Amantadine and rimantadine for influenza A in children and the elderly

  • Review
  • Intervention

Authors


Abstract

Background

The effectiveness and safety of amantadine (AMT) and rimantadine (RMT) for preventing and treating influenza A in adults has been systematically reviewed. However, little is known about these treatments in children and the elderly.

Objectives

To systematically review the effectiveness and safety of AMT and RMT in preventing and treating influenza A in children and the elderly.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 2) which contains the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register, MEDLINE (1966 to June week 3, 2011) and EMBASE (1980 to June 2011).

Selection criteria

Randomised controlled trials (RCTs) or quasi-RCTs comparing AMT and/or RMT with placebo, control, other antivirals or different doses or schedules of AMT or RMT, or both, or no intervention, in children and the elderly.

Data collection and analysis

Two review authors independently selected trials for inclusion and assessed methodological quality. We resolved disagreements by consensus. In all comparisons except for one, we separately analysed the trials in children and the elderly using Review Manager software.

Main results

A total of 12 studies involving 2494 participants (1586 children and adolescents and 908 elderly) compared AMT and RMT with placebo, paracetamol (one trial; 69 children) or zanamivir (two trials; 545 seniors). All studies were RCTs but most were still susceptible to bias. Two trials in the elderly had a high risk of bias because of incomplete outcome data. In one of those trials there was also a lack of outcome assessment blinding. Risk of bias was unclear in 10 studies due to unclear random sequence generation and allocation concealment. Only two trials in children were considered to have a low risk of bias.

AMT was effective in preventing influenza A in children. A total of 773 participants were included in this outcome (risk ratio (RR) 0.11; 95% confidence interval (CI) 0.04 to 0.30). The assumed risk of influenza in the control group was 10 per 100 and the corresponding risk in the RMT group was one per 100 (95% CI 0 to 3). The quality of the evidence was considered low.
For treatment purposes, RMT was beneficial for abating fever on day three of treatment. For this purpose one study was selected with low risk of bias and included 69 children (RR 0.36; 95% CI 0.14 to 0.91). The assumed risk was 38 per 100 and the corresponding risk in the RMT group was 14 per 100, 95% CI 5 to 34. The quality of the evidence was moderate.

RMT did not show a prophylactic effect against influenza in the elderly, but the quality of evidence was considered very low. There were 103 participants (RR 0.45; 95% CI 0.14 to 1.41, for an assumed risk of 17 per 100 and a corresponding risk in the RMT group of 7 per 100, 95% CI 2 to 23). We did not identify any AMT trials in the elderly that met our inclusion criteria.

There was no evidence of adverse effects of AMT and RMT in children or an adverse effect of RMT in the elderly. We did not identify any AMT trials in the elderly that met our inclusion criteria.

Authors' conclusions

AMT is effective in preventing influenza A in children but the NNTB is high (NNTB: 12 (95% CI 9 to 17). RMT probably helps the abatement of fever on day three of treatment, but the quality of the evidence is poor. Due to the small number of available studies, we could not reach a definitive conclusion on the safety of AMT or the effectiveness of RMT in preventing influenza in children and the elderly.

Résumé

Amantadine et rimantadine pour les cas de grippe A chez les enfants et les personnes âgées

Contexte

L'efficacité et l'innocuité de l'amantadine (AMT) et la rimantadine (RMT) pour la prévention et le traitement de la grippe A chez les adultes a fait l'objet d'une revue systématique. Toutefois, très peu d'informations sont disponibles sur ces traitements administrés aux enfants et aux personnes âgées.

Objectifs

Passer systématiquement en revue l'efficacité et l'innocuité de l'AMT et la RMT pour la prévention et le traitement de la grippe A chez les enfants et les personnes âgées.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre Cochrane des essais contrôlés (CENTRAL) (The Cochrane Library 2011, numéro 2), qui contient le registre spécialisé du groupe Cochrane sur les infections respiratoires aiguës (IRA), MEDLINE (1966 à la semaine 3 de juin 2011) et EMBASE (1980 à juin 2011).

Critères de sélection

Des essais contrôlés randomisés (ECR) ou quasi-randomisés comparant l'AMT et/ou la RMT à un placebo, au contrôle, à d'autres antiviraux ou différentes doses ou schémas posologiques de l'AMT et/ou la RMT ou à l'absence d'intervention chez les enfants et les personnes âgées.

Recueil et analyse des données

Deux auteurs de la revue ont indépendamment sélectionné les essais pouvant être inclus et évalué leur qualité méthodologique. Nous avons résolu les désaccords par des consensus. Dans toutes les comparaisons, sauf une, nous avons analysé séparément les essais réalisés chez les enfants et les personnes âgées à l'aide du logiciel Review Manager.

Résultats Principaux

Un total de 12 études incluant 2 494 participants (1 586 enfants et adolescents et 908 personnes âgées) comparaient l'AMT et la RMT à un placebo, au paracétamol (un essai ; 69 enfants) ou au zanamivir (deux essais ; 545 personnes âgées). Toutes les études étaient des ECR, mais la majorité d'entre elles pouvaient présenter des risques de biais. Deux essais réalisés chez des personnes âgées étaient particulièrement exposés au biais en raison de données de résultats incomplètes. Dans l'un de ces essais, on constatait également l'absence de mise en aveugle pour l'évaluation des résultats. Les risques de biais étaient indéterminés dans 10 études en raison d'une génération de séquence aléatoire et d'une assignation secrète incertaines. Seuls les risques de biais de deux essais réalisés auprès d'enfants étaient considérés comme étant faibles.

L'AMT était efficace pour la prévention de la grippe A chez les enfants. Un total de 773 participants étaient inclus dans ce résultat (rapport de risque (RR) 0,11 ; intervalle de confiance (IC) à 95 % 0,04 à 0,30). Le risque présumé de grippe dans le groupe témoin était de 10 pour 100 et le risque correspondant dans le groupe RMT était de 1 pour 100 (IC à 95 % à 3). La qualité des preuves était considérée comme étant mauvaise.
À des fins thérapeutiques, la RMT présentait des effets bénéfiques pour faire tomber la fièvre dès le troisième jour de traitement. Une étude avec de faibles risques de biais a été sélectionnée à cette fin et incluait 69 enfants (RR 0,36 ; IC à 95 % 0,14 à 0,91). Le risque présumé était de 38 pour 100 et le risque correspondant dans le groupe RMT était de 14 pour 100, IC à 95 % 5 à 34. La qualité des preuves était modérée.

La RMT n'a révélé aucun effet prophylactique contre la grippe chez les personnes âgées, mais la qualité des preuves était très mauvaise. Au total, 103 participants ont été dénombrés (RR 0,45 ; IC à 95 % 0,14 à 1,41 pour un risque présumé de 17 pour 100 et un risque correspondant dans le groupe RMT de 7 pour 100, IC à 95 % 2 à 23). Nous n'avons identifié aucun essai portant sur l'AMT chez les personnes âgées qui répondaient à nos critères d'inclusion.

Aucune preuve n'a permis de démontrer les effets indésirables de l'AMT et la RMT chez les enfants ou les effets indésirables de la RMT chez les personnes âgées. Nous n'avons identifié aucun essai portant sur l'AMT chez les personnes âgées qui répondaient à nos critères d'inclusion.

Conclusions des auteurs

L'AMT est efficace pour la prévention de la grippe A chez les enfants, mais le NST (Nombre de sujets à traiter) est élevé (NST : 12 (IC à 95 % 9 à 17). La RMT contribue probablement à faire tomber la fièvre dès le troisième jour de traitement, mais la qualité des preuves est insuffisante. En raison du nombre limité d'études disponibles, nous n'avons pu tirer aucune conclusion définitive sur l'innocuité de l'AMT ou l'efficacité de la RMT pour la prévention de la grippe chez les enfants et les personnes âgées.

Plain language summary

Amantadine and rimantadine to prevent and treat influenza A in children and the elderly

Influenza is a respiratory infection in which cough, runny nose, headache and fever are frequent manifestations. Most symptoms resolve without treatment within three to seven days. However, hospitalisation, pneumonia and even death may occur as rare complications of the illness, especially among children and the elderly. Pandemics are also a reason for concern. They occur when influenza spreads globally, infecting 20% to 40% of the world's population, resulting in as many as 10 million deaths.

Oseltamivir (also known as Tamiflu) is currently used for patients with influenza on the recommendation of the World Health Organization (WHO). In previous pandemics, the virus was susceptible to amantadine and rimantadine. So, if they are safe and if the circulating strain proves to be susceptible to these drugs, they could be a less expensive alternative in the management of influenza. This reinforces the importance of conducting reviews on a variety of drugs for the treatment and prevention of influenza. We conducted a review of trials in children and the elderly groups. We selected 12 trials on 1586 children and adolescents and 908 elderly were selected.

Amantadine can prevent influenza in children but it would be necessary to use the drug in up to 17 children during a 14- to 18-week period to prevent one case of influenza. There was no evidence of adverse effects of amantadine in children. We could not reach a conclusion on its use or adverse effects in the elderly, as we did not identify any amantadine trials in the elderly that met our inclusion criteria.

The only observed benefit of rimantadine was in the abatement of fever by day three of treatment in children.

Although it is not the objective of this review, it is possible to speculate if rimantadine can be prescribed in selected cases, such as in children with underlying medical conditions in which fever may lead to complications, or may impair treatment or control of diseases such as diabetes, cardiopulmonary illness and chronic anaemia, such as sickle cell disease. New trials should answer this issue.

Due to the small number of studies, we could not reach a definitive conclusion on the safety of amantadine or the effectiveness of rimantadine on preventing influenza in both age groups.

Résumé simplifié

Amantadine et rimantadine pour les cas de grippe A chez les enfants et les personnes âgées

Amantadine et rimantadine pour la prévention et le traitement de la grippe A chez les enfants et les personnes âgées

La grippe est une infection respiratoire qui se manifeste généralement par l'apparition de toux, d'écoulements nasaux, de maux de tête et de fièvre. La majorité de ces symptômes disparaissent sans traitement au bout de trois à sept jours. Toutefois, des cas de complications rares de la maladie peuvent entraîner une hospitalisation, une pneumonie, voire la mort, surtout chez les enfants et les personnes âgées. Les pandémies sont également source de préoccupations. Elles apparaissent lorsque la grippe se propage de façon globale, infectant 20 à 40 % de la population et entraînant ainsi la mort de dizaines de millions de personnes.

L'oseltamivir (aussi connu sous le nom de Tamiflu) est actuellement préconisé pour les patients atteints de la grippe sur recommandation de l'Organisation mondiale de la Santé (OMS). Lors des pandémies précédentes, le virus était sensible à l'amantadine et la rimantadine. Par conséquent, si leur innocuité est démontrée et que la souche en circulation se révèle être sensible à ces médicaments, ces derniers pourraient représenter une alternative moins coûteuse pour la gestion de la grippe. Ceci renforce l'importance des revues portant sur divers médicaments pour le traitement et la prévention de la grippe. Nous avons réalisé une revue d'essais portant sur des groupes d'enfants et de personnes âgées. Nous avons sélectionné 12 essais totalisant 1 586 enfants et adolescents, et 908 personnes âgées.

L'amantadine permet de protéger les enfants de la grippe, mais sa prise doit s'étendre sur une période allant de 14 à 18 semaines chez 17 enfants afin d'éviter son apparition. Aucune preuve n'a permis de démontrer les effets indésirables de l'amantadine chez les enfants. Nous n'avons pu tirer aucune conclusion quant à son administration ou ses effets indésirables chez les personnes âgées car nous n'avons identifié aucun essai réalisé auprès de personnes âgées qui répondaient à nos critères d'inclusion.

Les seuls effets bénéfiques observés de la rimantadine étaient une chute de la fièvre le troisième jour de traitement chez les enfants.

Bien qu'il ne s'agisse pas de l'objectif de cette revue, il est possible de supposer que la rimantadine puisse être prescrite dans des cas précis, comme chez les enfants présentant un état pathologique sous-jacent dans lequel la fièvre peut provoquer des complications ou remettre en cause le traitement ou le contrôle de maladies, telles que le diabète, les maladies cardio-pulmonaires et les anémies chroniques, comme la drépanocytose. De nouveaux essais devraient apporter plus de réponses.

En raison du nombre limité d'études, aucune conclusion définitive n'a pu être tirée sur l'innocuité de l'amantadine ou l'efficacité de la rimantadine pour la prévention de la grippe dans les deux groupes d'âge.

Notes de traduction

Traduit par: French Cochrane Centre 10th April, 2012
Traduction financée par: Ministère du Travail, de l'Emploi et de la Santé Français

Summary of findings(Explanation)

Summary of findings for the main comparison. 
  1. *The basis for the assumed risk (e.g. median control group risk across studies) was calculated on the basis of control event rate. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

    1Allocation concealment not used or unclear.

    2Sparse data.

    3Allocation concealment unclear.

    4Sparse data, confidence intervals do not rule out potential for null effect or harm.

    5High heterogeneity unexplained.

Amantadine compared with placebo for prevention and treatment of influenza A in children

Patient or population: children with no influenza A infection (prevention) or with influenza a (treatment)

Settings: all

Intervention: amantadine

Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ControlAmantadine

Cases of influenza A during prophylaxis

(follow up:14 to 18 weeks)

Medium risk populationRR 0.11 (0.04 to 0.3)773
(2])
⊕⊕⊝⊝
low1,2
 
10 per 1001 per 100
(0 to 3)

Fever after initiation of treatment

(follow-up: 3 days)

Medium risk populationRR 0.37 (0.08 to 1.75)104
(2)
⊕⊕⊝⊝
low3,4
 
23 per 1009 per 100
(2 to 40)
Cough after initiation of treatmentSee commentSee commentNot estimable

0

(0)

See commentNo selected trial

Dizziness

(follow-up: 7 days)

Medium risk populationRR 6.63 (0.32 to 137.33)599
(2)
⊕⊝⊝⊝
very low3,4
 
0 per 1000 per 100
(0 to 0)

Nausea/ vomiting

(follow-up: 7 days)

Medium risk populationRR 0.54 (0.15 to 2)599
(2)
⊕⊝⊝⊝
very low3,4,5
 
13 per 1007 per 100
(2 to 27)

Stimulation/ insomnia

(follow-up: 7 days)

Medium risk populationRR 0.46 (0.12 to 1.74)599
(2)
⊕⊕⊝⊝
low3,4
 
3 per 1007 per 100
(2 to 27)
CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence
High quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.

Summary of findings 2

Summary of findings 2. 
  1. *The basis for the assumed risk (e.g. median control group risk across studies) was calculated on the basis of control event rate. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

    1Allocation concealment unclear.

    2Sparse data and confidence intervals do not rule out the potential for no effect or harm

Rimantadine compared with placebo for prevention and treatment of influenza A in children

Patient or population: children with no influenza A infection (prevention) or with influenza a (treatment)

Settings: any

Intervention: rimantadine

Comparison: control (placebo or acetaminophen)

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ControlRimantadine
Cases of influenza A during prophylaxis (follow-up: 1 to 35 days)Medium risk populationRR 0.49 (0.21 to 1.15)178
(3)
⊕⊕⊝⊝
low1,2
 
24 per 10012 per 100
(5 to28)

Fever after initiation of treatment

(follow-up: 3 days)

Medium risk populationRR 0.36 (0.14 to 0.91)69
(1)
⊕⊕⊕⊝
moderate2
 
38 per 10014 per 100
(5 to 34)

Cough after initiation of treatment

(follow-up: 7 days)

Medium risk populationRR 0.83 (0.63 to 1.1)69
(1)
⊕⊕⊕⊝
moderate2
 
81 per 10067 per 100
(51 to 89)

Dizziness

(follow-up: 35 days)

Medium risk populationRR 3.21 (0.14 to 75.68)56
(1)
⊕⊝⊝⊝
very low1,2
 
0 per 1000 per 100
(0 to 0)

Nausea/vomiting

(follow-up: 7-35 days)

Medium risk populationRR 0.96 (0.1 to 9.01)125
(2)
⊕⊕⊝⊝
low2
 
2 per 1002 per 100
(0 to 15)
Stimulation/insomniaSee commentSee commentNot estimable0
(0)
See commentNo selected trial
CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence
High quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.

Summary of findings 3

Summary of findings 3. 
Amantadine compared with placebo for prevention and treatment of influenza A in the elderly

Patient or population: elderly people with no influenza A infection (prevention) or with influenza a (treatment)

Settings: any

Intervention: amantadine

Comparison: control

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ControlAmantadine
Cases of influenza A during prophylaxisSee commentNot estimable0
(0)
See commentNo selected trial
Fever after initiation of treatmentSee commentNot estimable0
(0)
See commentNo selected trial
Cough after initiation of treatmentSee commentNot estimable0
(0)
See commentNo selected trial
DizzinessSee commentNot estimable0
(0)
See commentNo selected trial
NauseaSee commentNot estimable0
(0)
See commentNo selected trial
VomitingSee commentNot estimable0
(0)
See commentNo selected trial
Stimulation/insomniaSee commentNot estimable0
(0)
See commentNo selected trial

Summary of findings 4

Summary of findings 4. 
  1. *The basis for the assumed risk (e.g. median control group risk across studies) was calculated on the basis of control event rate. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

    1Allocation concealment unclear and 1 study had high withdrawal rate.

