93至0.01);NNTH = 150 (NNTH 35至NNTB > 1000)以及噁心(RD 4.15%, 95% CI 0.86至9.51);NNTH = 25 (95% CI 11至116)的風險。

作者結論

Oseltamivir與zanamivir在縮短成人流感症狀緩解所需時間上有小而不特定的影響,但在氣喘兒童上則無。使用任一種藥品做為預防,可以減低罹患症狀性流感的風險。由於缺乏診斷定義,包含oseltamivir或zanamivir的治療試驗無法解決流感併發症(例如肺炎)是否減少的問題。Oseltamivir的使用,增加成人出現不良效應,例如噁心、嘔吐、精神影響及腎臟相關事件與兒童出現嘔吐的風險。較低的生體可用率也許可以解釋zanamivir的毒性為何較oseltamivir低。在做關於是否使用兩種NIs來預防或治療流感的決定時,需考量效益與危害之間的平衡。製造商提出的流感病毒特異作用機轉與臨床證據不符。

譯註

翻譯者:臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw

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.

Laienverständliche Zusammenfassung

Ergebnisse aus Zulassungsstudien mit Oseltamivir (Tamiflu) und Zanamivir (Relenza) für Grippe bei Erwachsenen und Kindern

Oseltamivir und Zanamivir wurden in vielen Ländern bevorratet, um eine saisonale oder pandemische Grippe zu behandeln bzw. ihr vorzubeugen, bevor eine Grippeimpfung verfügbar ist, die an den aktuell zirkulierenden Virustyp angepasst ist. Oseltamivir wird von der Welt- gesundheitsorganisation als notwendiges Medikament eingestuft.

Wie dieser Review durchgeführt wurde

Wir haben unsere Reviews zu den antiviralen Medikamenten Zanamivir und Oseltamivir bei Erwachsenen und Kindern auf den neuesten Stand gebracht und zusammengeführt. Dabei haben wir uns auf die Berichte der Hersteller an die Zulassungsbehörden (klinische Studien- berichte) und die Kommentare dieser Behörden gestützt. Diese Berichte und Kommentare werden im Weiteren als ‘Zulassungsdokumente’ bezeichnet. Klinische Studienberichte sind unveröffentlichte Dokumente, die umfangreiche Daten über Studien enthalten, welche die Grundlage für die Marktzulassung eines Medikamentes sind. Sie enthalten Studienprotokolle, sowie Beschreibungen der Methoden und Ergebnisse. Diese klinischen Studienberichte waren bisher vertraulich und nur den Herstellern und Zulassungsbehörden zugänglich.

Warum diese Vorgehensweise gewählt wurde

In vorherigen Versionen dieses Reviews hatten wir Unstimmigkeiten in den Daten der publizierten Studienberichte, die nicht geklärt werden konnten, sowie einen erheblichen Publikationsbias gefunden. Daher entschieden wir uns, statt der Daten aus den wissen- schaftlichen Artikeln die Dokumente aus den Zulassungsverfahren zu verwenden. Wir hatten Zugang zu Daten der Zulassungsbehörden in Grossbritannien, USA und Japan und der European Medicines Agency (EMA) und zu klinischen Studienberichten der Hersteller (nach einer langwierigen Medienkampagne). Dadurch waren wir in der Lage, die Informationen derjenigen randomisierten, plazebo-kontrollierten Studien zu überprüfen, an denen Erwachsene und Kinder mit bestätigter oder vermuteter Exposition gegenüber natürlich vorkommender Grippe teilgenommen hatten.

Wir kamen aufgrund unserer Auswertung der Zulassungsdokumente (mehr als 160000 Seiten) zum Schluss, dass für viele Studien sowohl das Studiendesign, die Durchführung, die Berichtsqualität als auch die Verfügbarkeit der Daten problematisch waren.

