Elsevier

The Lancet

Volume 395, Issue 10217, 4–10 January 2020, Pages 42-52
The Lancet

Articles
Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial

https://doi.org/10.1016/S0140-6736(19)32982-4Get rights and content

Summary

Background

Antivirals are infrequently prescribed in European primary care for influenza-like illness, mostly because of perceived ineffectiveness in real world primary care and because individuals who will especially benefit have not been identified in independent trials. We aimed to determine whether adding antiviral treatment to usual primary care for patients with influenza-like illness reduces time to recovery overall and in key subgroups.

Methods

We did an open-label, pragmatic, adaptive, randomised controlled trial of adding oseltamivir to usual care in patients aged 1 year and older presenting with influenza-like illness in primary care. The primary endpoint was time to recovery, defined as return to usual activities, with fever, headache, and muscle ache minor or absent. The trial was designed and powered to assess oseltamivir benefit overall and in 36 prespecified subgroups defined by age, comorbidity, previous symptom duration, and symptom severity, using a Bayesian piece-wise exponential primary analysis model. The trial is registered with the ISRCTN Registry, number ISRCTN 27908921.

Findings

Between Jan 15, 2016, and April 12, 2018, we recruited 3266 participants in 15 European countries during three seasonal influenza seasons, allocated 1629 to usual care plus oseltamivir and 1637 to usual care, and ascertained the primary outcome in 1533 (94%) and 1526 (93%). 1590 (52%) of 3059 participants had PCR-confirmed influenza infection. Time to recovery was shorter in participants randomly assigned to oseltamivir (hazard ratio 1·29, 95% Bayesian credible interval [BCrI] 1·20–1·39) overall and in 30 of the 36 prespecified subgroups, with estimated hazard ratios ranging from 1·13 to 1·72. The estimated absolute mean benefit from oseltamivir was 1·02 days (95% [BCrI] 0·74–1·31) overall, and in the prespecified subgroups, ranged from 0·70 (95% BCrI 0·30–1·20) in patients younger than 12 years, with less severe symptoms, no comorbidities, and shorter previous illness duration to 3·20 (95% BCrI 1·00–5·50) in patients aged 65 years or older who had more severe illness, comorbidities, and longer previous illness duration. Regarding harms, an increased burden of vomiting or nausea was observed in the oseltamivir group.

Interpretation

Primary care patients with influenza-like illness treated with oseltamivir recovered one day sooner on average than those managed by usual care alone. Older, sicker patients with comorbidities and longer previous symptom duration recovered 2–3 days sooner.

Funding

European Commission's Seventh Framework Programme.

Introduction

Guidelines recommend antiviral treatment for individuals presenting with suspected or confirmed influenza who have high-risk features.1, 2 However, antivirals are not often prescribed in primary care in many European countries,3 partly because of clinical and cost-effectiveness, because of potential side-effects, such as nausea and vomiting, and because individuals who will especially benefit have not been identified in prospective, non-industry-funded, and pragmatic studies.4 Whether treatment should be initiated only after a positive test for influenza or whether it should be based on syndromic presentation alone is unclear. Oseltamivir treatment is recommended by the Centers for Disease Control and Prevention as early as possible for patients with confirmed or suspected influenza who are hospitalised, severely ill, or have higher risk for influenza complications, and treatment can be considered for symptomatic outpatients with suspected influenza if treatment can be initiated within 48 h of illness onset, which is similar to European recommendations.1, 2, 5

Meta-analyses have found that oseltamivir improves the median time to alleviation of symptoms over placebo among adults by 17·8 h (95% CI 27·1–9·3),6 and time to first alleviation of symptoms by 16·8 h (21·8–8·4).7 Some of the included trials have been criticised for under-recruiting, selective reporting of outcomes, not including sufficient children or older people, and recruiting in a single season.7, 8 Additionally, the effect of antiviral treatment on return to daily activities, quality of life, and care-seeking is largely unknown, which is pivotal to assessing cost-effectiveness. We therefore aimed to determine whether adding antiviral treatment to usual primary care for patients with influenza-like illness is effective in reducing time to recovery both overall and in key subgroups.