    2Sparse data and confidence interval do not rule out no effect or harm.

    3 Allocation concealment unclear

    4High heterogeneity unexplained.

Rimantadine compared with placebo for prevention and treatment of influenza A in the elderly 

Patient or population: elderly people with no influenza A infection (prevention) or with influenza a (treatment)

Settings: any

Intervention: rimantadine

Comparison: placebo

 
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments 
Assumed riskCorresponding risk 
ControlRimantadine 
Cases of influenza A during prophylaxisMedium risk populationRR 0.45 (0.14 to 1.41)103
(2)
⊕⊝⊝⊝
very low1,2
  
17per 1007 per 100
(2 to 23)
 
Fever after initiation of treatmentSee comment0
(0)
See commentSee commentNo selected trial 
Cough after initiation of treatmentSee comment0
(0)
See commentSee commentNo selected trial 

Dizziness

(follow-up: 12 weeks)

Medium risk population     
12 per 10011 per 100 (2 to 70)RR 0.94
(0.15 to 5.97)

35

(1)

⊕⊕⊝⊝
low2,3
  

Nausea

(follow-up: 8 to 12 weeks)

Medium risk populationRR 1.99 (0.45 to 8.75)233
(2)
⊕⊝⊝⊝
very low1,2,4
  
8 per 10015 per 100
(3 to 66)
 

Vomiting

(follow-up: 8 to 12 weeks)

Medium risk populationRR 0.99 (0.38 to 2.6)233
(2)
⊕⊕⊝⊝
low1,2
  
7 per 1007 per 100
(3 to 17)
 
Stimulation/insomnia (follow-up: 8 to 12 weeks)Medium risk populationRR 1.61 (0.43 to 6.02)233
(2)
⊕⊕⊝⊝
low1,2
  
7 per 10011 per 100
(3 to 40)
 
CI: confidence interval; RR: risk ratio 
GRADE Working Group grades of evidence
High quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.
 

Background

Description of the condition

Influenza is an acute, usually self-limiting respiratory illness caused by infection with influenza viruses A or B, members of the Orthomyxoviridae family (Nicholson 1992). It is seasonal and occurs most frequently during autumn and winter in temperate regions, although in some tropical countries, it may occur throughout the year with one or two peaks during rainy seasons (Monto 2008; Yang 2010). The illness is characterised by an abrupt onset of symptoms. These symptoms include headache, fever, general aches, weakness and myalgia, accompanied by respiratory tract signs, particularly cough and sore throat. However, a wide spectrum of clinical presentations may occur, ranging from a mild, febrile upper respiratory illness, to severe prostration and respiratory and systemic signs and symptoms. The most common complication that occurs during outbreaks of influenza is pneumonia (both viral and bacterial). A number of extra-pulmonary complications may also occur. These include Reye's syndrome in children (most commonly between two and 16 years of age), myocarditis, pericarditis and central nervous system (CNS) diseases. Again these include encephalitis, transverse myelitis and Guillain-Barrè syndrome (Wiselka 1994).

Description of the intervention

Nowadays there are two main measures for the treatment and prophylaxis of influenza viruses: immunisation using influenza vaccines directly isolated from influenza A and B viruses, and antiviral agents (Demicheli 2000). Although vaccination is the primary strategy for the prevention of influenza, there are a number of likely scenarios for which effective antiviral agents would be of utmost importance. Immune systems of the elderly are less responsive to vaccination (Thomas 2010). Influenza vaccines are efficacious in children older than two, but little evidence is available for children under two (Jefferson 2010). During any influenza season, antigenic drift in the virus may occur after formulation of the year's vaccine. So, the vaccine can be less protective and outbreaks can more easily occur in high-risk populations. In the course of a pandemic, vaccine supplies would be inadequate. Vaccine production by current methods cannot be carried out with the speed required to halt the progress of a new strain of influenza virus; therefore, it is likely that vaccines would not be available for those infected by the first wave of the virus (Hayden 2004). Antiviral agents therefore form an important part of a rational approach to influenza management (Moscona 2005). Antiviral drugs for influenza currently include two classes, each with two drugs: M2 ion channel inhibitors: amantadine (AMT) and rimantadine (RMT) and neuraminidase inhibitors: zanamivir and oseltamivir. M2 ion channel inhibitors affect ion channel activity through the cell membrane. They are reported to be effective by interfering with the replication cycle of type A viruses (but not type B). The neuraminidase inhibitors interfere with the release of progeny influenza virus from infected host cells and are effective against influenza A and B (Moscona 2005). Both drug classes have shown partial effectiveness for prevention and treatment of influenza A viruses, although neuraminidase inhibitors are less likely to promote the development of drug-resistant influenza (Moscona 2005).

It is important that the patterns of sensitivity and resistance of influenza A viruses to antiviral drugs be permanently monitored, since these characteristics may change over time. Resistance to M2 inhibitors, remained low until 2003 (Bright 2005; Ziegler 1999). An epidemiological study into resistance to AMT carried out from 1991 to 1995 described a frequency of 1% (16/2017) of resistant variants among H1N1 and H3N2 viruses (Ziegler 1999). However, subsequently a dramatic increase occurred: strains of influenza A (H3N2) virus with a specific mutation (Ser31Asn) showed an increase in resistance to AMT in communities located in Asia and North America (Bright 2005; Bright 2006). This resistance in 70% to 90% of strains occurred despite the absence of sustained selective drug pressure (Bright 2005; Bright 2006).

During the 2005–2006 season, 16% of H1N1 and 91% of H3N2 viruses were resistant around the world. Although the estimate for the proportion of resistance of H1N1 viruses was very low, an analysis conducted in China showed that the frequency of resistant H1N1 viruses had greatly increased from 28% (8/29) in the 2004–2005 season to 72% (33/46) in the 2005–2006 season. Similar studies were conducted in other countries in the 2005–2006 season. The following frequencies of resistance were obtained: 45% (13/29) in Europe, 24% (4/17) in Taiwan and 33% (1/3) in Canada (Deyde 2007).

A global pandemic emerged in 2009, caused by a new influenza A strain (H1N1) (WHO 2010a). All influenza A (H1N1) viruses tested in WHO Collaborating Centres to date showed to be resistant to AMT and RMT (WHO 2011).

How the intervention might work

The use of AMT and RMT for treatment and prevention of influenza A in adults has already been the topic of a review (Jefferson 2009b). Results of that review confirmed that AMT and RMT had a comparable efficacy and effectiveness in the treatment of influenza A in healthy adults, although their effectiveness in interrupting transmission was probably low. As previous pandemics proved to be susceptible to this class of drugs, it seems reasonable to review the evidence of AMT and RMT for treating and preventing influenza A in children and the elderly (Hayden 2006b).

Why it is important to do this review

Although the disease occurs in all age groups (Pineda Solas 2006),, the risks of complications, hospitalisations and deaths from influenza are higher among three groups of people: 1) persons older than 65 years; 2) young children; and 3) persons of any age who have medical conditions that place them at increased risk. Rates of infection are highest amongst children, and children are also one of the most important links for transmission (Dolin 2005).

Pandemics occur when influenza spreads globally, infecting 20% to 40% of the world's population in one year. This results in as many as 10 million deaths (WHO 2003). They usually arise in China where pigs, ducks and humans live in close proximity to each other and spread westward to the rest of Asia, Europe and the Americas (Bonn 1997). In the past 110 years there have been five pandemics caused by different influenza A viral subtypes. The Spanish influenza pandemic (1918 to 1919) is considered to have caused an estimated 40 million deaths worldwide. Most years, typical influenza epidemics infect 5% to 20% of the population and result in anywhere between 250,000 and 500,000 deaths, according to the World Health Organization (WHO), although other estimates accounting for deaths due to complications of influenza are as high as 1 million to 1.5 million.

In 2009, a new influenza A strain (H1N1), caused a global pandemic. According to the WHO, as of 24 January 2010, more than 214 countries and overseas territories had reported laboratory-confirmed cases of pandemic influenza H1N1, resulting in at least 18,449 deaths (WHO 2010a).

In an earlier version of a Cochrane review in adults, the review authors stated that neuraminidase inhibitors were effective in reducing symptoms and complications, but criticisms led to doubts about their effectiveness against complications (Jefferson 2011). Doubts still remain about their effectiveness and safety because their evaluations were limited to manufacturer-sponsored trials. This fact led the authors to the development of a new Cochrane protocol (Jefferson 2011).

In a Cochrane review published in 2007, the review authors concluded that oseltamivir may be considered for the treatment of children aged one to 12 years with influenza infection (Matheson 2007). This antiviral is likely to shorten the duration of symptoms, hasten the return to normal activities and reduce the incidence of secondary complications. Nevertheless, the review authors also concluded that more data were needed to clarify the benefits of neuraminidase inhibitors for the treatment of influenza in asthmatic children (including addressing the potential confounder of prior vaccination).

Nowadays, neuraminidase inhibitors are used as a prescription drug for patients suffering from influenza on the recommendation of the WHO (WHO 2010b). Governments have spent billions of dollars stockpiling neuraminidase inhibitors as a public health measure (WHO 2010b). In previous pandemias, the influenza A virus was susceptible to AMT and RMT. Therefore, these antivirals could be a less expensive alternative in the management of influenza if the circulating strain proves to be susceptible to AMT and RMT (Hayden 2006b). However, we should emphasize the resistance patterns of the pandemic viruses in 2009. All influenza A (H1N1) viruses tested in WHO Collaborating Centres to date were sensitive to zanamivir and all were resistant to AMT and RMT (WHO 2011).

These facts reinforce the importance of conducting and maintaining reviews of a variety of treatments, especially less expensive ones, for the treatment and prevention of influenza.

Objectives

  1. To identify, retrieve and assess RCTs evaluating the effects of AMT or RMT on influenza A in children and the elderly.

  2. To assess the efficacy of AMT and RMT in preventing cases of influenza A in children and the elderly.

  3. To assess the efficacy of AMT and RMT in shortening the duration of influenza A manifestations in children and the elderly.

  4. To compare the frequency of adverse effects of AMT and RMT to control groups in children and the elderly.

In comparisons between groups intended for AMT or RMT prophylaxis or treatment compared with control groups we tested the following hypotheses:

  • there is no difference in the number of cases of influenza A or in the duration of influenza symptoms; and

  • there is no difference in the number of adverse effects.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) and quasi-RCTs comparing AMT and/or RMT with placebo, control drugs, different doses or schedules of AMT or RMT, or both, or no intervention, in children and the elderly.

Types of participants

We included studies where at least 75% of the population was up to 19 years of age, or 65 years of age or older. We also included trials with a wider age range where data by age subgroups were available.

Types of interventions

Comparisons of AMT and/or RMT to placebo, control drugs, other antivirals, no interventions or different doses of AMT and/or RMT as prophylaxis and/or treatment for influenza A.

Types of outcome measures

Primary outcomes
  1. Response to treatment (measured as cases on the specified day of treatment): fever on day three of treatment, cough on day seven of treatment, malaise on day six of treatment and conjunctivitis and eye symptoms on day five of treatment.

  2. Cases of influenza, studied in all prophylaxis comparisons, including those in which two antivirals (RMT and zanamivir) (Gravenstein 2005; Schilling 1998) and two different doses of RMT were compared (Monto 1995).

  3. Cases of side effects in children: diarrhoea, exanthema, malaise, muscular limb pain, headache, dyspnoea, dizziness, stimulation/insomnia, nausea, vomiting, arrhythmia, gastrointestinal (GI) symptoms, CNS symptoms, change in behaviour, hyperactivity and tinnitus.

  4. Cases of side effects in the elderly: headache, dizziness, stimulation/insomnia, nausea, vomiting, anxiety, confusion, fatigue, depression, impaired concentration, loss of appetite, rash or allergic reaction, seizures or clonic twitching, dry mouth, insomnia or sleeplessness, body weakness and debility.

We used dichotomous outcomes for all the comparisons.

Secondary outcomes

The following outcomes appeared in the protocol but were not considered at the end in the analysis, as they were not reported in the included trials: patients' well-being, admission to hospital, general practitioner's (GP) visits and other drugs used. We could not analyse deaths. Although cited by Monto 1995, they were included among other causes of withdrawal.

Search methods for identification of studies

Electronic searches

For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 2) which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (July 2007 to June week 3, 2011) and EMBASE.com (July 2007 to June 2011). Details of the previous search are in Appendix 1.

The search strategy for MEDLINE and CENTRAL is in Appendix 2. We combined the MEDLINE search strategy with the Cochrane highly sensitive search strategy for identifying randomised trials in MEDLINE: sensitivity- and precision-maximising version (2008 revision); Ovid format (Lefebvre 2011). See Appendix 3 for the EMBASE search strategy.

Searching other resources

We imposed no language or publication restrictions. We screened bibliographies of retrieved articles and reviews in order to identify further trials. We contacted pharmaceutical companies and researchers active in the field for unpublished trials.

Data collection and analysis

Selection of studies

Two review authors (MG and MS) independently applied the selection criteria to all retrieved articles and extracted data using a data extraction form, specifically designed for this review. We resolved disagreements by consensus. We appointed one review author (AC) as arbitrator when necessary.

We entered extracted data into RevMan 2011. Combination of data was dependent on population characteristics and outcomes studied.

Data extraction and management

Two review authors (MG, MS) independently read the retrieved trials and applied the selection criteria. We independently extracted and reviewed data using the data collection form previously developed for this review. Two review authors (MG, MS) resolved disagreements on the quality of the trials by consensus. We appointed a third author (AC) as arbitrator if necessary.

We emailed primary studies' authors when the complete information sought was not available in study reports. We obtained authors' contact details from the study reports, other recent publications, university directories or by searching the world wide web. We recorded the following data.

  1. Setting: hospital, emergency, offices or clinics, primary health care, nursing homes, communities, prisons, military personnel, nursery or day care.

  2. Participants: criteria for patients to join the trial, age, gender, diagnostic criteria and co-morbid conditions.

  3. Interventions: placebo, other than AMT and RMT antiviral controls, comparing different doses or schedules of AMT and/or RMT or no intervention.

  4. Outcome measures: global symptom improvements, relief, death, cases of influenza, malaise, fever, nausea, arthralgia, rash, headache, systemic and serious side effects, well-being, admission to hospital, GP's visits, other drugs used, cough, coryza, sore throat, hoarseness, vomiting, abdominal pain, insomnia, irritability, behaviour changes and anorexia.

  5. Adverse effects: dry mouth, drowsiness/fatigue, constipation, urinary retention, sweating, headache, diarrhoea, palpitations, irritability, blurred vision, dizziness/light headedness, and nausea/vomiting and any other systemic and serious side effects.

Assessment of risk of bias in included studies

Two review authors (MG, MS) independently screened trial quality. We resolved disagreements by discussion. We appointed a third author (AC) to act as arbitrator when necessary. We used the criteria recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) to assess the risk of bias. We developed a form and populated it to assess the risk of bias, based on a former Cochrane review (Ahovuo-Saloranta 2011). When applicable, we answered the questions, with 'Yes' indicating a low risk of bias, 'No' indicating a high risk of bias, and 'Unclear' indicating either a lack of information or uncertainty over the potential for bias.

1. Sequence generation was the method used to generate the allocation sequence appropriate to produce comparable groups. We answered 'Yes' if the authors described a random component in the sequence generation process (for example, a random number table, a computerised random number table, coin tossing, shuffling cards or envelopes, throwing dice, drawing of lots). If there was no or insufficient information about the sequence generation process, we marked this domain 'Unclear'. We marked “No” (high risk of bias) if the sequence was generated by: 1) odds and evens or date of birth; 2) some rule based on date (or day) of admission; 3) some rule based on hospital or clinic record number.

2. Allocation sequence concealment was the method used to conceal the allocation sequence appropriate to prevent the allocation being known in advance of, or during, enrolment. We marked this domain 'Yes' if the trial authors described adequate concealment (for example by means of either central allocation, sequentially numbered drug containers of identical appearance, or sequentially numbered opaque sealed envelopes), and 'No' if: 1) inadequate concealment was documented; 2) allocation concealment was not used (for example, using either an open random allocation schedule, assignment envelopes without appropriate safeguards, alternation or rotation, date of birth, or case record number). We marked ‘Unclear’ if: 1) insufficient information about allocation concealment was provided; 2) the information was unclearly reported.

3. Blinding of participants and personnel were adequate measures used to blind study participants and personnel from knowing which intervention a participant received. This domain was marked ’Yes’ if the RCT authors stated: 1) that there was no blinding; 2) incomplete blinding, but the review authors judged that the outcome was not likely to be influenced by said incomplete blinding; 3) blinding of participants and key study personnel was ensured, and it is unlikely that the blinding could have been broken. The domain was marked ‘No’, representing high risk of bias, if the RCT authors described: 1) no blinding; 2) incomplete blinding, and the outcome was likely to be influenced by said incomplete blinding; 3) blinding of key study participants and personnel, but it was likely that the blinding could have been broken. This domain was marked 'Unclear' if there was insufficient information or if the study did not address this outcome.