Was wir gefunden haben

In diesem Review wurden die Daten von 46 Studien (20 zu Oseltamivir und 26 zu Zanamivir) berücksichtigt. Im Design vieler eingeschlossener Studien fanden wir Schwachpunkte, weshalb die Ergebnisse nur bedingt vertrauenswürdig sind. Beide Wirkstoffe verkürzen die Dauer von Symptomen einer grippeähnlichen Erkrankung (unbestätigte Influenza-Erkrankung oder sogenannte «Grippe») um weniger als einen Tag. Basierend auf den Daten aller mit Oseltamivir durchgeführten Studien hatte der Wirkstoff keine Auswirkung auf die Zahl der Krankenhausaufnahmen. Für Zanamivir wurde dieser Studienendpunkt nicht erhoben. Die Wirksamkeit bezüglich Lungenentzündung und anderer Grippekomplikationen (wie z.B. Bronchitis, Mittelohrentzündung, Nasennebenhöhlenentzündung) wurde nicht verlässlich erfasst, wie aus den in den Zulassungsdokumenten enthalten Erhebungsbögen ersichtlich ist. In einigen dieser Erhebungsbögen waren die Kriterien für die Diagnose einer Lungenentzündung unzureichend bestimmt. In den Kommentaren der Zulassungsbehörden wurden Probleme mit fehlenden Akteneinträgen während der Nachbeobachtung der Teilnehmer verzeichnet. Bei Kindern mit Asthma gab es keine eindeutige Wirkung bezüglich der Zeit bis zur Besserung der Symptome.

In Studien zur Grippevorbeugung verminderten Oseltamivir und Zanamivir das Risiko einer symptomatischen Grippe sowohl bei Einzelpersonen als auch in Haushalten. Eine Wirksamkeit bezüglich Grippeinfektion ohne Symptome oder grippeähnlicher Erkrankungen ohne Influenza- Infektion konnte nicht nachgewiesen werden. Allerdings können aufgrund der Probleme bei der Durchführung der Studien keine definitiven Schlüsse gezogen werden.

Die Einnahme von Oseltamivir ging sowohl mit Übelkeit und Erbrechen einher als auch mit Kopfschmerzen, Nierenproblemen und psychiatrischen Symptomen. Die letztgenannten drei Nebenwirkungen traten auf, wenn Oseltamivir zur Vorbeugung (Prophylaxe) eingesetzt wurde. Seine Wirkung auf das Herz ist unklar: es vermindert möglicherweise kardiale Symptome, kann aber vermutlich schwere Herzrhythmusstörungen hervorrufen. In Zanamivir-Therapiestudien bei Erwachsenen bestand kein erhöhtes Risiko für (berichtete) Nebenwirkungen. Zu möglichen Nebenwirkungen bei der Behandlung von Kindern mit Zanamivir war die Datenlage dürftig.

Übereinstimmung mit anderen Ergebnissen

Das Fehlen von guter Evidenz dafür, dass beide Wirkstoffe Grippekomplikationen vermindern, stimmt mit den zurückhaltenden Schlussfolgerungen der US Food and Drug Administration (FDA) überein. Die FDA liess lediglich zu, dass die Wirksamkeit beider Medikamente für die Vorbeugung und Behandlung von Grippesymptomen genannt werden darf, nicht jedoch für andere Aspekte (wie die Unterbrechung der Weiterverbreitung des Grippevirus zwischen Personen und die Vorbeugung von Lungenentzündungen). Die FDA beschrieb die allgemeine Wirkung beider Medikamente als ‘mässig’.

Mechanismus der beabsichtigten Wirkung

Alle Ergebnisse legen nahe, dass die reduzierte Immunantwort mit niedrigen Spiegeln von entzündungsfördernden Zytokinen, die durch Oseltamivircarboxylat ausgelöst wird, die Grippesymptomatik vermindert, und dies unabhängig von einer Hemmung der Vermehrung des Grippevirus ist. Eine mögliche hypotherme oder fiebersenkende Wirkung von Oseltamivir als einem Stoff, der das zentrale Nervensystem dämpft, trägt möglicherweise ebenso zur Reduktion der Symptomatik bei. Die Daten, die uns zur Verfügung standen, bestätigen jedoch nicht die Aussage, dass Oseltamivir die Übertragung des Virus unterbricht und Komplikationen vermindert.

Der von den Herstellern angeführte (Influenzavirus-spezifische) Wirkmechanismus passt nicht zur klinischen Evidenz, die eine zentrale Wirkung in mehreren Organsystemen nahelegt.

Anmerkungen zur Übersetzung

Cochrane Schweiz

Laički sažetak

Priopćenja regulatornih tijela o kliničkim ispitivanjima oseltamivira (Tamiflu) i zanamivira (Relenza) u prevenciji i liječenju gripe (influenca) odraslih i djece

Lijekovi oseltamivir i zanamivir nabavljeni su u mnogim državama za liječenje i prevenciju sezonske i pandemične gripe prije nego što cjepivo protiv gripe koje se poklapa s cirkulirajućim sojem virusa gripe postane dostupno. Oseltamivir se nalazi na listi neophodnih lijekova Svjetske zdravstvene organizacije.