Research in context

Evidence before this study

At the conception of this trial on Jan 15, 2015, we searched PubMed for systematic reviews in any language using the following MEDLINE subject heading keywords: “neuraminidase inhibitors” and “influenza”. A systematic review of placebo-controlled randomised trials found that oseltamivir reduced the median time to alleviation of symptoms over placebo by 17·8 h (95% CI 27·1 to 9·3), and a Cochrane systematic review found oseltamivir reduced time to first alleviation of symptoms by 16·8 h (95% CI 21·8 to 8·4), both in intention-to-treat populations with influenza-like illness. A systematic review and meta-analysis of published and unpublished placebo-controlled trials in adults with suspected or confirmed influenza found a mean reduction in duration of symptoms from oseltamivir of 20·7 h (95% CI 13·3–28·0) in five studies that included 3833 participants in an intention-to-treat population, and a mean reduction of 25·4 h (95% CI 17·2–33·5) in the intention-to-treat infected population (7 studies, 2690 patients), a difference of about 5 h. Trials have found relatively greater benefits in individuals treated within 24 h of symptom onset, and guidelines recommend initiating oseltamivir within 48 h of symptom onset. Some of the trials included in the systematic reviews have been criticised for under-recruiting, selective reporting of outcomes, not including sufficient children or older people, and recruiting in a single season. Additionally, the effects of antiviral treatment on return to daily activities, quality of life, and care-seeking in key subgroups is largely unknown.

Added value of this study

In an open-label, pragmatic, randomised controlled trial that included 3266 adults and children presenting in primary care with influenza-like illness, patients treated with oseltamivir recovered sooner, irrespective of influenza virus test results. Older, sicker, patients with comorbidities and longer previous symptom duration showed greater absolute benefit. Our overall estimate of benefit is similar to effects found in placebo-controlled trials, but we identified additional benefit in those with certain risk factors. Previous trials have found relatively greater benefit in those treated within 24 h of symptom onset, but additional benefit from earlier treatment was not apparent in our trial. Similarly, unlike some trials, benefit in our trial was similar regardless of influenza test results.

Implications of all the available evidence

Adding oseltamivir to usual primary care for patients with influenza-like illness accelerates recovery by a mean of about one day, and slightly longer in individuals with risk factors, irrespective of influenza status. Initiating oseltamivir 48–72 h after illness onset appears to give similar benefit to earlier initiation. Clinicians might consider treatment in patients who are sicker or older, who have comorbidities, and who have been unwell for longer, because oseltamivir might reduce their illness by as much as 2–3 days.

Section snippets

Study design and participants

ALIC⁴E was an investigator-initiated, open-label, pragmatic, response-adaptive, platform, randomised controlled trial. The trial protocol has been published previously.9

Independent trial steering, data monitoring, and ethics committees provided study oversight. The funder (European Commission's Seventh Framework Programme) had no influence on the design or conduct of the trial. The trial protocol, available online, was approved by National Research Ethics Service Committee South Central—Oxford

Results

Between Jan 15, 2016, and April 12, 2018, 3266 participants (data from 7 patients needed to be deleted) were recruited from 21 networks covering 209 primary care practices in 15 European countries over three consecutive influenza seasons: 495 in 2015–16, 1225 in 2016–17, and 1546 in 2017–18 (figure 1; appendix p 5). Each season's recruitment period was based on reports of national incidences of influenza-like-illness presentation rising above or falling below country-specific thresholds, using

Discussion

The ALIC4E trial was a large-scale, international, publicly-funded, pragmatic, randomised controlled trial of the effectiveness of adding oseltamivir to usual primary care for people with influenza-like illness over three influenza seasons powered to detect effects in key clinical subgroups. Overall, these patients returned to their usual activities with mild residual symptoms minimally interfering after about 6·5 days, and about one day earlier with oseltamivir addition, which is consistent

Data sharing

After publication of the full trial report, formal requests for study data should be made to the corresponding author (CCB) using a bespoke data request form delineating research aims, methods, and the variables needed. Such requests will be considered by the core ALIC4E team (CCB, TV, BS, AWV, and EB) and the PREPARE coordinator (HG). If research questions and methods are considered relevant and valid, the Data Management Department of the Julius Center, UMC Utrecht, will securely transfer the

References (26)

  • Influenza antiviral medications: summary for clinicians

    (2018)
  • N Adriaenssens et al.

    European Surveillance of Antimicrobial Consumption (ESAC): systemic antiviral use in Europe

    J Antimicrob Chemother

    (2011)
  • D Mertz et al.

    Populations at risk for severe or complicated influenza illness: systematic review and meta-analysis

    BMJ

    (2013)
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