4. Blinding of outcome assessment were adequate measures used to blind outcome assessors from knowing which intervention a participant received. This domain was marked ’Yes’ if there was: 1) no blinding of outcome assessment, but the review authors judged that the outcome measurement was not likely to be influenced by lack of blinding; 2) blinding of outcome assessors is ensured, and it is unlikely that the blinding could have been broken. This domain was marked ‘No’, representing a high risk of bias, if: 1) no blinding of outcome assessment was stated, and the outcome measurement was likely to be influenced by lack of blinding; 2) there was blinding of outcome assessors, but it was likely that the blinding could have been broken. This domain was marked ‘Unclear” if there was insufficient information or if the study did not address this outcome.

5. Incomplete outcome data describes how complete were the data for the clinical outcomes. Were drop-out rates and reasons for withdrawals reported? Were missing data imputed appropriately? This domain was marked 'Yes' (low risk of bias) if the RCT authors stated: 1) that there were no missing outcome data; 2) the reasons for missing outcome data were unlikely to be related to true outcome: 3) missing outcome data balanced out  across intervention groups, with similar reasons for missing data across said groups; 4) the proportion of missing outcomes compared with observed event risk was not enough to have a clinically relevant impact on the intervention effect estimate; 5) missing data were imputed using appropriate methods. This domain was marked 'No', representing a high risk of attrition bias, if: 1) the reason for missing outcome data was likely to be related to true outcome, with either an imbalance in numbers or reasons for missing data across intervention groups; 2) the proportion of missing outcomes compared with observed event risk was enough to induce clinically relevant bias in the intervention effect estimate; 3) ‘as-treated’ analysis was done with substantial departure of the intervention received from that assigned at randomisation; 4) was potentially inappropriate application of simple imputation. 'Unclear' risk of bias there was the expected classification of studies in which there was insufficient reporting of attrition/exclusions to permit the classification as ‘Low risk’ or ‘High risk’ (e.g. number of randomised patients not stated, no reasons for missing data provided), or if the study did not address this outcome.

We completed a 'Risk of bias' table for each included study (see 'Risk of bias' tables in the Characteristics of included studies table).  

Measures of treatment effect

We calculated risk ratios (RRs) and 95% confidence intervals (CI) for each study as all the outcomes studied were dichotomous. We tested for heterogeneity for each outcome.

Unit of analysis issues

In the Gravenstein 2005 trial, the author stated that the study was conducted over three winter seasons and that some participants were randomised more than once. Taking into account that influenza was the outcome of interest, and that in each season different influenza viruses emerge, participants that had acquired the infection in one of the seasons could not be considered to be immunologically resistant to influenza in the next season. Consequently, we decided to include all participants described by the trial authors, as this does not seem to produce bias.

In the Crawford 1988 and Clover 1991 studies, eligible family members were randomly assigned as a block to study RMT in the prevention of influenza. For the purpose of this review, we selected the children as the subgroup of interest. It could be expected that children from families in the intervention group could be more protected from influenza than children in the control group. Nevertheless, no effect was shown in either of the three trials selected for this comparison (Clover 1986b; Clover 1991; Crawford 1988).

Dealing with missing data

We contacted the trial authors to request missing data when data were not clearly stated. We analysed the available data, taking into account the relatively small number and randomness of missing data.

Assessment of heterogeneity

We stored the data extracted from primary studies in the Review Manager software (RevMan 2011). All the outcomes we studied were dichotomous.
We determined if there were sufficiently homogeneous data to combine when there were two or more selected studies for a given comparison. We grouped the previously selected articles according to the characteristics of interventions, outcomes and populations studied. We had to take into account that pooled studies may still differ from each other even though the initial application of this filter was supposed to reduce the possibility of heterogeneity.

We initially inspected forest plots generated by RevMan 2011 to evaluate the possibility of heterogeneity between studies. We applied the Cochrane test for homogeneity. With this aim we set a P value of 0.1 as the limit for considering the existence of heterogeneity (CCI 2006). We also applied the I2 statistic to quantify heterogeneity among the trials and to verify the impact on the meta-analysis, considering that some clinical and methodological diversity always occurs in a meta-analysis. We considered values above 50% to be representative of significant heterogeneity (Higgins 2011) and explored the causes. We used the subgroup analysis of participants or a subgroup analysis of the studies selected for each comparison when the heterogeneity was relevant to the outcome of the meta-analysis.

Assessment of reporting biases

We considered assessment of reporting biases to be at risk because of the small number of studies selected for each comparison. Nevertheless, we relied on extensive research and carefully examined the references of the studies found in the search results to avoid reporting biases. We analysed all trials that met the inclusion criteria, independently of the journal's impact factor, the year of publication, the language in which the article was written and the origin of both author and publication. The use of these criteria can be confirmed by checking the lists of included and excluded studies.

Data synthesis

We used the risk ratio (RR) and respective 95% confidence interval (CI) as a summary measure to combine data. We calculated the necessary number of patients to be treated for an individual to benefit from treatment with respect to an outcome (number needed to treat to benefit (NNTB)) and its 95% CI, when a statistical difference was found. We estimated the occurrence of an event in the population, or absolute risk (baseline risk) based on the rate of event occurrence in controls (control group rate (CGR)) for this calculation.

We used the random-effects model to calculate the summary measure, with the assumption that although the articles could have addressed somewhat different issues, they could be viewed as a family of studies on similar questions. We considered that the articles were a random sample of all studies that addressed the questions we were interested in. Therefore, even considering the possibility of failure of the statistical tests of homogeneity, the combination of similar studies would still be a reasonable procedure. Although it is impossible to state if the articles were really a random sample of all research on an issue, this model contributes to a more realistic and less prone to overestimate accuracy (Fletcher 2006).

Subgroup analysis and investigation of heterogeneity

We pre-specified some subgroup analyses to investigate heterogeneity. We planned to take into account the drugs used for control and treatment, their doses and the previous use of anti-influenza vaccine(s). However, we stress that the subgroup analysis does not take into account the randomisation processes, so these results must be considered with caution.

Sensitivity analysis

We carried out sensitivity analyses to explore heterogeneity. We conducted subgroup analyses for subsets of participants. We had planned to analyse RMT and AMT separately and together. However, when we identified the use of different antivirals being used as a control, we performed a subgroup analysis. We separated the trials in which the comparison was made using different antiviral medications from those in which the control was made with placebo or other drugs. We also carried out subgroup analyses for subsets of immunised and non-immunised participants as well as according to the dosages of antivirals tested in the trials.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Results of the search

We retrieved a total of 31 records in this updated search. Out of a total of 205 abstracts, titles and studies that we retrieved through the searches, 195 were written in English, three in Russian, two in Czech, three in German, one in French and one in Japanese. We discarded 129 studies. We assessed the remaining 78 articles in detail. It was necessary to contact 46 trial authors to verify that their studies met our selection criteria. We included 12 trials in this review. All of them are published trials and are described in the Characteristics of included studies table. We added another 38 trials in 2011 when we updated this review; we excluded all of them and our conclusions remain unchanged.

Included studies

The 12 included studies (Clover 1986b; Clover 1991; Crawford 1988; Finklea 1967; Gravenstein 2005; Hall 1987; Kitamoto 1968; Kitamoto 1971; Monto 1995; Patriarca 1984; Payler 1984; Schilling 1998) were all randomised trials; 11 were blinded and one was unblinded (Schilling 1998). The methods of randomisation and the follow-up period were poorly described in all studies, although we could estimate that follow-up ranged from eight to 120 days. We classified the included trials into two major groups: those conducted in children and those in the elderly.

Trials in children

Eight selected studies looked at the following.

  1. Treatment with AMT (Kitamoto 1968; Kitamoto 1971) and RMT (Hall 1987).

  2. Prophylaxis with AMT (Finklea 1967; Payler 1984) and RMT (Clover 1986b; Clover 1991; Crawford 1988).

  3. Adverse effects due to AMT (Kitamoto 1968; Kitamoto 1971) and RMT (Clover 1986b; Crawford 1988; Hall 1987).

For treatment trials and the outcome fever on day three of treatment, the AMT arm size was 51 and the control arm size was 53 children (Kitamoto 1968; Kitamoto 1971). The RMT arm size was 37 and the control arm size was 32 children (Hall 1987). For the other outcomes, cough on day seven, malaise on day six and eye symptoms on day five, we selected just one trial (Hall 1987). The RMT arm size was 37 and control arm size was 32 children for each of these outcomes.

In the five prophylaxis trials, we applied wider age ranges for children than the definition stated in the protocol (participants up to 16 years of age). These trials included older participants who were adolescents by WHO definition (WHO 2007). Data regarding the proportion of the subgroup which strictly fulfilled the age criterion were not available in these studies or by contacting the trial authors. The respective age ranges were one to 17 years (Clover 1991), 13 to 19 years (Payler 1984), one to 18 years (Clover 1986b; Crawford 1988) and eight to 19 years of age (Finklea 1967). The AMT arm size was 368 (Finklea 1967 (104); Payler 1984 (264)) and the control arm size was 373 children (Finklea 1967 (133); Payler 1984 (240)). The RMT arm size was 84 (Clover 1986b (35); Clover 1991 (22); Crawford 1988 (27)) and the control arm size was 94 participants (Clover 1986b (41); Clover 1991 (24); Crawford 1988 (29)).

Reported adverse effects of AMT included exanthema, malaise, muscular limb pain, headache, arrhythmia and stimulation/insomnia. The antiviral arm size was 264 children (Kitamoto 1968 (75); Kitamoto 1971 (189)) and the control arm size was 335 (Kitamoto 1968 (84); Kitamoto 1971 (251)).

A reported adverse effect of AMT was dyspnoea. The antiviral arm size was 75 and control arm size was 84 children (Kitamoto 1968). For the adverse effects of hyperreactivity and tinnitus the RMT arm size was 27 and the control arm size was 29 children (Crawford 1988).

Nausea/vomiting, diarrhoea and dizziness were described as possible adverse effects for both antivirals. For nausea/vomiting, the AMT arm size was 264 children (Kitamoto 1968 (75); Kitamoto 1971 (189)) and the control arm size was 335 (Kitamoto 1971 (251); Kitamoto 1968 (84)). The RMT arm size was 38 (Crawford 1988 (1); Hall 1987 (37)) and the control arm size was 61 (Crawford 1988 (29); Hall 1987 (32)).

For diarrhoea and dizziness the AMT arm size was 264 children (Kitamoto 1968 (75); Kitamoto 1971 (189)) and the control arm size was 335 (Kitamoto 1968 (84), Kitamoto 1971 (251). The RMT arm size was 27 and the control arm size was 29 children for these adverse effects (Crawford 1988).

Trials in the elderly

We selected three trials in this age group that reported on prophylaxis with RMT; we did not select any treatment trials. We studied the following outcomes.

  1. Prophylaxis of laboratory and clinical infection (Monto 1995; Patriarca 1984).

  2. Adverse reactions (Monto 1995; Patriarca 1984).

  3. Different doses of RMT as a prophylactic antiviral (Monto 1995).

  4. Comparison to other antivirals in the prophylaxis of influenza (Gravenstein 2005; Schilling 1998).

For prophylaxis of laboratory and clinical infection, the RMT (200 mg/day) arm size was 44 (Monto 1995 (26); Patriarca 1984 (18)) and the placebo arm size was 31 participants (Monto 1995 (14); Patriarca 1984 (17)). The trial authors stated they limited this analysis to vaccinated participants in nursing homes with confirmed influenza, as it provided an estimate of the additional protective efficacy of RMT. The sample studied by Patriarca 1984 was made up of previously vaccinated participants, so all the participants were analysed (Monto 1995; Patriarca 1984).

In the adverse reaction studies focusing on stimulation/insomnia, confusion, fatigue, nausea, depression, loss of appetite and vomiting, the RMT (200 mg/day) arm size was 150 (Monto 1995 (132); Patriarca 1984 (18)) and the placebo arm size was 83 participants (Monto 1995 (66); Patriarca 1984 (17)). All randomly assigned participants were analysed.

In the adverse reaction study focusing on headache, impaired concentration, rash or allergic reaction, seizures or clonic twitching, the RMT (200 mg/day) arm size was 132 and the placebo arm size was 66 participants (Monto 1995).

In another adverse reaction study focusing on dizziness and anxiety, the RMT (200 mg/day) arm size was 18 and the placebo arm size was 17 participants (Patriarca 1984).

In the unique study evaluating different doses of RMT as a prophylactic drug to clinical and confirmed influenza A, the RMT (100 mg/day) arm size was 28 and the RMT (200 mg/day) arm size was 26 participants (Monto 1995).

Only one selected study focused on adverse effects related to different doses of RMT. The studied effects were confusion, depression, impaired concentration, insomnia or sleeplessness, loss of appetite, rash or allergic reaction, seizure or clonic twitching, dry mouth, fatigue or drowsiness, headache, body weakness and debility. The 100 mg/day arm size was 130 and the 200 mg/day arm size was 132 participants (Monto 1995).

We selected two trials for the comparison of RMT to another antiviral and the participants were also the elderly (Gravenstein 2005; Schilling 1998). The RMT arm size was 254 and the zanamivir arm size was 291 participants. No study used AMT for this kind of comparison.

Excluded studies

We excluded 91 studies for the following reasons.

  1. They were carried out in different age groups.

  2. They were not controlled trials.

  3. They assessed other drugs.

  4. They were non-human or laboratory studies.

Risk of bias in included studies

The overall risk of bias is presented graphically in Figure 1 and summarised in Figure 2.

Figure 1.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

The trial authors of the 12 included studies stated that participants had been randomly allocated into treatment or control groups. In two of the studies (Hall 1987; Payler 1984) we obtained the following information by contacting the trial authors. Hall reported that a computer system was used to randomise participants. The university pharmacy was chosen to allocate and store the study drugs (Hall 1987). In Payler's study, randomisation had been carried out by the statistical department of a pharmaceutical company, which kept the key to the randomisation, and only when the study was analysed was the code broken (Payler 1984). There was no mention of any particular randomisation method in the other studies.

Blinding

Ten studies were described as double-blinded (Clover 1986b; Clover 1991; Crawford 1988; Finklea 1967; Gravenstein 2005; Hall 1987; Kitamoto 1968; Kitamoto 1971; Monto 1995; Patriarca 1984). However, only in one trial were blinded people listed (Monto 1995). Although there was no blinding stated in Payler 1984, we judged that the outcome was not likely to be influenced by a lack of blinding. Schilling 1998 was described as an unblinded study; we also judge that the outcomes were unlikely to be influenced by a lack of blinding.

Incomplete outcome data

There were no missing participants in either Kitamoto 1971, Kitamoto 1968 or Payler 1984. The review authors considered that the reasons for missing outcome data were unlikely to be related to true outcome in the following studies: Clover 1986b; Clover 1991; Crawford 1988; Finklea 1967; Gravenstein 2005. In the Hall 1987 trial, we considered that the proportion of missing outcomes compared with observed event risk was not enough to have a clinically relevant impact on the intervention effect estimate. On the other hand, we considered the reasons for missing outcome data likely to be related to the true outcome data in two studies (Monto 1995; Patriarca 1984). In Schilling 1998 there was insufficient report of exclusion.

Selective reporting

The review authors did not identify any possible sources of reporting biases.

Other potential sources of bias

The review authors did not identify any other possible sources of bias.

Effects of interventions

See: Summary of findings for the main comparison; Summary of findings 2; Summary of findings 3; Summary of findings 4

We intended to carry out 12 comparisons, although we could only conduct eight comparisons.

Comparisons in children

  1. AMT and RMT compared to control (placebo and acetaminophen) in the treatment of influenza A in children.

  2. AMT and RMT compared to control (placebo and a specific treatment) in the prophylaxis of influenza A in children.

  3. Adverse effects of AMT and RMT compared to control (placebo and acetaminophen) in children.

  4. Use of different doses of AMT and RMT for prophylaxis or treatment of influenza A in children.

  5. Adverse effects related to different doses of AMT and RMT in children.

  6. AMT and RMT compared to other antivirals in children.

Comparisons in the elderly

  1. AMT and RMT compared to control in the treatment of influenza A in the elderly.

  2. AMT and RMT compared to control (placebo and zanamivir) in the prophylaxis of influenza A in the elderly.

  3. Adverse effects of AMT and RMT compared to control (placebo) in the elderly.

  4. Use of different doses of AMT and RMT for prophylaxis and treatment of influenza A in the elderly.

  5. Adverse effects related to different doses of AMT and RMT in the elderly.

  6. AMT and RMT compared to other antivirals in the elderly.

Additional comparison (children plus the elderly)

We made a thirteenth comparison: the effect of RMT to control (placebo) in the prophylaxis of influenza A in children and the elderly.

Comparisons in children
Comparison 1: AMT and RMT compared to control (placebo and acetaminophen) in the treatment of influenza A in children

In the protocol, we originally planned to study the drug effect on reduction of fever and cough as they are considered the best predictors on influenza diagnosis. After collecting data, we verified that specific timelines for reduction of signs and symptoms were not reported in the included trials. We searched for another way to present an estimation of the response to AMT and RMT in patients with influenza. For this unplanned analysis, we considered the available data and arbitrarily chose a day of antiviral use to evaluate the response to the treatment. This choice was based on the Eccle 2005 study in which clinical manifestations were classified in early and later symptoms. Typically fever may last four to eight days, so we chose day three of treatment as the cut-off point to which it could be considered that the response to the drug would be useful. Cough is considered a later manifestation that develops slowly and can still be present a week later (Eccle 2005). In the same way, we chose day seven of treatment as the cut-off point by when the response to the drug could be considered useful.