Kako se pristupilo izradi ovoga sustavnog pregleda?

Obnovljeni su i objedinjeni Cochrane sustavni pregledi o antivirusnim lijekovima zanamiviru i oseltamiviru kao terapija u odraslih i djece za gripu temeljem izviješća proizvođača navedenih lijekova regulatornim tijelima (izvješća o kliničkim ispitivanjima koja se predaju regulatornim tijelima u svrhu odobrenja lijeka na tržištu) i tumačenja regulatornih tijela. Navedena tumačenja i izvješća nazvana su priopćenja regulatornih tijela. Izvješća kliničkih ispitivanja se javno ne objavljuju i najopsežniji su dokumenti koji sadrže detaljne podatke iz kliničkih ispitivanja, a čine temeljnu dokumentaciju koju je potrebno dostaviti regulatornim tijelima za odobrenje stavljanja lijekova na tržište. Uključuju plan kliničkog ispitivanja, metode i rezultate. Izvješća kliničkih ispitivanja dugo su bila povjerljiva, dostupna samo proizvođačima lijekova i regulatornim tijelima.

Zašto je upotrijebljen takav pristup ovom istraživanju?

U prethodnim inačicama sustavnog pregleda uočena je neusklađenost podataka u objavljenim kliničkim ispitivanjima i značajna pristranost prilikom objavljivanja kliničkih ispitivanja. Zbog toga su autori sustavnog pregleda odlučili da neće proučiti podatke iz znanstvenih časopisa (kako se inače rade sustavni pregledi) već iz dokumentacije nastale tijekom postupka dobivanja odobrenja za stavljanje lijekova na tržište. Ti su podaci dobiveni od regulatornih tijela Velike Britanije, Sjedinjenih Američkih Država, Europske agencije za lijekove, Japana, a dobivena su i izvješća o kliničkih ispitivanja proizvođača navedenih lijekova (nakon dugotrajne medijske kampanje). To je autorima sustavnog pregleda omogućilo provjeru podataka iz randomiziranih placebo-kontroliranih kliničkih ispitivanja provedenih u odraslih i djece s potvrđenom ili sumnjom na prirodnu izloženost gripi.

Autori su nakon procjene oko 160.000 stranica regulatornih dokumenata zaključili kako postoje značajni problemi u ustroju i provedbi ispitivanja, prikazu rezultata i dostupnosti podataka iz mnogih kliničkih ispitivanja.

Što je pronađeno?

U sustavnom pregledu korišteni su podatci 46 kliničkih ispitivanja (20 u kojih je primijenjen oseltamivir i 26 u kojih je primijenjen zanamivir). Uočeni su problemi u ustroju mnogih uključenih kliničkih ispitivanja, što je utjecalo na pouzdanost u rezultate. Oba lijeka smanjuju trajanje simptoma gripe manje od jednog dana. Oseltamivir nije imao utjecaj na broj hospitalizacija, temeljem podataka svih ljudi koji su sudjelovali u kliničkim ispitivanjima oseltamivira. Klinička ispitivanja zanamivira nisu bilježila navedeni ishod. Učinci na upalu pluća i druge komplikacije gripe (kao bronhitis, upala srednjeg uha i upala sinusa) nisu pouzdano opisivani, što je vidljivo iz test-lista ispitanika u dokumentaciji kliničkih ispitivanja. Ukazano je na ograničenja dijagnostičkih kriterija za upalu pluća. Regulatorna tijela uočila su nedostatak u dnevnicima ispitanika tijekom njihova praćenja. Kod djece s astmom nije bilo jasnog učinka na vrijeme potrebno do prvog ublažavanja simptoma gripe.

Klinička ispitivanja u prevenciji gripe pokazala su da oseltamivir i zanamivir smanjuju rizik simptomatske gripe u pojedinaca i ukućana. Nema dokaza učinkovitosti na gripu bez simptoma ili na bolest sličnu gripi, ali uočeni problemi u provedbi kliničkih ispitivanja onemogućavaju donošenje konačnog zaključka.

