Elsevier

The Lancet

Volume 367, Issue 9507, 28 January–3 February 2006, Pages 303-313
The Lancet

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Antivirals for influenza in healthy adults: systematic review

https://doi.org/10.1016/S0140-6736(06)67970-1Get rights and content

Summary

Background

Use of antivirals is recommended for the control of seasonal and pandemic influenza. Our aim was to review the evidence of efficacy, effectiveness, and safety of registered antivirals against naturally occurring influenza in healthy adults.

Methods

We searched various Databases to October, 2005, and contacted manufacturers and corresponding authors. We included randomised controlled trials comparing prophylactic (n=27) or treatment (n=27) efficacy against symptomatic or asymptomatic influenza. We did a meta-analysis and expressed prophylactic efficacy as a proportion (1–relative risk [RR]). For treatment trials, because of inconsistent and non-standardised reporting, we expressed continuous outcomes either as means or as hazard ratios.

Findings

We included 51 reports of 52 randomised controlled trials. Amantadine prevented 61% (95% CI 35–76) of influenza A cases and 25% (13–36) of cases of influenza-like illness, but caused nausea (OR 2·56, 1·37–4·79), insomnia and hallucinations (2·54, 1·50–4·31), and withdrawals because of adverse events (2·54, 1·60–4·06). There was no effect on asymptomatic cases (RR 0·85, 0·40–1·80). In treatment, amantadine significantly shortened duration of fever compared with placebo (by 0·99 days, −1·26 to −0·71), but had no effect on nasal shedding of influenza A viruses (0·93, 0·71–1·21). The fewer data for rimantadine showed comparable effects. In prophylaxis, compared with placebo, neuraminidase inhibitors have no effect against influenza-like illness (1·28, 0·45–3·66 for oral oseltamivir 75 mg daily, 1·51, 0·77–2·95 for inhaled zanamivir 10 mg daily). Higher doses appear to make no difference. The efficacy of oral oseltamivir 75 mg daily against symptomatic influenza is 61% (15–82), or 73% (33–89) at 150 mg daily. Inhaled zanamivir 10 mg daily is 62% efficacious (15–83). Neither neuraminidase inhibitor appeared effective against asymptomatic influenza. Oseltamivir induces nausea (OR 1·79, 1·10–2·93), especially at higher prophylactic doses (2·29, 1·34–3·92). Oseltamivir in a post-exposure prophylaxis role has a protective efficacy of 58·5% (15·6–79·6) for households and from 68% (34·9–84·2) to 89% (67–97) in contacts of index cases. In influenza cases, compared with placebo the hazard ratios for time to alleviation of symptoms were 1·33, 1·29–1·37 for zanamivir; 1·30, 1·13–1·50 for oseltamivir provided medication was started within 48 h of symptom onset. Viral nasal titres were significantly diminished by both drugs (weighted mean difference −0·62, −0·82 to −0·41). Oseltamivir at 150 mg daily was effective in preventing lower respiratory tract complications in influenza cases (OR 0·32, 0·18–0·57). We could find no credible data on the effects of oseltamivir on avian influenza.

Interpretation

The use of amantadine and rimantadine should be discouraged. Because of their low effectiveness, neuraminidase inhibitors should not be used in seasonal influenza control and should only be used in a serious epidemic or pandemic alongside other public-health measures.

Introduction

The M2 ion channel-blocking drugs amantadine and rimantadine and the newer generation, more expensive antiviral compounds (neuraminidase inhibitors) nebulised zanamivir (Relenza, Glaxo Wellcome, NC, USA) and oral oseltamivir (Tamiflu, Gilead Sciences, CA, USA, and Hoffman La Roche, Basel, Switzerland) have anti-influenza activity.1, 2 In 2005, WHO encouraged member countries to use antivirals in influenza interpandemic periods because “wide scale use of antivirals and vaccines during a pandemic will depend on familiarity with their effective application during the interpandemic period. The increasing use of these modalities will expand capacity and mitigate the morbidity and mortality of annual influenza epidemics”.3 The European Medicines Agency maintains that neuraminidase inhibitors (especially oseltamivir) are complementary to vaccines, and should be used in an influenza pandemic4 for treatment of index cases and for influenza prophylaxis in key personnel—namely, police officers, fire fighters, health-care workers. None of the systematic reviews done5, 6, 7 of the effects of antivirals, however, is up to date, and none has assessed their potential role in an influenza pandemic, where high viral load and high transmission seem to be the norm. In this context, trade-off between dose and adverse-event profile in prophylaxis, activity against influenza infection in those with and without symptoms, and extent of viral excretion through body fluids become important.2 Cost is also likely to be a factor when choosing a drug for use in epidemic or pandemic situations.

Our aim, was to assess the comparative studies of the efficacy (against laboratory-confirmed influenza with or without symptoms), effectiveness (against influenza-like illness), and safety of antivirals against influenza in healthy adults. This report is based on two Cochrane reviews,8, 9 which we are in the process of updating.

Section snippets

Search strategy (webappendix) and selection criteria

We searched Ovid MEDLINE (to August, 2005), WebSpirs EMBASE (to June, 2005), and the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2005), and checked the references of systematic reviews of the topic5, 6, 7 and of retrieved trials, for relevant published work. We wrote to manufacturers and authors of identified studies for further information.

We considered for inclusion in our systematic review randomised controlled trials that assessed the prophylactic or

Results

We identified 87 reports of studies possibly fulfilling our inclusion criteria (figure 1).14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64 We included 20 reports of 21 prophylaxis and safety trials for amantadine and rimantadine and 13 treatment trials. Two trials contained both treatment and prophylaxis data,27, 43 but only one27 had

Discussion

The evidence does not support the use of M2 ion channel inhibitors for influenza. Furthermore, it suggests that neuraminidase inhibitors should not be used routinely for seasonal influenza and only with associated public-health measures in a pandemic situation.

As for all systematic reviews, our findings and interpretation are limited by the quantity and quality of available evidence on the effects of a specific intervention for a disease (influenza) or syndrome (influenza-like illness). Because

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