Finally, we also decided to include other treatment outcomes as they were available in Hall's electronic correspondence to us. In the same way, we arbitrarily chose a day of antiviral use to evaluate the response to the treatment to make this unplanned analysis: 'malaise on day six', as it begins early but could still be present for one or two weeks (Eccle 2005; Smith 2006) and 'eye manifestations on day five', as it can occur early on in the course of the illness (Treanor 2005; Wright 2004)

AMT was compared to placebo (Kitamoto 1968; Kitamoto 1971) and RMT to acetaminophen (Hall 1987).

There was a protective effect of AMT and RMT in the occurrence of fever on day three of antiviral treatment, when trials using both antivirals were combined (Hall 1987; Kitamoto 1968; Kitamoto 1971) RR 0.39; 95% CI 0.20 to 0.79 (Analysis 1.1).

The baseline risk of fever on day three of treatment was 0.28, calculated on the basis of the control group risk (CGR). The number of children needed to treat to benefit (NNTB) to prevent one case of fever on day three of treatment was six (95% CI 4 to 17) (Analysis 1.1)

We also verified a protective effect of RMT for this outcome: RR 0.36; 95% CI 0.14 to 0.91 (Analysis 1.1.2). The baseline risk of fever on day three of treatment was 0.38, calculated on the basis of the CGR. The NNTB was five (95% CI 3 to 25) (Analysis 1.1). Just one trial reported this outcome (Hall 1987).

We observed no protective effect of AMT in the occurrence of fever on day three of treatment: RR 0.37; 95% CI 0.08 to 1.75 (Analysis 1.1.1) (Kitamoto 1968; Kitamoto 1971).

We saw no protective effect of RMT regarding the occurrence of any of the following outcomes assessed: cases of pain on movement and visual distortion on day five (RR 0.58; 95% CI 0.10 to 3.24) (Analysis 1.5), conjunctivitis on day five (RR 0.17; 95% CI 0.01 to 3.49) (Analysis 1.4), malaise on day six (RR 1.04; 95% CI 0.63 to 1.70) (Analysis 1.3) and cough on day seven (RR 0.83; 95% CI 0.63 to 1.10) (Analysis 1.2). Just one study reported this outcome (Hall 1987).

No selected studies reported the use of AMT for these latter outcomes.

Comparison 2: AMT and RMT compared to control (placebo and to specific treatment) in the prophylaxis of influenza A in children

AMT was compared to placebo and specific treatment (Finklea 1967; Payler 1984) and RMT to placebo (Clover 1986b; Clover 1991; Crawford 1988).

The AMT (Finklea 1967; Payler 1984) and RMT trials (Clover 1986b; Clover 1991; Crawford 1988) were heterogeneous (Chi2 test 9.27, P = 0.05, I2 statistic 56.8%) and could not be combined.

A protective effect of AMT was observed with a RR 0.11; 95% CI 0.04 to 0.30 (Analysis 2.1.1). The baseline risk of influenza was 0.10, calculated on the basis of the CGR. The NNTB was 12 (95% CI 9 to 17) for a period ranging from 14 (Payler 1984) to 18 weeks (Finklea 1967).

On the other hand, no protective effect of RMT was seen in the prophylaxis of cases of influenza (RR 0.49; 95% CI 0.21 to 1.15) (Analysis 2.1.2) (Clover 1986b; Clover 1991; Crawford 1988).

Comparison 3: adverse effects of AMT and RMT compared to control (placebo and acetaminophen) in children

AMT was compared to placebo (Kitamoto 1968; Kitamoto 1971). RMT was compared to placebo (Clover 1986b; Crawford 1988) and to acetaminophen (Hall 1987).

AMT was not related to a higher risk of the following adverse effects: diarrhoea (RR 0.79; 95% CI: 0.42 to 1.47) (Analysis 3.1), exanthema (RR 0.69; 95% CI 0.21 to 2.34) (Analysis 3.2), muscular limb pain (RR 0.85, 95% CI 0.46 to 1.59) (Analysis 3.4), headache (RR 0.73; 95% CI 0.52 to 1.03) (Analysis 3.5), and stimulation and insomnia (RR 0.46; 95% CI: 0.12 to 1.74) (Analysis 3.11) (Kitamoto 1968; Kitamoto 1971).

In the same way, AMT was not related to the outcomes dizziness and dyspnoea. For dizziness the RR was 6.63 (95% CI 0.32 to 137.33) (Analysis 3.8.1) (Kitamoto 1968; Kitamoto 1971) and for dyspnoea the RR was 0.37 (95% CI 0.02 to 9.02) (Analysis 3.6) (Kitamoto 1968).

The studies were heterogeneous for the outcomes malaise (Chi2 test 3.75, P = 0.05, I2 statistic 73.3%) and nausea/vomiting (Chi2 test 4.26, P = 0.04, I2 statistic 76.5%), although it seems that the author had used the same protocol. Nevertheless the heterogeneity for the outcome nausea/vomiting does not seem to be relevant, as AMT could be related either to an increase or to a reduction in the occurrence of this adverse effect (Kitamoto 1968; Kitamoto 1971).

No cases of arrhythmia were reported in those two trials.

RMT was not related to a higher risk of any of the following adverse effects assessed: CNS symptoms (RR 0.23; 95% CI 0.01 to 4.70) (Analysis 3.9); change in behaviour (RR 0.23; 95% CI 0.01 to 4.70) (Analysis 3.10); diarrhoea (RR 0.36; 95% CI 0.02 to 8.41) (Analysis 3.1.2); dizziness (RR 3.21; 95% CI 0.14 to 75.68) (Analysis 3.8.2); GI manifestations (RR 1.17; 95% CI 0.08 to 18.05) (Analysis 3.7); hyperactivity (RR 0.36; 95% CI 0.02 to 8.41) (Analysis 3.13); tinnitus (RR 3.21; 95% CI 0.14 to 75.68) (Analysis 3.14); and cerebellar ataxia (RR 2.61; 95% CI 0.11 to 61.80) (Analysis 3.12) (Clover 1986b; Crawford 1988; Hall 1987).

Each one of the adverse effects described above was studied in just one included study, except for nausea and vomiting (Crawford 1988; Hall 1987). In the same way, RMT was not related to a higher risk of nausea and vomiting: RR 0.96; 95% CI 0.10 to 9.01 (Analysis 3.15.2).

Comparison 4: use of different doses of AMT and RMT for prophylaxis and treatment of influenza in children

There was no selected study conducted in children for this comparison.

Comparison 5: adverse effects related to different doses of AMT and RMT in children

There were no selected studies conducted in children for this comparison.

Comparison 6: AMT and RMT compared to other antivirals in children

There was no selected study conducted in children for this comparison.

Comparisons in the elderly
Comparison 7: AMT and RMT compared to control in the treatment influenza A in the elderly

There was no study selected for this comparison.

Comparison 8: AMT and RMT compared to control (placebo and zanamivir) in the prophylaxis of influenza A in the elderly

RMT to placebo (Monto 1995; Patriarca 1984) and to zanamivir (Schilling 1998). No protective effect of RMT was seen regarding the prophylaxis of influenza in the elderly: RR 0.74; 95% CI 0.13 to 4.07 (Analysis 4.1).

Although care must be taken in the interpretation of the Chi2 test due to its low power in detecting heterogeneity in meta-analyses, we should emphasise the high P value observed in this comparison, considered alongside the I2 statistic value under 50%: Chi2 test 3.28; P = 0.19, I2 statistic 39%. We decided to explore the reasons of these findings as if the studies were heterogeneous, even though it would result in smaller samples impairing reaching to any definitive conclusion (Monto 1995; Patriarca 1984; Schilling 1998) .

Monto and Patriarca analysed previously vaccinated participants in blinded trials and used a placebo as control (Monto 1995; Patriarca 1984). Schilling did not state if the participants were vaccinated, although it was stated that the majority of the studied population had been previously immunised (Schilling 1998). This was an unblinded trial in which another antiviral (zanamivir) was used as a control drug.

When we excluded this study (Schilling 1998), the remaining trials (Monto 1995; Patriarca 1984) were shown to be homogeneous, but no protective effect of RMT prophylaxis in the occurrence of cases of influenza persisted (RR 0.45; 95% CI 0.14 to 1.41) (Analysis 4.4).

Monto 1995 used two different doses of RMT in his trial (100 mg/day and 200 mg/day) and Patriarca 1984 used the conventional dose of 200 mg/day. Schilling 1998 used a single dose of 100 mg/day. We also combined Monto's 200 mg/day subgroup with Patriarca's study in which the same dose was administered, but again no protective effect of RMT was observed in the prophylaxis of influenza: RR 0.44; 95% CI 0.12 to 1.63) (Analysis 4.2) (Monto 1995; Patriarca 1984; Schilling 1998).

Schilling's sample and Monto's 100 mg/day subgroup were heterogeneous and could not be combined (Chi2 test 2.55, P = 0.11, I2 statistic 60.8%) (Monto 1995; Schilling 1998).

There was no AMT study selected for comparison.

Comparison 9: adverse effects of AMT and RMT compared to control (placebo) in the elderly

There were two selected studies for these outcomes, both using RMT and placebo (Monto 1995; Patriarca 1984).

No effect of RMT was seen regarding any of the adverse outcomes assessed in the combined studies: stimulation and insomnia (RR 1.61; 95% CI 0.43 to 6.02) (Analysis 5.2), confusion (RR 0.79; 95% CI 95% 0.40 to 1.56) (Analysis 5.5), fatigue (RR 0.81; 95% CI 0.41 to 1.60) (Analysis 5.6) and vomiting (RR 0.99, 95% CI 0.38 to 2.60) (Analysis 5.14) (Monto 1995; Patriarca 1984).

In the same way, RMT was not related to the outcomes studied by Monto: headache (RR 0.83; 95% CI 0.21 to 3.38) (Analysis 5.1); impaired concentration (RR 0.50; 95% CI 0.10 to 2.41); rash or allergic reaction (RR 3.53; 95% CI 0.18 to 67.28); seizures or clonic twitching (RR 2.00; 95% CI 0.23 to 17.54) and dry mouth (RR 0.70; 95% CI 0.23 to 2.12), as well as in those studied by Patriarca: dizziness (RR 0.94; 95% CI 0.15 to 5.97) (Analysis 5.3) and anxiety (RR 2.83; 95% CI 0.92 to 8.74) (Analysis 5.4) (Monto 1995; Patriarca 1984).

The articles were heterogeneous just for the occurrence of nausea (test for heterogeneity: Chi2 test 2.02; P = 0.16; I2 statistic 50.5%). Nevertheless, this heterogeneity does not seem to be relevant as RMT could be related either to an increase or to a reduction in the occurrence of nausea in each one of the studies: Patriarca 1984: RR 5.67; 95% CI 0.76 to 42.32 and Monto 1995: RR 1.17; 95% CI 0.47 to 2.90) (Analysis 5.7).

It is important to stress the small samples studied in both trials. There was no AMT trial selected for comparison.

Comparison 10: use of different doses of AMT and RMT for prophylaxis and treatment of influenza A in the elderly

A reduced RMT dose of 100 mg/day was comparable to the full dose of 200 mg daily for prophylaxis of influenza in the elderly, although a wide CI was verified (RR 0.93; 95% CI 0.21 to 4.20) (Analysis 6.1). It should be emphasised the were few data available for these comparisons (Monto 1995).

There was no selected study using different doses of RMT in the elderly, nor any selected trial comparing different doses of AMT for prophylaxis and treatment of influenza in the elderly.

Comparison 11: adverse effects related to different doses of AMT and RMT in the elderly

There was no protective effect of a reduced dose of RMT in the occurrence of the following adverse reactions in the elderly: confusion (RR 0.82; 95% CI 0.41 to 1.65) (Analysis 7.1), depression (RR 0.44; 95% CI 0.12 to 1.65) (Analysis 7.2), impaired concentration (RR 0.68; 95% CI 0.11 to 3.98) (Analysis 7.3), insomnia or sleeplessness (RR 1.02; 95% CI 0.26 to 3.97) (Analysis 7.4), loss of appetite (RR 0.62; 95% CI 0.27 to 1.46) (Analysis 7.5), rash or allergic reaction (RR 0.34; 95% CI 0.04 to 3.21) (Analysis 7.6), seizures or clonic twitching (RR 0.11; 95% CI 0.01 to 2.07) (Analysis 7.7), dry mouth (RR 1.16; 95% CI 0.43 to 3.11) (Analysis 7.8), fatigue or drowsiness (RR 1.14; 95% CI 0.45 to 2.87) (Analysis 7.9), headache (RR 1.02; 95% CI 0.30 to 3.42) (Analysis 7.10) and body weakness or debility (RR 0.91; 95% CI: 0.38 to 2.18) (Analysis 7.11) (Monto 1995).

There was no AMT trial selected for this comparison in the elderly.

Comparison 12: AMT and RMT compared to other antivirals in the elderly

In Gravenstein's, but not in Schilling's study identical placebo was used (Gravenstein 2005; Schilling 1998). When RMT was compared to zanamivir it was shown that zanamivir prevented influenza A more effectively than RMT in the elderly (Gravenstein 2005; Schilling 1998).

There was no AMT trial selected for this comparison in the elderly.

Additional comparison (children plus the elderly)
Comparison 13: RMT compared to control (placebo) in the prophylaxis of influenza A in children and the elderly

Originally in the protocol we planned only to make the above 12 comparisons. However, whilst analysing data we considered doing an additional comparison and put the two age groups together. As the small samples studied in RMT trials for prophylaxis might have influenced the observed results, we tried to overcome this limitation by combining the trials with RMT in children and in the elderly. RMT had no proven effect in preventing influenza in either age group, but could be effective when we combined the results from both groups. However, it must be stressed that extraneous characteristics between those groups, other than age or previous immunisations, may have occurred, impairing generalisation of these results. There were five studies selected for this comparison (Clover 1986b; Clover 1991; Crawford 1988; Monto 1995; Patriarca 1984) with 156 patients in the treatment group and 125 in the placebo control group. The combination of the trials showed a protective effect of RMT in preventing influenza A (RR 0.49; 95% CI 0.27 to 0.92).

The baseline risk of influenza A was 0.22, calculated on the basis of the CGR. The NNTB was 9.09 (95% CI 6.25 to 50). We should emphasise that the follow-up period ranged from 3 to 11 weeks.

Discussion

Summary of main results

We used a comprehensive search strategy, and made every effort to identify relevant studies. In the majority of our comparisons, drawing definitive conclusions was impaired by the small number of selected articles and the small sample numbers. The studies demonstrated a decreased incidence of influenza A in children using AMT during a period ranging from 14 to 18 weeks. The NNTB indicates that for every nine to 17 children receiving AMT, one case of influenza A can be prevented.

RMT had no proven effect in preventing influenza in either age group, but could be effective when we combined the results of both groups. Nevertheless, any inferences from combining these groups must be treated with considerable caution, as they are different clinical groups combined with a small number of studies. Extraneous characteristics between those groups, other than age or previous immunisations, may also have occurred impairing generalisation of these results. Multiple comparisons should also be taken into account in the interpretation of these results.

When AMT and RMT were combined, they appeared to prevent the occurrence of fever on day three in children. However, when analysed separately, this effect was confirmed only for RMT. It must be emphasised that there was just one RMT trial selected for this outcome (Hall 1987) in which the baseline risk for the occurrence of fever on day three was 38%. For every five children (ranging from three to 25) treated with RMT in this unique small sample, it would be possible to prevent one case of fever on day three of treatment.

Overall completeness and applicability of evidence

It could be suggested that AMT is well tolerated by children, as its use was not related to an increase in the occurrence of the analysed adverse effects. Nevertheless, it may be difficult to distinguish between an adverse effect to the drug and a clinical manifestation of influenza itself. The outcomes muscular pain, headache, malaise, diarrhoea and nausea/vomiting may be adverse effects of AMT as well as clinical manifestations of influenza in children (MS 2006). In the same way, the outcome dyspnoea (Kitamoto 1968) may also occur due to other respiratory diseases, such as asthma, since an asthmatic episode may be triggered by respiratory viruses. So we must emphasise that adverse effects of the drug and clinical manifestations of influenza may had been confounded, since the selected trials were carried out in ill children.

RMT, administered exclusively on a prophylactic basis, was not related to an increase in the occurrence of the analysed adverse effects. In contrast to AMT studies, just nausea/vomiting could be confounded with influenza manifestations. The other adverse effects could not be confounded, as two of the three selected studies were about prophylaxis and were conducted in children without influenza (Clover 1986b; Crawford 1988). The third study (Hall 1987) was the only one carried out in children with influenza. Cerebellar ataxia and nausea/vomiting were the studied adverse effects in this trial. Cerebellar ataxia could not be confounded as it had not been described as an influenza manifestation. Cases of nausea/vomiting, which were also cited by Crawford, could have been confounded with influenza manifestations in Hall's article. The side effects nausea/vomiting were described in two studies (Crawford 1988; Hall 1987), while all the other adverse effects were mentioned in just one: diarrhoea, dizziness, hyperreactivity, tinnitus (Crawford 1988), GI symptoms, CNS symptoms, changes in behaviour (Clover 1986b) and cerebellar ataxia (Hall 1987). RMT also was considered to be well tolerated by the elderly, since it was not related to an increase in the incidence of adverse effects in this age group. But the studied samples were even smaller in the elderly than in the children's age group, and this fact may have influenced our results (Monto 1995; Patriarca 1984).