Oseltamivir je povezan s nastankom mučnine, povraćanja, glavobolje, bubrežnih i psihijatrijskih događaja; zadnje tri nuspojave pojavile su se nakon korištenja lijeka u svrhu sprječavanja gripe (profilaksa). Nejasan je učinak na srce: ispitivani lijekovi mogu smanjiti srčane simptome, ali mogu dovesti do ozbiljnih problema srčanog ritma. Terapijska klinička ispitivanja zanamivirom u odraslih nisu dovela do povećanog rizika neželjenih događaja. Nedostatni su dokazi mogućeg štetnog djelovanja u terapijskim kliničkim ispitivanjima zanamivirom u djece.

Podudarnost s procjenom drugih tijela

Nedostatak prikladnih dokaza koji pokazuju učinak na komplikacije gripe slaže se sa zaključkom Američke agencije za hranu i lijekove (FDA). FDA dozvoljava tvrdnju učinkovitosti oba lijeka za prevenciju i liječenje simptoma gripe, ali ne i ostale učinke uključujući prekid prijenosa širenja virusa gripe između osoba ili prevencije upale pluća. FDA opisuje sveukupno djelovanje oba lijeka kao umjereno.

Mehanizam djelovanja blagotvornih učinaka

Ovi rezultati pokazuju da snižen imunološki odgovor s niskom razinom tvari koje potiču upalu (proinflamatornih citokina) pod utjecajem oseltamivir karboksilata može smanjiti simptome gripe neovisno o zaustavljanju umnažanja virusa gripe. Mogući učinak oseltamivira na smanjenje temperature (hipotermički ili antipiretički učinak) na središnji živčani sustav može doprinijeti ublažavanju simptoma. Tvrdnja da oseltamivir ima učinak na prekid širenja virusa i smanjenje komplikacija nije potkrijepljena dostupnim podatcima.

Predloženi mehanizam djelovanja sa strane proizvođača specifičan za virus gripe ne podudara se s kliničkim dokazima koji upućuju na sustavno i centralno djelovanje.

Bilješke prijevoda

Cochrane Hrvatska
Prevela: Mirjana Huić
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Резюме на простом языке

Регуляторная информация о клинических испытаниях осельтамивира (Taмифлю) и занамивира (Реленза) при гриппе у взрослых и детей

Осельтамивир и занамивир были складированы во многих странах для лечения и профилактики сезонного и пандемического гриппа, [чтобы использовать] до того как вакцина против гриппа, соответствующая циркулирующему вирусу, станет доступной. Осельтамивир классифицируется Всемирной организацией здравоохранения как основное (жизненно-важное) лекарственное средство.

Какие подходы к этому обзору использовались

Мы обновили и объединили наши обзоры по противовирусным средствам занамивир и осельтамивир при гриппе у взрослых и детей на основании отчетов производителей в регуляторные органы (отчеты о клинических исследованиях) и комментариев регуляторов. Мы назвали эти комментарии и отчеты "регуляторная информация'. Отчеты о клинических исследованиях не опубликованы, это обширные документы с очень подробными деталями испытаний, которые сформировали базу для маркетингового одобрения. Они включают в себя протоколы, методы и результаты. Отчеты о клинических исследованиях до сих пор были конфиденциальными, их видели только производители и регуляторы.

Почему мы предприняли этот подход

В предыдущих версиях этого обзора мы выявили неразрешенные несоответствия в данных, представленных в опубликованных отчетах по клиническим испытаниям, и существенную предвзятость публикаций (публикационное смещение). Исходя из этого, мы решили не использовать данные из журнальных статей, а включили документы, созданные во время процессов лицензирования (маркетингового одобрения). Мы получили доступ к таким данным из Великобритании, США, Европейского лекарственного агентства (EMA), от японских регуляторов и к отчетам по клиническим исследованиям от производителей (после затяжной кампании в средствах массовой информации). Это позволило нам проверить информацию из рандомизированных плацебо-контролируемых клинических испытаний на взрослых и детях с подтвержденным или предполагаемым контактом с естественно встречающимся гриппом.

Исходя из наших оценок регуляторных документов (более 160 000 страниц), мы пришли к выводу, что были существенные проблемы с дизайном, проведением, отчетностью и доступностью информации во многих из этих клинических испытаний.