When analysing the antivirals adverse reactions, we could not even try to overcome the limitation of the small number of articles and the small samples studied by combining the results of both age groups, as the trial authors had described different outcomes (Clover 1986b; Crawford 1988; Hall 1987; Kitamoto 1968; Kitamoto 1971; Monto 1995; Patriarca 1984).

Comparison of different doses of antiviral drugs was available only for RMT and was tested in only one study related to the elderly group. There was no selected trial regarding the treatment either in children or in participants using AMT in both age groups. Both doses showed to be comparable in the prophylaxis of influenza as well as in the occurrence of adverse effects with no proven efficacy (Monto 1995).

Data on comparison to other antivirals was available just for RMT and zanamivir for prophylaxis of influenza A in the elderly group. This fact allowed a comparison of drugs of the two different classes of antivirals: M2 ion channel inhibitors and neuraminidase inhibitors. Zanamivir more effectively prevented influenza A in the elderly group (Gravenstein 2005; Schilling 1998).

Although the M2 ion channel inhibitors are increasingly subject to viral resistance (Goodman 2006), it does not mean that we should abandon AMT and RMT. These antivirals proved to be effective prophylactics against influenza in the 1968 Hong Kong pandemic and in the 1977 pandemic-like event 'Russian influenza'. Although the same resistance marker (Ser31Asn) was present in two isolates of influenza A (H5N1) obtained from patients in China in 2003 and in one lineage of avian and human H5N1 viruses in Thailand, Vietnam and Cambodia, most tested isolates from a second lineage that had been circulating in Indonesia, China, Mongolia, Russia and Turkey appear to be sensitive to AMT (Hayden 2005). Furthermore, the next pandemic virus may be one that, like H2N2, is susceptible to this class of drug. If the circulating strain were known to be susceptible to M2 inhibitors, these drugs would offer a less costly alternative to other antivirals (neuraminidase inhibitors) for prophylaxis against influenza.

Quality of the evidence

We selected a total of 12 RCTs (2494 participants: 1586 children and adolescents and 908 elderly participants).

The main factors that affect the strength of evidence are the sparsity of data and the unclear risk of selection bias (Clover 1986b; Clover 1991; Crawford 1988; Finklea 1967; Gravenstein 2005; Kitamoto 1968; Kitamoto 1971; Monto 1995; Patriarca 1984; Schilling 1998). Two of these studies, both on the elderly, were classified as high risk of bias because of incomplete outcome data (Monto 1995; Patriarca 1984) and high probability of detection bias (Monto 1995). Two trials, both in children and adolescents, were considered to have a low risk of bias (Hall 1987; Payler 1984).

Potential biases in the review process

The use of unpublished data, obtained in electronic correspondence with two of the 12 contact trial authors (Hall 1987; Payler 1984), was the identified potential of bias in this review process.

Agreements and disagreements with other studies or reviews

Although a systematic review carried out in adults (Jefferson 2009a) showing that both AMT and RMT are efficacious and safe in the prophylaxis and treatment of influenza A symptoms, we could not reach the same conclusion in children and the elderly, except for prophylaxis with AMT in children. This antiviral was effective in preventing influenza A in children. As in the adults review, RMT shortens the duration of fever in children.

Authors' conclusions

Implications for practice

According to available data, AMT was effective in the prophylaxis against influenza A in children. The safety of the drug was not well established, but it should be tried if one takes into account the important role of children in transmitting infections. Currently, RMT cannot be recommended as a prophylactic drug for either age group. Nevertheless, if we consider: 1) it is a safe drug; 2) the results of the combined age groups, and 3) the possibility that the next pandemic virus is susceptible to this class of drug, as indicated in former pandemics, we can still consider this 'old' drug as a less costly alternative to neuraminidase inhibitors.

Our conclusions regarding the effectiveness of both antivirals for the treatment of influenza A in children was limited to a proven benefit of RMT in the abatement of fever by day three of treatment with RMT. This benefit does not seem to justify a recommendation for using RMT to treat all children with influenza A infection, but only for selected cases in which fever may cause undesirable consequences. We could not reach a conclusion regarding AMT in the elderly, or antiviral treatment in this age group, as no trials fulfilled our selection criteria.

Caution must be taken when considering the results, as multiple comparisons were developed using the same sample. Therefore, it is possible that statistically significant results could have occurred by chance.

Implications for research

Definitive conclusions may have been impaired by the small number of selected studies and the small sample numbers used. Further research is necessary for:

Treatment

AMT for the treatment of influenza A in children to increase the sample numbers and the power of the studies.
RMT for the treatment of influenza A in children in order to confirm the observed result from the only selected study and to see if the drug could be useful in treating other clinical manifestations of influenza.
AMT and RMT for the treatment of influenza A in the elderly, as no identified studies fulfilled our inclusion criteria.

Prophylaxis

RMT in children to increase the sample numbers and the power of the studies, in order to achieve more definitive conclusions.
AMT in the elderly as there was no identified studies fulfilling our inclusion criteria for this age group.
RMT in the elderly to increase the sample numbers and the power of the studies, in order to achieve more definitive conclusions.

Adverse effects

AMT in children without influenza to avoid confounding adverse reactions of the antiviral with clinical manifestations of influenza.
RMT in the elderly to increase the sample numbers and the power of the studies.

Different doses of AMT and RMT

Further information is necessary on both drugs in both age groups.

Acknowledgements

The authors would like to thank Amanda Burls, Rebecca Mears, David Moore, Lisa Gold and Karen Elley for the use of their protocol. We also would like to thank Tom Jefferson and Richard Stubbs for comments provided on the draft protocol. We acknowledge Elizabeth Dooley from the Cochrane Acute Respiratory Infections Group for helping us in all phases of the review process; Ruth Foxlee and Sarah Thorning, for their essential help with the search strategy, the Iberoamerican Cochrane Centre and especially the kindness of Marta Roque, who helped us in the statistical and methodological aspects of the review. We also acknowledge Raimundo Santos, Vladmír Plesnik, Oleg Borisenko and Stuko Nakano with the assessment and translation of the essential topics for this review of the clinical trials published in German, French, Czech, Russian and Japanese. We also thank Jonathan Haliburton for reviewing the English version of this manuscript.The review authors wish to thank Caroline Hall, David Payler and Vladmír Plesnik, who generously provided us with unpublished trial data. Finally, we wish to thank the following referees who gave their permission to be acknowledged for commenting on this review: Maryann Napoli, Nelcy Rodriguez, and Tom Jefferson.

Data and analyses

Download statistical data

Comparison 1. AMT and RMT compared to control in the treatment of influenza A in children
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Fever day 33173Risk Ratio (M-H, Random, 95% CI)0.39 [0.20, 0.79]
1.1 AMT2104Risk Ratio (M-H, Random, 95% CI)0.37 [0.08, 1.75]
1.2 RMT169Risk Ratio (M-H, Random, 95% CI)0.36 [0.14, 0.91]
2 Cough day 7169Risk Ratio (M-H, Random, 95% CI)0.83 [0.63, 1.10]
2.1 RMT169Risk Ratio (M-H, Random, 95% CI)0.83 [0.63, 1.10]
3 Malaise day 6169Risk Ratio (M-H, Random, 95% CI)1.04 [0.63, 1.70]
3.1 RMT169Risk Ratio (M-H, Random, 95% CI)1.04 [0.63, 1.70]
4 Conjunctivitis day 5169Risk Ratio (M-H, Random, 95% CI)0.17 [0.01, 3.49]
4.1 RMT169Risk Ratio (M-H, Random, 95% CI)0.17 [0.01, 3.49]
5 Eye symptoms day 5 (pain on movement and visual distortion)169Risk Ratio (M-H, Random, 95% CI)0.58 [0.10, 3.24]
5.1 RMT169Risk Ratio (M-H, Random, 95% CI)0.58 [0.10, 3.24]
Analysis 1.1.

Comparison 1 AMT and RMT compared to control in the treatment of influenza A in children, Outcome 1 Fever day 3.

Analysis 1.2.

Comparison 1 AMT and RMT compared to control in the treatment of influenza A in children, Outcome 2 Cough day 7.

Analysis 1.3.

Comparison 1 AMT and RMT compared to control in the treatment of influenza A in children, Outcome 3 Malaise day 6.

Analysis 1.4.

Comparison 1 AMT and RMT compared to control in the treatment of influenza A in children, Outcome 4 Conjunctivitis day 5.

Analysis 1.5.

Comparison 1 AMT and RMT compared to control in the treatment of influenza A in children, Outcome 5 Eye symptoms day 5 (pain on movement and visual distortion).

Comparison 2. AMT and RMT compared to control in the prophylaxis of influenza A in children
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Infection5951Risk Ratio (M-H, Random, 95% CI)0.25 [0.09, 0.66]
1.1 AMT2773Risk Ratio (M-H, Random, 95% CI)0.11 [0.04, 0.30]
1.2 RMT3178Risk Ratio (M-H, Random, 95% CI)0.49 [0.21, 1.15]
Analysis 2.1.

Comparison 2 AMT and RMT compared to control in the prophylaxis of influenza A in children, Outcome 1 Infection.

Comparison 3. Adverse effects of AMT and RMT compared to control in children
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Diarrhoea3655Risk Ratio (M-H, Random, 95% CI)0.79 [0.42, 1.47]
1.1 AMT2599Risk Ratio (M-H, Random, 95% CI)0.81 [0.43, 1.53]
1.2 RMT156Risk Ratio (M-H, Random, 95% CI)0.36 [0.02, 8.41]
2 Exanthema2599Risk Ratio (M-H, Random, 95% CI)0.69 [0.21, 2.34]
2.1 AMT2599Risk Ratio (M-H, Random, 95% CI)0.69 [0.21, 2.34]
3 Malaise2599Risk Ratio (M-H, Random, 95% CI)0.89 [0.41, 1.96]
3.1 AMT2599Risk Ratio (M-H, Random, 95% CI)0.89 [0.41, 1.96]
4 Muscular, limb pain2599Risk Ratio (M-H, Random, 95% CI)0.85 [0.46, 1.59]
4.1 AMT2599Risk Ratio (M-H, Random, 95% CI)0.85 [0.46, 1.59]
5 Headache2599Risk Ratio (M-H, Random, 95% CI)0.73 [0.52, 1.03]
5.1 AMT2599Risk Ratio (M-H, Random, 95% CI)0.73 [0.52, 1.03]
6 Dyspnoea1159Risk Ratio (M-H, Random, 95% CI)0.37 [0.02, 9.02]
6.1 AMT1159Risk Ratio (M-H, Random, 95% CI)0.37 [0.02, 9.02]
7 Gastrointestinal symptoms176Risk Ratio (M-H, Random, 95% CI)1.17 [0.08, 18.05]
7.1 RMT176Risk Ratio (M-H, Random, 95% CI)1.17 [0.08, 18.05]
8 Dizziness3655Risk Ratio (M-H, Random, 95% CI)4.69 [0.53, 41.75]
8.1 AMT2599Risk Ratio (M-H, Random, 95% CI)6.63 [0.32, 137.33]
8.2 RMT156Risk Ratio (M-H, Random, 95% CI)3.21 [0.14, 75.68]
9 Central nervous system symptoms176Risk Ratio (M-H, Random, 95% CI)0.23 [0.01, 4.70]
9.1 RMT176Risk Ratio (M-H, Random, 95% CI)0.23 [0.01, 4.70]
10 Change in behaviour176Risk Ratio (M-H, Random, 95% CI)0.23 [0.01, 4.70]
10.1 RMT176Risk Ratio (M-H, Random, 95% CI)0.23 [0.01, 4.70]
11 Stimulation/insomnia2599Risk Ratio (M-H, Random, 95% CI)0.46 [0.12, 1.74]
11.1 AMT2599Risk Ratio (M-H, Random, 95% CI)0.46 [0.12, 1.74]
12 Cerebelar ataxia169Risk Ratio (M-H, Random, 95% CI)2.61 [0.11, 61.80]
12.1 RMT169Risk Ratio (M-H, Random, 95% CI)2.61 [0.11, 61.80]
13 Hyperreactivity156Risk Ratio (M-H, Random, 95% CI)0.36 [0.02, 8.41]
13.1 RMT156Risk Ratio (M-H, Random, 95% CI)0.36 [0.02, 8.41]
14 Tinnitus156Risk Ratio (M-H, Random, 95% CI)3.21 [0.14, 75.68]
14.1 RMT156Risk Ratio (M-H, Random, 95% CI)3.21 [0.14, 75.68]
15 Nausea/vomiting4724Risk Ratio (M-H, Random, 95% CI)0.61 [0.24, 1.58]
15.1 AMT2599Risk Ratio (M-H, Random, 95% CI)0.54 [0.15, 2.00]
15.2 RMT2125Risk Ratio (M-H, Random, 95% CI)0.96 [0.10, 9.01]
16 Arrythmia2599Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
16.1 AMT2599Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
Analysis 3.1.

Comparison 3 Adverse effects of AMT and RMT compared to control in children, Outcome 1 Diarrhoea.

Analysis 3.2.

Comparison 3 Adverse effects of AMT and RMT compared to control in children, Outcome 2 Exanthema.

Analysis 3.3.

Comparison 3 Adverse effects of AMT and RMT compared to control in children, Outcome 3 Malaise.

Analysis 3.4.

Comparison 3 Adverse effects of AMT and RMT compared to control in children, Outcome 4 Muscular, limb pain.

Analysis 3.5.

Comparison 3 Adverse effects of AMT and RMT compared to control in children, Outcome 5 Headache.

Analysis 3.6.

Comparison 3 Adverse effects of AMT and RMT compared to control in children, Outcome 6 Dyspnoea.

Analysis 3.7.

Comparison 3 Adverse effects of AMT and RMT compared to control in children, Outcome 7 Gastrointestinal symptoms.

Analysis 3.8.

Comparison 3 Adverse effects of AMT and RMT compared to control in children, Outcome 8 Dizziness.

Analysis 3.9.

Comparison 3 Adverse effects of AMT and RMT compared to control in children, Outcome 9 Central nervous system symptoms.

Analysis 3.10.

Comparison 3 Adverse effects of AMT and RMT compared to control in children, Outcome 10 Change in behaviour.

Analysis 3.11.

Comparison 3 Adverse effects of AMT and RMT compared to control in children, Outcome 11 Stimulation/insomnia.

Analysis 3.12.

Comparison 3 Adverse effects of AMT and RMT compared to control in children, Outcome 12 Cerebelar ataxia.

Analysis 3.13.

Comparison 3 Adverse effects of AMT and RMT compared to control in children, Outcome 13 Hyperreactivity.

Analysis 3.14.

Comparison 3 Adverse effects of AMT and RMT compared to control in children, Outcome 14 Tinnitus.

Analysis 3.15.

Comparison 3 Adverse effects of AMT and RMT compared to control in children, Outcome 15 Nausea/vomiting.

Analysis 3.16.

Comparison 3 Adverse effects of AMT and RMT compared to control in children, Outcome 16 Arrythmia.

Comparison 4. AMT and RMT compared to control in the prophylaxis of influenza A in the elderly
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 RMT (proved and clinical infection)3191Risk Ratio (M-H, Random, 95% CI)0.74 [0.13, 4.07]
2 RMT 200275Risk Ratio (M-H, Random, 95% CI)0.44 [0.12, 1.63]
3 RMT 1002130Risk Ratio (M-H, Random, 95% CI)1.42 [0.10, 21.10]
4 RMT Monto (100 + 200) and Patriarca2103Risk Ratio (M-H, Random, 95% CI)0.45 [0.14, 1.41]
Analysis 4.1.

Comparison 4 AMT and RMT compared to control in the prophylaxis of influenza A in the elderly, Outcome 1 RMT (proved and clinical infection).

Analysis 4.2.

Comparison 4 AMT and RMT compared to control in the prophylaxis of influenza A in the elderly, Outcome 2 RMT 200.

Analysis 4.3.

Comparison 4 AMT and RMT compared to control in the prophylaxis of influenza A in the elderly, Outcome 3 RMT 100.

Analysis 4.4.

Comparison 4 AMT and RMT compared to control in the prophylaxis of influenza A in the elderly, Outcome 4 RMT Monto (100 + 200) and Patriarca.

Comparison 5. Adverse effects of AMT and RMT compared to control in the elderly
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Headache1198Risk Ratio (M-H, Random, 95% CI)0.83 [0.21, 3.38]
1.1 RMT1198Risk Ratio (M-H, Random, 95% CI)0.83 [0.21, 3.38]
2 Stimulation/insomnia2233Risk Ratio (M-H, Random, 95% CI)1.61 [0.43, 6.02]
2.1 RMT2233Risk Ratio (M-H, Random, 95% CI)1.61 [0.43, 6.02]
3 Dizziness135Risk Ratio (M-H, Random, 95% CI)0.94 [0.15, 5.97]
3.1 RMT135Risk Ratio (M-H, Random, 95% CI)0.94 [0.15, 5.97]
4 Anxiety135Risk Ratio (M-H, Random, 95% CI)2.83 [0.92, 8.74]
4.1 RMT135Risk Ratio (M-H, Random, 95% CI)2.83 [0.92, 8.74]
5 Confusion2233Risk Ratio (M-H, Random, 95% CI)0.79 [0.40, 1.56]
5.1 RMT2233Risk Ratio (M-H, Random, 95% CI)0.79 [0.40, 1.56]
6 Fatigue2233Risk Ratio (M-H, Random, 95% CI)0.81 [0.41, 1.60]
6.1 RMT2233Risk Ratio (M-H, Random, 95% CI)0.81 [0.41, 1.60]
7 Nausea2233Risk Ratio (M-H, Random, 95% CI)1.99 [0.45, 8.75]
7.1 RMT2233Risk Ratio (M-H, Random, 95% CI)1.99 [0.45, 8.75]
8 Depression2233Risk Ratio (M-H, Random, 95% CI)1.63 [0.53, 4.98]
8.1 RMT2233Risk Ratio (M-H, Random, 95% CI)1.63 [0.53, 4.98]
9 Impaired concentration1198Risk Ratio (M-H, Random, 95% CI)0.5 [0.10, 2.41]
9.1 RMT1198Risk Ratio (M-H, Random, 95% CI)0.5 [0.10, 2.41]
10 Loss of appetite2233Risk Ratio (M-H, Random, 95% CI)1.11 [0.56, 2.17]
10.1 RMT2233Risk Ratio (M-H, Random, 95% CI)1.11 [0.56, 2.17]
11 Rash or allergic reaction1198Risk Ratio (M-H, Random, 95% CI)3.53 [0.18, 67.28]
11.1 RMT1198Risk Ratio (M-H, Random, 95% CI)3.53 [0.18, 67.28]
12 Seizures or clonic twitching1198Risk Ratio (M-H, Random, 95% CI)2.0 [0.23, 17.54]
12.1 RMT1198Risk Ratio (M-H, Random, 95% CI)2.0 [0.23, 17.54]
13 Dry mouth1198Risk Ratio (M-H, Random, 95% CI)0.7 [0.23, 2.12]
13.1 RMT1198Risk Ratio (M-H, Random, 95% CI)0.7 [0.23, 2.12]
14 Vomiting2233Risk Ratio (M-H, Random, 95% CI)0.99 [0.38, 2.60]
14.1 RMT2233Risk Ratio (M-H, Random, 95% CI)0.99 [0.38, 2.60]
Analysis 5.1.

Comparison 5 Adverse effects of AMT and RMT compared to control in the elderly, Outcome 1 Headache.

Analysis 5.2.

Comparison 5 Adverse effects of AMT and RMT compared to control in the elderly, Outcome 2 Stimulation/insomnia.

Analysis 5.3.

Comparison 5 Adverse effects of AMT and RMT compared to control in the elderly, Outcome 3 Dizziness.

Analysis 5.4.

Comparison 5 Adverse effects of AMT and RMT compared to control in the elderly, Outcome 4 Anxiety.

Analysis 5.5.

Comparison 5 Adverse effects of AMT and RMT compared to control in the elderly, Outcome 5 Confusion.

Analysis 5.6.

Comparison 5 Adverse effects of AMT and RMT compared to control in the elderly, Outcome 6 Fatigue.

Analysis 5.7.

Comparison 5 Adverse effects of AMT and RMT compared to control in the elderly, Outcome 7 Nausea.

Analysis 5.8.

Comparison 5 Adverse effects of AMT and RMT compared to control in the elderly, Outcome 8 Depression.

Analysis 5.9.

Comparison 5 Adverse effects of AMT and RMT compared to control in the elderly, Outcome 9 Impaired concentration.

Analysis 5.10.

Comparison 5 Adverse effects of AMT and RMT compared to control in the elderly, Outcome 10 Loss of appetite.

Analysis 5.11.

Comparison 5 Adverse effects of AMT and RMT compared to control in the elderly, Outcome 11 Rash or allergic reaction.

Analysis 5.12.

Comparison 5 Adverse effects of AMT and RMT compared to control in the elderly, Outcome 12 Seizures or clonic twitching.

Analysis 5.13.

Comparison 5 Adverse effects of AMT and RMT compared to control in the elderly, Outcome 13 Dry mouth.

Analysis 5.14.

Comparison 5 Adverse effects of AMT and RMT compared to control in the elderly, Outcome 14 Vomiting.

Comparison 6. Use of different doses of AMT and RMT for prophylaxis and treatment of influenza A in the elderly
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Clinical and laboratorial infection154Risk Ratio (M-H, Random, 95% CI)0.93 [0.21, 4.20]
1.1 RMT154Risk Ratio (M-H, Random, 95% CI)0.93 [0.21, 4.20]
Analysis 6.1.

Comparison 6 Use of different doses of AMT and RMT for prophylaxis and treatment of influenza A in the elderly, Outcome 1 Clinical and laboratorial infection.

Comparison 7. Adverse effects related to different doses of AMT and RMT in the elderly
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Confusion1262Risk Ratio (M-H, Random, 95% CI)0.83 [0.41, 1.65]
1.1 RMT1262Risk Ratio (M-H, Random, 95% CI)0.83 [0.41, 1.65]
2 Depression1262Risk Ratio (M-H, Random, 95% CI)0.44 [0.12, 1.65]
2.1 RMT1262Risk Ratio (M-H, Random, 95% CI)0.44 [0.12, 1.65]
3 Impaired concentration1262Risk Ratio (M-H, Random, 95% CI)0.68 [0.11, 3.98]
3.1 RMT1262Risk Ratio (M-H, Random, 95% CI)0.68 [0.11, 3.98]
4 Insomnia or sleeplessness1262Risk Ratio (M-H, Random, 95% CI)1.02 [0.26, 3.97]
4.1 RMT1262Risk Ratio (M-H, Random, 95% CI)1.02 [0.26, 3.97]
5 Loss of appetite1262Risk Ratio (M-H, Random, 95% CI)0.62 [0.27, 1.46]
5.1 RMT1262Risk Ratio (M-H, Random, 95% CI)0.62 [0.27, 1.46]
6 Rash or allergic reaction1262Risk Ratio (M-H, Random, 95% CI)0.34 [0.04, 3.21]
6.1 RMT1262Risk Ratio (M-H, Random, 95% CI)0.34 [0.04, 3.21]
7 Seizure or clonic twitching1262Risk Ratio (M-H, Random, 95% CI)0.11 [0.01, 2.07]
7.1 RMT1262Risk Ratio (M-H, Random, 95% CI)0.11 [0.01, 2.07]
8 Dry mouth1262Risk Ratio (M-H, Random, 95% CI)1.16 [0.43, 3.11]
8.1 RMT1262Risk Ratio (M-H, Random, 95% CI)1.16 [0.43, 3.11]
9 Fatigue and drowsiness1262Risk Ratio (M-H, Random, 95% CI)1.14 [0.45, 2.87]
9.1 RMT1262Risk Ratio (M-H, Random, 95% CI)1.14 [0.45, 2.87]
10 Headache1262Risk Ratio (M-H, Random, 95% CI)1.02 [0.30, 3.42]
10.1 RMT1262Risk Ratio (M-H, Random, 95% CI)1.02 [0.30, 3.42]
11 Body weakness or debility1262Risk Ratio (M-H, Random, 95% CI)0.91 [0.38, 2.18]
11.1 RMT1262Risk Ratio (M-H, Random, 95% CI)0.91 [0.38, 2.18]
Analysis 7.1.

Comparison 7 Adverse effects related to different doses of AMT and RMT in the elderly, Outcome 1 Confusion.

Analysis 7.2.

Comparison 7 Adverse effects related to different doses of AMT and RMT in the elderly, Outcome 2 Depression.

Analysis 7.3.

Comparison 7 Adverse effects related to different doses of AMT and RMT in the elderly, Outcome 3 Impaired concentration.

Analysis 7.4.

Comparison 7 Adverse effects related to different doses of AMT and RMT in the elderly, Outcome 4 Insomnia or sleeplessness.

Analysis 7.5.

Comparison 7 Adverse effects related to different doses of AMT and RMT in the elderly, Outcome 5 Loss of appetite.

Analysis 7.6.

Comparison 7 Adverse effects related to different doses of AMT and RMT in the elderly, Outcome 6 Rash or allergic reaction.

Analysis 7.7.

Comparison 7 Adverse effects related to different doses of AMT and RMT in the elderly, Outcome 7 Seizure or clonic twitching.

Analysis 7.8.

Comparison 7 Adverse effects related to different doses of AMT and RMT in the elderly, Outcome 8 Dry mouth.

Analysis 7.9.

Comparison 7 Adverse effects related to different doses of AMT and RMT in the elderly, Outcome 9 Fatigue and drowsiness.

Analysis 7.10.

Comparison 7 Adverse effects related to different doses of AMT and RMT in the elderly, Outcome 10 Headache.

Analysis 7.11.

Comparison 7 Adverse effects related to different doses of AMT and RMT in the elderly, Outcome 11 Body weakness or debility.

Comparison 8. AMT and RMT compared to other antivirals in the elderly
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 RMT and zanamivir2545Risk Ratio (M-H, Random, 95% CI)4.63 [1.46, 14.72]
Analysis 8.1.

Comparison 8 AMT and RMT compared to other antivirals in the elderly, Outcome 1 RMT and zanamivir.

Comparison 9. Additional comparison: RMT compared to control in the prophylaxis of influenza A in children and the elderly
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Infection5281Risk Ratio (M-H, Random, 95% CI)0.49 [0.27, 0.92]
1.1 RMT5281Risk Ratio (M-H, Random, 95% CI)0.49 [0.27, 0.92]
Analysis 9.1.

Comparison 9 Additional comparison: RMT compared to control in the prophylaxis of influenza A in children and the elderly, Outcome 1 Infection.

Appendices

Appendix 1. Previous searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 3); MEDLINE (1966 to July 2007); and EMBASE (1980 to July 2007).

The MEDLINE and CENTRAL search strategy are shown below. We combined the MEDLINE search string with the Cochrane highly sensitive search strategy phases one and two as published in Appendix 5b of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2005). We adapted the search strategy to search EMBASE.

MEDLINE (OVID)
1 exp INFLUENZA/
2 influenza.mp.
3 or/1-2
4 exp AMANTADINE/
5 amantadine.mp.
6 exp RIMANTADINE/
7 rimantadine.mp.
8 or/4-7
9 3 and 8

EMBASE (Embase.com)
1 exp INFLUENZA/
2 influenza.ti. or influenza.ab.
3 or/1-2
4 exp AMANTADINE/
5 amantadine.ti. or amantadine.ab.
6 exp RIMANTADINE/
7 rimantadine.ti. or rimantadine.ab.
8 or/4-7
9 3 and 8
10 Randomized Controlled Trial/
11 Controlled Study/
12 exp RANDOMIZATION/
13 Single Blind Procedure/
14 Double Blind Procedure/
15 Crossover Procedure/
16 Phase 3 Clinical Trial/
17 Phase 4 Clinical Trial/
18 or/10-17
19 9 and 18

Appendix 2. MEDLINE search strategy

MEDLINE (OVID)
1 exp Influenza, Human/
2 influenza*.tw.
3 flu.tw.
4 exp Influenzavirus A/
5 or/1-4
6 exp Amantadine/
7 amantadine.tw,nm.
8 symmetrel.tw,nm.
9 Rimantadine/
10 rimantadine.tw,nm.
11 flumadine.tw,nm.
12 or/6-11
13 5 and 12

Appendix 3. EMBASE.com search strategy

#13. #9 AND #12
#12. #10 OR #11
#11. random*:ab,ti OR placebo*:ab,ti OR factorial*:ab,ti OR crossover*:ab,ti OR 'cross over':ab,ti OR 'cross-over':ab,ti OR volunteer*:ab,ti OR allocat*:ab,ti OR assign*:ab,ti OR ((singl* OR doubl*) NEAR/2 (blind* OR mask*)):ab,ti
#10. 'randomized controlled trial'/exp OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR 'crossover procedure'/exp
#9. #3 AND #8
#8. #4 OR #5 OR #6 OR #7
#7. rimantadine:ab,ti OR flumadine:ab,ti
#6. 'rimantadine'/de
#5. amantadine:ab,ti OR symmetrel:ab,ti
#4. 'amantadine'/de
#3. #1 OR #2
#2. influenza*:ab,ti OR flu:ab,ti
#1. 'influenza'/de OR 'influenza virus a'/exp

Feedback

Amantadine and rimantadine for influenza A in children and the elderly, 24 January 2008

Summary

A year ago CDC provided a recommendation not to use these drugs for 'flu supporting this recommendation by newly acquired resistance of the virus. I believe that this recommendation ought to be at least discussed in the review and better, addressed e.g. by analysis of RCTs data for time periods e.g. before 2000 and after etc.
Also it would be nice to have the abstract rich with data, not just a statement.

Submitter agrees with default conflict of interest statement:
I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback.

Reply

We do agree that the issue of viral resistance is of utmost importance. We have stressed this concern in the Background and in the Discussion sections. We expect, from what is written in the text, that readers would be aware of the problem.

Background: ...Both drug classes have shown partial effectiveness for prevention and treatment of influenza A viruses, although neuraminidase inhibitors are less likely to promote the development of drug-resistant influenza ( Moscona 2005 )

Discusion : Data on comparison to other antivirals was available just for RMT and zanamivir for prophylaxis of influenza A in the elderly group. This fact allowed a comparison of drugs of the two different classes of antivirals: M2 ion channel inhibitors and neuraminidase inhibitors. Zanamivir more effectively prevented influenza A in the elderly group (Gravenstein 2005; Schilling 1998). Although the M2 ion channel inhibitors are increasingly subject to viral resistance ( Goodman 2006 ) it does not mean that we should abandon AMT and RMT. These antivirals proved effective for prophylaxis against influenza illness in the 1968 pandemic of “Hong Kong Influenza” and in 1977 pandemic-like event involving “Russian influenza”. Although the same resistance marker (Ser31Asn) was present in two isolates of influenza A (H5N1) obtained from patients in China in 2003 and in one lineage of avian and human H5N1 viruses in Thailand, Vietnam, and Cambodia, most tested isolates from a second lineage that has been circulating in Indonesia, China, Mongolia, Russia, and Turkey appear to be sensitive to amantadine ( Hayden 2005 ). Futhermore, the next pandemic virus may be one that, like H2N2, is susceptible to this class of drugs. If the circulating strain were known to be susceptible to M2 inhibitors, these drugs would offer a less costly alternative to other antivirals (neuraminidase inhibitors) for prophylaxis against illness.

Contributors

Vasiliy Vlassov
Feedback comment added 12 June 2008

What's new

Last assessed as up-to-date: 27 June 2011.

DateEventDescription
27 June 2011New search has been performedSearches updated. No new trials fulfilled our inclusion criteria. We excluded 38 new trials (Bantia 2010; Boltz 2010; Brammer 2009; Burch 2009; Cady 2011; Carter 2008; Cayley 2010; Chawla 2009; Chen 2007; Cheng 2009; Choi 2009; Chou 2008; Cowling 2008; Curran 2010; De la Camara 2007; DeLaney 2010; Falagas 2010; Farlow 2008; Fiore 2008; Guo 2007; Hota 2007; Kalia 2008; Kim 2011; Kirkby 2010; Korenke 2008; Langlet 2009; Matheson 2007; Miyachi 2011; Moffat 2008; Morrison 2007; Nuesch 2007; Sato 2008; Simeonova 2009; Tappenden 2009; Thomas 2008; Wailoo 2008; Welton 2008; Whitley 2007).
27 June 2011New citation required but conclusions have not changedThe conclusions remain unchanged.

History

Protocol first published: Issue 4, 2000
Review first published: Issue 1, 2008

DateEventDescription
13 May 2009AmendedNo changes - republished to fix technical problem.
12 June 2008Feedback has been incorporatedFeedback comment added.
25 May 2008AmendedConverted to new review format.
26 July 2007New search has been performedSearches conducted.

Contributions of authors

Márcia G Alves Galvão (MG) selected the trials, extracted data and was responsible of the methodological aspects of the review.
Marilene Augusta Rocha Crispino Santos (MS) selected the trials, extracted data, was responsible of the methodological aspects of the review and supervised the day-to-day work of the review.
Antonio Ledo Alves da Cunha (AC) was appointed as an arbitrator to solve disagreements between MG and MS on the selection of the trials. He supervised the work in all phases and provided his experience on the development of the review.

Declarations of interest

None known.

Differences between protocol and review

Originally in the protocol we planned to study the drug effect on reduction of fever and cough, as they are considered the best predictors on influenza diagnosis. After collecting data, we verified that specific timelines for reduction of signs and symptoms were not reported in the included trials. So, we considered the available data and arbitrarily chose a day of antiviral use to evaluate the response to the treatment. This choice was based on Eccle's study in which clinical manifestations were classified in early and later symptoms (Eccle 2005).