Что мы нашли

Мы использовали в этом обзоре данные из 46 клинических испытаний (20 по осельтамивиру и 26 исследований по занамивиру). Мы определили проблемы в дизайне многих исследований, которые мы включили, и которые отразились на нашей уверенности в их результатах. Мы обнаружили, что оба лекарства сокращали продолжительность симптомов гриппоподобного заболевания (неподтвержденный грипп или "грипп") менее, чем на один день. Осельтамивир, на основании данных от всех людей, включенных в клинические испытания по лечению осельтамивиром, не влиял на число госпитализаций. Клинические испытания по занамивиру этот исход не регистрировали. Сообщения о влиянии на пневмонии и другие осложнения гриппа, такие как бронхит, инфекции среднего уха (средний отит) и синуситы, были не надёжны, как показали истории болезни по документам клинического испытания. Некоторые формы показали ограничения (проблемы) диагностических критериев пневмонии. Регуляторные комментарии отметили проблемы с недостающими дневниками наблюдения у участников. У детей с астмой не было ясного влияния на время до первого облегчения симптомов.

Клинические испытания по профилактике (заболевания) показали, что осельтамивир и занамивир снижали риск симптоматического гриппа у отдельных лиц и в семье. Не было доказательств влияния на бессимптомный грипп или на не грипп, на гриппоподобные заболевания, но проблемы в проведении испытаний препятствуют любому определённому заключению.

Применение осельтамивира было связано с тошнотой, рвотой, головными болями, почечными и психиатрическими событиями; последние три случались, когда его [осельтамивир] применяли для профилактики гриппа. Его [осельтамивира] действие на сердце остается неясным: он может уменьшать симптомы со стороны сердца, но может и вызывать серьезные проблемы сердечного ритма. В клинических испытаниях занамивира у взрослых не было повышенного риска по сообщённым неблагоприятным событиям. Свидетельства возможного вреда, связанного с лечением детей занамивиром, были разрозненные.

Соответствие другим результатам

Отсутствие качественных доказательств, демонстрирующих влияние на осложнения [гриппа], согласуется с осторожными выводами по обоим лекарствам, сделанными Администрацией по контролю за лекарствами и пищевыми продуктами США (FDA). FDA разрешила заявления только по эффективности обоих лекарств в профилактике и лечении симптомов гриппа, но не по другим эффектам (в том числе прерывание распространения вируса от человека к человеку или профилактика пневмонии). FDA описала эффективность обоих препаратов в целом, как "скромную".

Механизм развития благоприятных эффектов

Эти результаты позволяют предположить, что низкий иммунный ответ с низким уровнем прововоспалительных цитокинов, вызванный действием осельтамивира карбоксилата, может уменьшать симптомы гриппа, не связанные с подавлением размножения (репликации) вируса гриппа. Потенциальный гипотермический или жаропонижающий эффект осельтамивира как депрессанта центральной нервной систем, также может вносить вклад в очевидное сокращение симптомов пораженного организма. Заявления о способности осельтамивира прерывать передачу [от человека к человеку] вируса и уменьшать осложнения не поддерживаются никакими данными, к которым мы имели доступ.

Механизм действия, предложенный производителем, (специфичный для вируса гриппа) не соответствует клиническим доказательствам, что позволяет предполагать мультисистемное и центральное действие.

Заметки по переводу

Перевод: Абакумова Татьяна Рудольфовна. Редактирование: Зиганшина Лилия Евгеньевна. Координация проекта по переводу на русский язык: Казанский федеральный университет - аффилированный центр в Татарстане Северного Кокрейновского Центра. По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: lezign@gmail.com

Resumo para leigos

Informação regulatória dos estudos com oseltamivir (Tamiflu) e zanamivir (Relenza) para influenza em adultos e crianças

O oseltamivir e o zanamivir vêm sendo estocados em vários países para o tratamento e prevenção da influenza sazonal e pandêmica, antes de uma vacina adequada para o vírus circulante se tornar disponível. O oseltamivir é classificado pela Organização Mundial da Saúde como um medicamento essencial.

Como esta revisão foi realizada

Nós atualizamos e combinamos as nossas revisões sobre as drogas antivirais zanamivir e oseltamivir para influenza em adultos e crianças com base nos relatos dos fabricantes para os órgãos regulatórios (relatos de estudos clínicos) com os comentários dos órgãos regulatórios. Nós chamamos esses comentários e relatos como “informação regulatória”. Os relatos de estudos clínicos são documentos extensos e não publicados, com excelentes detalhes sobre os estudos que formaram a base para a aprovação das drogas no mercado. Eles incluem protocolos, métodos e resultados. Até recentemente, os relatos de estudos clínicos eram confidenciais, acessíveis apenas a fabricantes e agências regulatórias.