We applied wider age ranges for children than the definition stated in the protocol (participants up to 16 years of age). Trials in older participants who were adolescents by WHO definition (WHO 2007) were also included. Data regarding the proportion of the subgroup which strictly fulfilled the age criterion in protocol were not available in five studies or by contacting the trial authors. The respective age ranges were one to 17 years (Clover 1991), 13 to 19 years (Payler 1984), one to 18 years (Clover 1986b; Crawford 1988), and eight to 19 years of age (Finklea 1967).

We planned only to make 12 comparisons. However, whilst analysing data we considered doing an additional comparison and put the two age groups together. As the small samples studied in RMT trials for prophylaxis might have influenced the observed results, we tried to overcome this limitation by combining the trials with RMT in children and in the elderly. It must be stressed that extraneous characteristics between those groups, other than age or previous immunisations, may have occurred, impairing generalisation of these results.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Clover 1986b

MethodsRandomised, parallel, double-blind comparison of RMT with PB. The trial took place during an outbreak of influenza A/H1N1 in Oklahoma. Study duration: 5 weeks. Patients and providers were blinded. Outcome assessor method of blinding was unclear. Dropouts: 3 families who moved outside the study area, 1 in the placebo group whose parents attributed the 'medication' to the reducing the child's performance at school, and 1 in the RMT group due to a non-influenza illness in a 4-year-old child. Co-interventions and other potential confounders were not observed
ParticipantsThere was a total of 146 participants, including 76 children which was our subgroup of interest. Inclusion criteria: children within 35 families during a naturally occurring outbreak of influenza A. Exclusion criteria: if any family member was known to have cardiac, pulmonary, or neurologic disease; if a female family member was pregnant or actively trying to become pregnant; if any family member had received the influenza vaccine during the past year; if any member was taking medications that might interfere with the study. Gender: both females and males were included (proportion not specified). Disease stage: RMT was administered as a prophylactic when influenza A was identified within community
InterventionsRMT: 5 mg/kg/d, max: 100 mg/ d (< 10 years) or 200 mg/ d (> 10 years). Oral route. Duration: 5 weeks
OutcomesLaboratory proved infection cases and reported adverse effects
Notes1 to 18 years old
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskIt is reported that "...children...received either RMT or PB in a double-blind, random assignment". Nevertheless, randomisation method is not described
Allocation concealment (selection bias)Unclear riskConcealment is not clearly described
Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for missing outcome data are unlikely to be related to true outcome
Blinding of participants and personnel (performance bias)
All outcomes
Low riskIt is stated that "...children...received either RMT or PB in a double-blind, random assignment", but the specific people who were blinded are not listed
Blinding of outcome assessment (detection bias)
All outcomes
Low riskIt is stated that "...children...received either RMT or PB in a double-blind, random assignment", but the specific people who were blinded are not listed

Clover 1991

MethodsRandomised, parallel, comparison of RMT with PB. Multicentre trial that took place during an influenza season for 3 to 4 weeks after the start of treatment. Patients were blinded. Outcome assessor blinding was unclear. Dropouts: none (in the subgroup of interest), co-interventions and other potential confounders were not observed
ParticipantsThere was a total of 84 participants, including 46 children which was our subgroup of interest. Inclusion criteria: children within families consisting of 2 to 5 members with at least one adult (ranging in age from 18 to 75 years and one child aged between 1 to 17 years during a naturally occurring outbreak of influenza A. Exclusion criteria: participants who had a history of AMT hypersensitivity, chronic respiratory disease, severe medical illness, neuropsychiatric disorder; were pregnant or lactating; had a recently documented influenza A virus infection; required long-term drug therapy with AMT or drugs that could interfere with RMT or with clinical assessments (e.g., aspirin, tranquillizers, antihistamines and decongestants. Gender: unclear. Disease stage: all the eligible participants were given the assigned drug as soon as influenza was first recognised in family members (the index patient) and after the member had been evaluated by a study nurse
InterventionsRMT: 5 mg/kg/d, max: 150 mg/d (= or < 10 years or weighing less than 30 kg) or 200 mg/d (> 9 years who weighed more than 30 kg). Oral route. Duration: 10 days
OutcomesThe outcome of interest was laboratory proved infection cases
Notes1 to 17 years old
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskAuthors stated it was a randomised study and that randomisation is described in another article (Hayden 1989): "all eligible family members...were randomly assigned as a block to receive either RMT or PB". The method used is not described
Allocation concealment (selection bias)Low riskRandomisation was carried out in one of the centres where this multicentric trial was conducted
Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for missing outcome data are unlikely to be related to true outcome
Blinding of participants and personnel (performance bias)
All outcomes
Low riskAuthors stated it was a double-blinded trial as described in other article (Hayden 1989): "the study was double-blind...trial". Nevertheless, the specific people who were blinded are not listed
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAuthors stated it was a double-blinded trial as described in other article (Hayden 1989): "the study was double-blind...trial". Nevertheless, the specific people who were blinded are not listed

Crawford 1988

MethodsRandomised, parallel, double-blind trial in which prophylactic efficacy of RMT against influenza A infection in children was evaluated. RMT was compared to PB. The trial took place during a naturally occurring outbreak of influenza A (H3N2) in Oklahoma City, USA, from November, 1984 to March, 1985. Study duration: 5 weeks. Withdrawal: 3 children in the RMT group were found post-study to have had documented influenza A infection before or on the day of institution of prophylaxis and were excluded from the analysis. 17 people from 5 families withdrew because of relocation or refusal to have a second blood specimen drawn. Their age group was not stated
ParticipantsThere was a total of 110 participants from 29 families, including 56 children which was our subgroup of interest. Inclusion criteria: children within 29 families during a naturally occurring outbreak of influenza A infection. Exclusion criteria: if any family member was known to have cardiac, pulmonary, or neurologic disease; if a female family member was pregnant or actively trying to become pregnant; if any family member had received the influenza vaccine during the past year; if any member was taking medications that might interfere with the study. Gender: both females and males were included (proportion not specified). Disease stage: RMT was administered as a prophylactic when influenza A was identified within community
InterventionsRMT: 5 mg/kg/d, max: 100 mg/d (< 10 years) or 200 mg/d (> 10 years). Oral route
OutcomesLaboratory proved infection cases. Adverse effects
Notes1 to 18 years old
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskAuthors stated it was a "... a randomised...clinical trial" although randomisation methods are not described
Allocation concealment (selection bias)Unclear riskThe authors state that their " study design has been previously reported" (Clover 1986b), but even in that trial, the method of concealment is not clearly described
Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for missing outcome data unlikely to be related to outcome
Blinding of participants and personnel (performance bias)
All outcomes
Low riskAuthors stated it was "a double-blind PB controlled clinical trial". Nevertheless, the specific people who are blinded are not listed
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAuthors stated it was "a double-blind PB controlled clinical trial". Nevertheless, the specific people who are blinded are not listed

Finklea 1967

MethodsRandomised, parallel, double-blind, trial in which AMT use as prophylaxis in naturally-occurring acute respiratory illness. AMT was compared to PB. The trial took place between February 1965 to June 1965. The method of blinding is unclear. Study duration: 18 weeks. Withdrawal was the same for the two groups - discharge from school (19%). The proportion was not stated
ParticipantsThere were 293 participants from both sexes (proportion not stated), from 8 to 19 years of age. The participants were volunteers at a school for intellectually handicapped but educable children. Sera pairs tests were obtained in 237 children. Exclusion criteria: children receiving tranquillizers, sympathomimetic amines or anticonvulsives. Co-morbid conditions: intellectually handicapped children
InterventionsAMT: 1 to 2.5 mg/kg. (Pre-puberal: 60 mg/dose, 2 x/d, during the first week and 1 X/d during the rest of the period of the study. Older children: 100 mg/dose, 2 x/d, during the first week and 1 x/d during the rest of the period of the study
OutcomesFourfold rises in CF and/or HI tilter against A2/AA/1/65
Notes8 to 19 years old
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskAuthors stated "volunteers were assigned to AMT or the PB group by randomisation", although randomisation method is not described
Allocation concealment (selection bias)Unclear riskConcealment is not clearly described
Incomplete outcome data (attrition bias)
All outcomes
Low riskIt is stated that "The rate of withdrawal...(the same for the two groups) was small. The reason for withdrawal was discharge from school"
Blinding of participants and personnel (performance bias)
All outcomes
Low riskAlthough it was "a double-blind study", the specific people who are blinded are not listed
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAlthough the trial is described as "a double-blind study", the specific people who are blinded are not listed

Gravenstein 2005

MethodsRandomised, parallel, double-blind comparison of RMT with zanamivir. Identical PB (inhaled or tablets) were used. The trial took place in nine long-term care facilities in the United States over 3 winter seasons. Because the study was conducted over multiple influenza seasons, some participants were randomised more than once. Study duration: 3 winter seasons. Co-interventions and other potential confounders were not observed
ParticipantsThere were 231 participants in the RMT group and 226 in the zanamivir group (intent-to-treat population) of both sexes (29% female in RMT group and 30% female in zanamivir group. More than 75% of the participants were 65 years of age or older (90% in RMT group and 89% in zanamivir group)
InterventionsUpon an influenza outbreak participants were randomised (1:1) to inhaled zanamivir plus PB or inhaled PB plus zanamivir 100 mg tablets for 14 days
OutcomesThe outcome of interest was laboratory proved infection cases
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskAuthors describe the trial as "a randomised, parallel comparison of RMT with zanamivir", but randomisation methods are not described
Allocation concealment (selection bias)Unclear riskConcealment is not clearly described
Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for missing outcome data are unlikely to be related to the true outcomes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe trial is described as a " double-blind comparison of RMT with zanamivir. Identical PB (inhaled or tablets) were used". Nevertheless, the specific people who are blinded are not listed
Blinding of outcome assessment (detection bias)
All outcomes
Low riskThe trial is described as a " double-blind comparison of RMT with zanamivir. Identical PB (inhaled or tablets) were used". Nevertheless, the specific people who are blinded are not listed

Hall 1987

MethodsRandomised, parallel, double-blind comparison of RMT with acetaminophen. Study duration: 7 days. 1 patient dropped out, due to AE. Co-interventions and other potential confounders were not observed
Participants69 children were included, 40 females and 29 males. The inclusion criteria were: clinical illness and viral isolation. Exclusion criteria: previously unhealthy aged 1 to 15 years. Disease stage: clinical illness and confirmed laboratory infection
InterventionsRMT: 6.6 mg/kg/d, max: 150 mg/d (< 9 years) and 200 mg/d (>= 9 years), 2 x/d; by oral route, for 5 days
OutcomesMean symptom score of: fever, conjunctivitis, eye symptoms (pain on movement, fever up to 3rd day, conjunctivitis up to 3rd day, eyes symptoms (pain on movement and visual distortion); cough up to 7th day; malaise up to 6th day; CNS symptoms
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskIt is stated in the published study that "Patients were assigned to the RMT or acetaminophen treatment group under a double-blind, randomised allocation". The investigators also reported in their correspondence to the reviewers that computer random system was used to randomise participants
Allocation concealment (selection bias)Low riskParticipants and investigators enrolling participants could not foresee assignment because a pharmaceutical-controlled randomisation was used to conceal allocation, as stated in the authors' correspondence to the reviewers
Incomplete outcome data (attrition bias)
All outcomes
Low riskOne "child receiving RMT complained of nausea and vomiting and withdrew from the study on the second day". The proportion of missing outcomes compared with observed event risk is not enough to have a clinically relevant impact on the intervention effect estimate
Blinding of participants and personnel (performance bias)
All outcomes
Low riskAlthough "patients were assigned to the RMT or acetaminophen treatment group under a double-blind, randomised allocation", the specific people who are blinded are not listed
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAlthough "patients were assigned to the RMT or acetaminophen treatment group under a double-blind, randomised allocation", the specific people who are blinded are not listed

Kitamoto 1968

MethodsRandomised, parallel, double-blind comparison of AMT with PB. This trial took place during an outbreak of influenza in Japan. Study duration: 7 days. Patient, provider and outcome assessor method of blinding is unclear. Dropouts: none co-interventions and other potential confounders were not observed
ParticipantsThere were 355 participants. Although the proportions are not cited, it is stated that the groups are comparable in the following criteria: sex, age, influenza vaccination history, distribution and geometric mean of HI and CF titre in acute sera, interval between onset of symptoms and start of treatment, and maximum body temperature before the treatment. 158 participants of both genders met the age criteria. 91 children were cases of clinical influenza with serological confirmation The proportion of males and females was not stated. Inclusion criteria: respiratory symptoms evident within the 2nd day of illness. Disease stage: clinical symptoms within 2nd day of illness
InterventionsAMT: 50 mg/d (one to two years old); 100 mg/d (three to five years old); 150 mg/d (6 to 10 years old), by oral route, for 7 days
OutcomesFever up to 4th day. AE: nausea/ vomiting; diarrhoea; exanthema; malaise; muscular, limb pain; headache; dyspnoea; cyanosis; stimulation/insomnia; dizziness; arrhythmia
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskIt was stated that "AMT or PB was given to the patient at random" , although randomisation method is not described
Allocation concealment (selection bias)Unclear riskConcealment is not described
Incomplete outcome data (attrition bias)
All outcomes
Low riskThere was no missing patients, although "four cases were shown to be influenza B and were excluded from statistical analysis"
Blinding of participants and personnel (performance bias)
All outcomes
Low riskAlthough "AMT or PB was given to the patient at random by double-blind method" the specific people who are blinded are not listed
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAlthough "AMT or PB was given to the patient at random by double-blind method" the specific people who are blinded are not listed

Kitamoto 1971

MethodsRandomised, parallel, double-blind comparison of AMT with PB. The trial took place during an outbreak of influenza in the winter of 1968 to 1969 in Japan. The study duration was at least seven days. Patient, provider and outcome assessor method of blinding was unclear. Dropouts were not stated. Co-interventions and other potential confounders: concomitant administration of antipyretics. It was also performed an analyses with patiens who received concomitant antipyretics
ParticipantsOf the 737 participants, 155 participants of both genders met the inclusion criteria. Although the proportions are not cited, it is stated that the groups are comparable in the following criteria: sex, age, influenza vaccination history, distribution and geometric mean of HI and CF titer in acute sera, interval between onset of symptoms and start of treatment, and maximum body temperature before the treatment. Inclusion criteria: respiratory symptoms evident within the 2nd day of illness. Disease stage: clinical symptoms within 2nd day of illness
InterventionsAMT: 50 mg/d (one to two years old); 100 mg/d (3 to 5 years old); 150 mg/d (6 to 10 years old), by oral route, for 7 days
OutcomesFever up to 4th day. AE: nausea/vomiting; diarrhoea; exanthema; malaise; muscular, limb pain; headache; stimulation/insomnia; dizziness; arrhythmia
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe author states "patients were given AMT or PB according to randomly distributed individual code of the double-blind method", although randomisation method is not described
Allocation concealment (selection bias)Unclear riskConcealment is not described
Incomplete outcome data (attrition bias)
All outcomes
Low riskAthough there was no missing outcome data, the author states that "only patients with Hong Kong influenza in whom medication was started within 2 days" were included in statistical analysis". "In order to exclude the possible influence of concomitantly administered antipyretics on the defervescent effect of AMT the same analysis was performed with 134 Hong Kong influenza patients who had received no concomitant antipyretics"
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe author states "patients were given AMT or PB according to randomly distributed individual code of the double-blind method". Nevertheless, the specific people who are blinded are not listed
Blinding of outcome assessment (detection bias)
All outcomes
Low riskThe author states "patients were given AMT or PB according to randomly distributed individual code of the double-blind method". Nevertheless, the specific people who are blinded are not listed

Monto 1995

MethodsRandomised, parallel, double-blind comparison of two different dosis of RMT with PB. The trial took place during an outbreak of influenza A/H3N2 during 1993. Study duration: eight weeks. 62% withdrew because of side effects, death, discharge, hospitalisation, physician's request and refusal to continue participation. Co-interventions and other potential confounders were not observed
ParticipantsA total of 328 participants, 275 females and 53 males were included. Inclusion criteria: residents of 10 nurse homes who agreed to participate in the study. Exclusion criteria: patients with significant renal or hepatic disease. Disease stage: RMT was administered as prophylaxis
InterventionsRMT: 100 mg/d; RMT: 200 mg/d; PB. Ratio: 2:2:1 Duration: up to 8 weeks
OutcomesDeath. Adverse effects: dry mouth, drowsiness/fatigue, headache, irritability, dizziness/light headedness, nausea/vomiting, abdominal pain, body weakness or disability, confusion, depression, impaired concentration, insomnia or sleeplessness, loss of appetite, rash or allergic reaction, seizure or clonic twitching
NotesThree groups: RMT 100 AMT 200 and PB
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskAlthough the authors state that the participants were randomly assigned to receive of active medication (100 or 200 mg of RMT per day) or placebo, the randomisation method is not described
Allocation concealment (selection bias)Unclear riskConcealment is not described
Incomplete outcome data (attrition bias)
All outcomes
High riskAuthors cited that an "increased risk of withdrawal from the study only on the basis of perceived side effects was demonstrated among participants in both groups receiving active medication, especially the 200 mg/day group, compared with the placebo group; however, these associations were not statistically significant" The reasons for missing outcome data are likely to be related to true outcome
Blinding of participants and personnel (performance bias)
All outcomes
Low riskIt is stated that "staff and residents were blinded to group assignment"
Blinding of outcome assessment (detection bias)
All outcomes
High riskNo blinding is stated. The outcome is likely to be influenced by lack of blinding

Patriarca 1984

MethodsRandomised, parallel, double-blind comparison of RMT with PB. The trial took place during an outbreak of influenza A (H3N2) viruses were isolated from patients in the community. The study was conducted from early January 1983 to 6 April. Patient, provider and outcome assessor method of blinding is unclear
Participants35 participants, 68 to 102 years old, of non-specified gender, all of whom had been vaccinated the previous autumn. Inclusion criteria: residents of 3 nursing homes who agreed to participate in the study. Exclusion criteria: patients with medical conditions that might increase the severity of side effects or require careful adjustments in the dosage of RMT, which include: significant renal impairment (SCr > 2 mg/d) or liver disease, acute congestive heart failure, seizure disorders, psychosis, severe pitting oedema, orthostatic hypotension, and conditions requiring central nervous system stimulants. Disease stage: RMT was administered as prophylaxis
InterventionsRMT: 100 mg twice a day; PB. Duration: 80 (+/- 4,9) days prophylaxis
OutcomesAdverse reactions: anxiety, confusion, insomnia, anorexia, fatigue, dizziness, nausea and vomiting
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe authors stated that "participants ... were randomly assigned to receive either RMT or PB". Nevertheless, randomisation method is not described
Allocation concealment (selection bias)Unclear riskConcealment is not described
Incomplete outcome data (attrition bias)
All outcomes
High riskIt was cited that 2 participants from the intervention group withdrew because of side effects. 1 suffered a generalised convulsion of undetermined etiology (a participant with an underlying idiopathic seizure disorder). 3 later withdrew for no described reasons. 2 participants of PB group also withdrew. Reasons for missing outcome data are likely to be related to the true outcome, with imbalance in reasons for missing data across intervention and control groups
Blinding of participants and personnel (performance bias)
All outcomes
Low riskIt is stated that "a double-blind, placebo-control trial" was conducted. Nevertheless the specific people who were blinded are not listed
Blinding of outcome assessment (detection bias)
All outcomes
Low riskIt is stated that "a double-blind, placebo-control trial" was conducted. Nevertheless the specific people who were blinded are not listed

Payler 1984

MethodsRandomised, parallel trial. Blindness is not stated. AMT use as prophylaxis in naturally-occurring acute respiratory illness. AMT was compared to no specific treatment. The trial took place in the autumn of 1982. Study duration: 14 days. Patients excluded from analysis were similar in the two groups and the reasons were: students were day boys from whom samples were not available: students infected before the start of AMT; compliance failures
ParticipantsThere were 604 randomised students and 536 were analysed. All of them were male, from 13 to 19 years of age. The participants were students of a boarding school. Once influenza A outbreak had been detected, samples were taken from all boys who were sufficiently unwell to be absent from lessons even if they did not have a fever. Nasopharyngeal aspirates were examined for viruses by rapid immunofluorescent microscopy and tissue culture. Once outbreaks had been identified, only culture methods were used
InterventionsAMT: 100 mg/ dose, 1 x/d, during the 14 days
OutcomesClinical and laboratory-proved influenza A
Notes13 to 19 years old
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskIn a correspondence to the reviewers, the author reported that the randomisation had been carried out by the statistical department of a pharmaceutical company
Allocation concealment (selection bias)Low riskParticipants and investigators enrolling participants could not foresee assignment because a pharmaceutical company-controlled randomisation was used to conceal allocation, and kept the key to the randomisation, and only when the study was analysed was the code broken, as stated in the authors' correspondence to the reviewers
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Blinding of participants and personnel (performance bias)
All outcomes
Low riskAthough there was no blinding stated, the review authors judge that the outcome is not likely to be influenced by the lack of blinding
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAthough there was no blinding stated, the review authors judge that the outcome is not likely to be influenced by the lack of blinding

Schilling 1998

  1. a

    ACM: acetaminophen
    AE: adverse effects
    AMT: amantadine
    bid: twice a day
    CF: complement fixation
    CNS: central nervous system
    d: day
    GI: gastrointestinal
    HI: Hemagglutination inhibition
    NC: not clear
    PB: placebo
    RMT: rimantadine
    SCr: serum creatinine
    STGO: aspartate aminotransferase

MethodsRandomised, parallel, unblinded trial. RMT and zanamivir were compared for prophylaxis of influenza A. The trial began in November 1996. Drug administration: 14 days. Number of respiratory illness was monitored until January 1997. The participants were volunteers residents of a nursing home for veterans and their spouses. Inclusion criteria: volunteers living in a unit of the nursing home where outbreak of influenza was declared. Exclusion criteria: symptoms of new respiratory illness within the previous 7 days of the declared outbreak
Participants65 volunteers of both sexes received zanamivir and 23 rimantadine were analysed. Age range: 50 to 95 years old and 75% older than 65 years of age. The participants were volunteers residents of a nursing home for veterans and their spouses. Inclusion criteria: volunteers living in a unit of the nursing home where outbreak of influenza was declared
InterventionsRMT: 100 mg/dose, 1 x/day, during 14 days. Zanamivir: 10 mg inhaled bid and 4.4 mg intranasally bid
OutcomesClinical and laboratory proved influenza A
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe authors stated that it was a "randomised unblinded study" but randomisation method is not described
Allocation concealment (selection bias)Unclear riskConcealment is not described
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThere is Insufficient reporting of exclusions.It is stated that "six volunteers receiving zanamivir withdrew. One withdrew due to mild adverse effects" The other reasons for withdraw are not clear. It is also unclear if there were withdraws among RMT group
Blinding of participants and personnel (performance bias)
All outcomes
Low riskAthough it was a "randomised unblinded study", the review authors judge that the outcome is not likely to be influenced by the lack of blinding
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAthough it was a "randomised unblinded study", the review authors judge that the outcome is not likely to be influenced by the lack of blinding

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    AMT: amantadine
    RMT: rimantadine
    PB: placebo
    RCT: randomised controlled trial

AAPCID 2007Not an RCT
Allen 2006Not an RCT
Anonymous 2006Not an RCT
Anonymous 2007Article about oseltamivir and vaccination
Aoky 1985aPharmacokinetics study of AMT and RMT
Aoky 1985bAges of participants were outside protocol age range
Aoky 1986Ages of participants were outside protocol age range
Atmar 1990Ages of participants were outside protocol age range
Baker 1969Ages of participants were outside protocol age range (participants were aged between 17 to 57 years old)
Bantia 2010Non-human trial
Barr 2007Not an RCT
Barr 2007bNot an RCT
Bauer 2007Non-human trial
Belenky 1998Ages of participants were outside protocol age range (participants were aged between 17 to 57 years old)
Bloomfield 1970Ages of participants were outside protocol age range
Boltz 2010Review article about other anti-viral drugs
Brady 1990Ages of participants were outside protocol age range
Brammer 2009Article focusing influenza surveillance
Bricaire 1990Analyses by age subgroups of interest were not available
Bryson 1990Insufficient data available
Burch 2009A systematic review about the use of other antivirals
Cady 2011Not an RCT
Callmander 1968Ages of participants were outside protocol age range (participants were 20 to 60 years old)
Carter 2008A review of the use of the influenza vaccine
Cayley 2010Article about of neuraminidase inhibitors in healthy adults,
Chawla 2009Article about strategies for pandemic preparedness
Chemaly 2006Not an RCT
Chen 2007Article about Chinese medical herbs
Cheng 2004The authors studied other antivirals, included other viral infections and ages of participants were outside protocol age range
Cheng 2009Review study with diffferent objectives
Choi 2009A trial conducted in influenza isolates
Chou 2008Article about chronic hepatitis C
Cohen 1976Ages of participants were outside protocol age range (participants were aged between 20 to 39 years old)
Cohen 2006It was a study that compared patient access to phamaceuticals in the UK and US
Cowling 2008Preliminary findings of non-pharmacetical interventions trial
Curran 2010Article about an influenza vaccine
Dawkins 1968This study assessed the prophylatic efficacy of an analogue of AMT
De la Camara 2007Review study
DeLaney 2010Review study
Denys 1963Ages of human participants were outside protocol age range (participants were aged between 19 to 21 years old). Animals were also studied
Dolamore 2003Case-control study
Dolin 1982Ages of participants were outside protocol age range (participants were aged between 18 to 45 years old)
Doyle 1998Ages of participants were outside protocol age range (participants were aged between 18 to 50 years old)
Drinevskii 1998Randomisation was not stated
Drinka 1998Groups characteristics not stated. Analyses by age subgroup of interest not available
Enger 2004Article about oseltamivir
Falagas 2010Review study
Farlow 2008Article about Alzheimers
Fiore 2008Article about Glycyrrhiza species
Furuta 2005It was a study about the mechanism of action of T-705 against influenza virus
Galabov 2006Non-human trial
Galbraith 1969aAnalyses by age subgroups of interest were not available
Galbraith 1969bOutcomes of interest were not studied
Galbraith 1971Analyses by age subgroups of interest were not available
Galbraith 1973Insufficient data available
Garman 2004Trial about drugs that inhibit the virus's neuramidase
Gerth 1966Not an RCT
Griffin 2004Pharmacological study
Guo 2007Review article
Hay 1986Study about molecular basis resistance of influenza A to amantadine
Hayden 1979Ages of participants were outside protocol age range
Hayden 1980Ages of participants were outside protocol age range
Hayden 1981Ages of participants were outside protocol age range
Hayden 1982Ages of participants were outside protocol age range
Hayden 1985Pharmacokinetics study in which ages of participants were outside protocol age range
Hayden 1986Ages of participants were outside protocol age range
Hayden 1989Analysis by age subgroups of interest was not available
Hayden 1991Analysis by age subgroups of interest was not available
Hayden 2000The drug studied was zanamivir
Hayden 2006Not an RCT
Hornick 1969Ages of participants were outside protocol age range
Hota 2007Not an RCT
Hout 2006It is a study about the human immunodeficiency virus
Hout 2006bIt is a study about the human immunodeficiency virus
Hurt 2007Not an RCT
Ilyushina 2005Not an RCT
Ilyushina 2006It was examined if the combined therapy with two classes of anti-influenza drugs could affect the emergence of resistant virus variants in vitro
Ilyushina 2007Non-human trial
Ilyushina 2007bNon-human trial
Ison 2006A case series
Ito 2000Ages of participants were outside protocol age range
Ito 2006Study about influenza vaccination
Jefferson 2006aSystematic review about antivirals for influenza in healthy adults
Jefferson 2009aSystematic review about effect and safety of AMT and RMT in healthy adults
Jones 2006A trial in which a 20-amino-acid peptide was used
Kalia 2008Article about neurological diseases
Kantor 1980Ages of participants were outside protocol age range (participants were aged between 17 to 53 years old)
Kawai 2005Not an RCT
Khakoo 1981AMT and/or RMT were not tested in this trial
Kim 2011Article about the effect of corticosteroids treatment
Kirkby 2010Article about complementary and alternative medicine. Not an RCT
Kiso 2004Descriptive study to investigate oseltamivir resistance in children treated for influenza
Kitamoto 1969Duplicated results
Knight 1969Ages of participants were outside protocol age range
Knight 1970aAges of participants were outside protocol age range
Knight 1970bAges of participants were outside protocol age range
Knight 1981Ribavirin study in which ages of participants were outside protocol age range (participants were aged between 22 to 42 years old)
Korenke 2008Article about multiple sclerosis treatment
Krylov 1978Analysis by age subgroups of interest was not available
Kulichenko 2003Ages of participants were outside protocol age range
Langlet 2009Article about the use of anti-virals for chronic hepatitis C
Le Tissier 2005Non-human trial
Leeming 1969Insufficient data available
Leone 2005Article about the use of AMT for traumatic brain injury
Leung 1979Outcomes of interest were not studied
Lim 2007A study about an influenza-like illness
Lin 2006A study about neurologic manifestations in children with influenza B
Linder 2005The authors measured the rates of antiviral and antibiotic prescribing for patients with influenza
Lipatov 2007The study was conducted in influenza viruses isolated from poultry
Little 1976Analyses by age subgroups of interest were not available
Little 1978Article is about hyperreactivity and airway dysfunction in influenza infection and not about treatment or prevention of influenza
Lutz 2005It is a study about a method for detecting and quantifying influenza A virus replication
Lynd 2005Not an RCT
Machado 2004Article was about the use of oseltamivir to control influenza complications after bone marrow transplantation
Mallia 2007Not an RCT
Maricich 2004Not an RCT
Mase 2007The study was conducted in influenza viruses isolated from poultry
Mate 1970Ages of participants were outside protocol age range
Mate 1971Ages of participants were outside protocol age range
Matheson 2007Systematic review of the use of neuraminidase inhibitors
Matsuya 2007A study about the synthesis and evaluation of dihydrofuran-fused perhydrophenanthrenes as a new anti-influenza agent
Matthews 2004Review article about treatment of viral hepatitis and oncological conditions
McCullers 2004Non-human trial
McKay 2006Non-human trial
Mishin 2005Not a clinical trial
Miyachi 2011Insufficient data available
Moffat 2008Article about biophysical aspects of the influenza virus
Monto 1979Ages of participants were outside were outside protocol age (participants were aged between 18 to 24 years old)
Morrison 2007Ages of participants were outside protoocol age range
Muldoon 1976Ages of participants were outside protocol age range
Nafta 1970A wilder range of age was considered. Analysis by age subgroups of interest was not available
Natsina 1994Randomisation was not stated. Additional information not available
Nuesch 2007Review study
O'Donoghute 1973Analysis by age subgroups of interest was not available
Obrosova-Serova 1972Study about effectiveness of midantan and interferon inducers as means of non-specific prevention of influenza
Oker-Blom 1970Ages of participants were outside protocol age range (participants were aged between 20 to 28 years old)
Ong 2007Not an RCT
Pachucki 2004Article about a diagnostic test
Peiris 2004The aim of the authors was not to study AMT and RMT to prevent or treat influenza
Pemberton 1986Article about AMT resistance in clinical influenza A and virus isolates
Petterson 1980Insufficient data available
Pritchard 1989Article about the treatment of juvenile chronic arthritis with antivirals
Quarles 1981Ages of participants were outside protocol age range
Quilligan 1966Not an RCT
Rabinovich 1969Ages of participants were outside protocol age range
Reis 2006It is an article about neurologic effects of AMT
Reuman 1989aAges of participants were outside protocol age range (participants were aged between 18 to 40 years old)
Reuman 1989bAges of participants were outside protocol age range (participants were aged between 18 to 55 years old)
Risenbrough 2005Not an RCT
Rose 1980Not an RCT
Rothberg 2005Not an RCT
Saito 2006Not an RCT
Sato 2008An article about oseltamivir treatment
Sauerbrei 2006Not an RCT
Schapira 1971Analysis by age subgroups of interest was not available
Schmidt 2004Review article
Sears 1987Ages of participants were outside protocol age range (participants were aged between 18 to 40 years old)
Semlitsch 1992The purpose of this article was to study the acute effects of AMT infusions on event-related potentials
Serkedjieva 2007Non-human trial
Shuler 2007Case-control study
Shvetsova 1974The trial authors studied different populations. No information was available about clinical outcomes and confirmation of influenza diagnosis
Simeonova 2009Non-human article
Skoner 1999Ages of participants were outside protocol age range (participants were aged between 18 to 50 years old)
Smorodintsev 1970aAges of participants were outside protocol age range
Smorodintsev 1970bAges of participants were outside protocol age range
Smorodintsev 1970cAges of participants were outside protocol age range (participants were aged between 18 to 30 years old)
Somani 1991Randomisation was not stated. The groups were not similar at baseline
Tajima 2006It is a study about etiology and treatment in hospitalised children with pneumonia
Takemura 2005Not a study about influenza A
Tappenden 2009Systematic review
Terabayashi 2006The article is about the inhibition of influenza-virus-induced cytopathy by sialyglycoconjugates
Thomas 2008Article about multiple sclerosis
Thompson 1987Insufficient data presented
Togo 1968Ages of participants were outside protocol age range
Togo 1970Ages of participants were outside protocol age range
Togo 1972The drug studied was cyclooctylamine
Townsend 2006Not an RCT
Van der Wouden 2005Not an RCT
Van Voris 1981Ages of participants were outside protocol age range
Van Voris 1985Study about four antibody techniques to assess influenza infection
Wailoo 2008Article about the use of neuraminidase inhibitors in adults
Webster 1986Non-human trial
Welton 2008Not an RCT
Wendel 1966Ages of participants were outside protocol age range (participants were aged between 17 to 54 years old)
Whitley 2007Not an RCT
Wingfield 1969Ages of participants were outside protocol age range
Wong 2006Not an RCT
Wright 1976Analysis by age subgroups of interest was not available
Wultzler 2004Not a clinical trial
Yamaura 2003The studied antiviral was oseltamivir
Younkin 1983Ages of participants were outside protocol age range (participants were aged between 17 to 20 years old)
Yuen 2005Not an RCT
Zeuzem 1999The purpose of the authors was to study treatment for chronic hepatitis C

Ancillary