Porque nós escolhemos esta conduta

Nas versões anteriores desta revisão, identificamos divergências não resolvidas nos dados apresentados nos relatos dos estudos publicados, e viés de publicação importante. Como consequência, optamos por não usar os dados de artigos publicados; preferimos incluir os documentos gerados durante o processo de licenciamento desses medicamentos. Nós avaliamos os dados de órgãos regulatórios do Reino Unido, Estados Unidos, Europa, Japão e relatos de estudos clínicos dos fabricantes (depois de uma longa campanha na mídia). Isso nos permitiu verificar os dados contidos em estudos randomizados e placebo-controlados em adultos e crianças com exposição confirmada ou suspeita à influenza que ocorre naturalmente.

Com base nas nossas análises dos documentos regulatórios (com mais de 160.000 páginas), nós concluímos que, em muitos dos ensaios clínicos, houve problemas substanciais com o desenho, condução, relato e disponibilidade da informação.

O que nós encontramos

Nós utilizamos os dados de 46 estudos (20 estudos com oseltamivir e 26 com zanamivir) nesta revisão. Identificamos problemas no desenho de vários estudos que nós incluímos, o que afeta a confiabilidade dos resultados. Encontramos que as duas drogas diminuem a duração dos sintomas da doença parecida com influenza (influenza não confirmada ou “gripe”) em menos de um dia. O oseltamivir não mudou o número de internações, com base nos dados de todas as pessoas que participaram de estudos de tratamento com oseltamivir. Os estudos com o zanamivir não relataram esse desfecho. Os efeitos desses remédios sobre a pneumonia e outras complicações da influenza, como bronquite, infecção do ouvido médio (otite média) e sinusite, não foram descritos de forma confiável, conforme pudemos ver nos formulários de relato de caso dos documentos do estudo. Alguns formulários eram limitados no critério de diagnóstico para pneumonia. Os comentários regulatórios notaram problemas de falta de diários de seguimento para participantes com pneumonia. Nas crianças com asma, não houve efeito claro no tempo para o primeiro alívio dos sintomas.

Os estudos de profilaxia mostraram que o oseltamivir e o zanamivir reduziram o risco de influenza sintomática em indivíduos e em domicílios. Não houve evidência de efeito sobre influenza assintomática ou sobre doenças parecidas com influenza, mas que não são influenza, mas os problemas de condução dos estudos impediram que fosse tirada qualquer conclusão definitiva.

O uso do oseltamivir foi associado com náusea, vômito, dores de cabeça, eventos renais e psíquiátricos; estes últimos três ocorreram quando foi usado para prevenir a influenza (profilaxia). O seu efeito no coração é incerto: pode reduzir os sintomas cardíacos, mas pode induzir a sérios problemas de ritmo cardíaco. Nos estudos de tratamento com zanamivir em adultos, não houve risco aumentado de eventos adversos. Existe pouca evidência sobre possíveis danos associados ao tratamento com zanamivir em crianças.

Concordância com outros achados

A falta de boas evidências demonstrando efeito nas complicações concorda com as conclusões conservadoras sobre as duas drogas apresentadas pelo US Food and Drug Administration (FDA). O FDA somente autorizou alegações de efetividade das duas drogas para a prevenção e tratamento dos sintomas da influenza e não para outros efeitos (incluindo a interrupção da transmissão do vírus da influenza de pessoa para pessoa ou a prevenção de pneumonia). O FDA descreveu o desempenho geral das duas drogas como sendo “modesto”.

Mecanismos de ação para efeitos benéficos

Esses achados sugerem que a baixa resposta imunológica, com baixos níveis de citocinas pró-inflamatórias, que é induzida pela ação do carboxilato de oseltamivir, pode reduzir os sintomas da influenza não relacionados com a inibição da replicação do vírus. O efeito hiportérmico potencial ou antipirético do oseltamivir como depressor do sistema nervoso central pode contribuir com a redução aparente dos sintomas do doente. Declarações feitas sobre a capacidade do oseltamivir de interromper a transmissão viral e reduzir os sintomas não são apoiadas por nenhum dado ao qual nós tivemos acesso.

O mecanismo de ação proposto pelos fabricantes (específico para o vírus da influenza) não se enquadra à evidência clínica, que sugere uma ação central e em diversos sistemas.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Maíra Tristão Parra).

淺顯易懂的口語結論

成人與兒童流感的oseltamivir (Tamiflu)及zanamivir (Relenza)試驗法規資訊

在取得與流行病毒吻合的流感疫苗前,很多國家會儲備oseltamivir跟zanamivir來治療與預防季節性及傳染性的流感,世界衛生組織將oseltamivir列為不可缺少的藥品。

如何進行本文獻回顧

我們根據製造商給主管機關的報告(臨床研究報告)與主管機關的評論,修正並結合有關成人及兒童流感抗病毒藥zanamivir與oseltamivir的文獻。我們稱這些評論與報告為「法規資訊」。臨床研究報告為未發表、範圍廣泛且富含詳盡試驗細節的文件,是構成市場認可的根基,包括研究協定、方法及結果。直至今日,臨床研究報告仍是機密,只有製造商與主管機關看過。

我們為何採取這個方式

在之前的文獻裡,我們在已發表的試驗報告資料中,找到未解決的差異與大量的出版偏誤。我們因而選擇不要採用期刊文章裡的資料,改收錄在許可程序中產生的資料。我們由英國、美國、歐洲藥物管理局(EMA)、日本主管機關以及來自製造商的臨床研究報告(長期的媒體宣傳之後)取得資料,讓我們得以驗證來自成人及兒童已確診或疑似暴露在自然產生的流感中之隨機安慰劑對照試驗資料。

根據我們對法規文件(超過160,000頁)的評估,得到的結論是,許多試驗的設計、執行、記錄以及資訊的可得性有相當多的問題。

我們發現了什麼

本文獻中我們採用來自46個試驗(20個oseltamivir研究與26個 zanamivir研究)的資料。在收錄的許多研究中找出了研究設計的問題,影響我們對結果的信賴。我們發現兩種藥品對類流感(未確診的流感或流行性感冒)症狀期的縮短天數不到1天。根據由所有參與oseltamivir 試驗的人得到的資料顯示,oseltamivir對住院人數沒有影響,zanamivir試驗則沒有記錄這項結果。誠如試驗資料的個案記錄表所示,對於肺炎與其他流感併發症如支氣管炎、中耳感染(中耳炎)及鼻竇炎的影響記錄是不可靠的,有些記錄顯示肺炎診斷標準的限制。主管機關的評論注意到受試者追蹤日誌遺失的問題。對於有氣喘的兒童,到初次症狀緩解所需時間沒有明確的影響。

預防試驗顯示在個人與家庭中,oseltamivir與zanamivir降低了感染症狀性流感的風險。沒有對於無症狀流感或非流感、類流感影響的證據,但試驗執行的問題阻礙了任何明確的結論。

Oseltamivir的使用與噁心、嘔吐、頭痛、腎臟及精神相關的事件有關,其中後三項出現在使用oseltamivir來預防流感的時候(預防)。它對心臟的影響仍不明確,可能減低心臟相關的症狀,但也可能導致嚴重的心律問題。成人的zanamivir治療試驗沒有增加不良事件的記錄,少有與兒童zanamivir治療有關的可能危害之證據。

與其他發現的一致性

缺少顯示對於併發症影響的良好證據與美國食品藥物管理局(FDA)提出的、與兩種藥品有關的保守結論一致;FDA只認可兩種藥品對預防及治療流感症狀有效的說法,不承認其他效應(包括阻礙流感病毒在人與人之間傳播或預防肺炎)。FDA描述兩種藥品的整體效能為「適當」。

有益效應的作用機轉

這些發現全都指出,由oseltamivir carboxylate引發的低免疫反應與低階促發炎細胞激素,可能減輕與流感病毒複製的抑制作用無關的流感症狀。以oseltamivir做為中樞神經系統抑制劑的潛在低溫或退熱效應,可能也有助於主要症狀明顯減少。有關oseltamivir干預病毒傳播及減少併發症的能力之陳述,不被任何我們能取得的資料所支持。

由製造商提出的作用機轉(流感病毒特異)與臨床證據不符,顯示多系統與核心作用。

譯註

翻譯者:臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw