Grand Rounds

The ALIC4E RCT: Does Oseltamivir Lead to Shorter Recoveries for Patients with Flu-Like Symptoms?

BACKGROUND AND PURPOSE:

Butler et al. (Lancet, 2019) investigated whether adding antiviral treatment oseltamivir (Tamiflu) to usual care for patients with influenza-like illness reduces time to recovery overall

Open-label, pragmatic, adaptive, randomized controlled trial (RCT)
- Antivirals for influenza-Like Illness? An rCt of Clinical and Cost effectiveness in primary CarE (ALIC4E)
Setting
- 15 European countries
Participants
- Patients ≥1 year |Influenza-like illness | Primary care setting
Interventions
- Oseltamivir group: Oseltamivir added to usual care
  - Adults: 75 mg oral oseltamivir twice daily for 5 days
  - Pediatric doses used ofr children <13 years
- Control group: Usual care
Influenza-like illness: Sudden onset of self-reported fever with
- ≥1 respiratory symptom
  - Cough | Sore throat | Running or congested nose
- And 1 systemic symptom
  - Headache | Muscle ache | Sweats or chills | Tiredness
- Symptom duration of ≤72 h during flu season
Analysis
- Oseltamivir benefit was assessed overall and in 36 prespecified subgroups defined by age, comorbidity, previous symptom duration, and symptom severity
- Analysis was performed using a Bayesian primary analysis model
Primary outcome
- Time to recovery (patient reported): Return to usual activities, with fever, headache, and muscle ache minor or absent

3,266 participants were recruited over three seasonal influenza seasons
Of those that the primary outcome could be determined
- 1,533 were in the oseltamivir group | 1,562 were in the usual care group
- 52% had PCR-confirmed influenza infection
Time to recovery was shorter in participants randomly assigned to oseltamivir
- Overall: Hazard ratio (HR) 1.29 (95% Bayesian credible interval [BCrI] 1.20 to 1.39)
- Similar benefit found in 30 of the 36 prespecified subgroups
Estimated absolute mean benefit
- Overall
  - 1.02 days (95% BCrI 0.74 to 1.31)
- <12 years of age, with less severe symptoms, no comorbidities, and shorter previous illness duration
  - 0.70 days (95% BCrI 0.30 to 1.20)
- ≥65 years who had more severe illness, comorbidities, and longer previous illness duration
  - 3.20 days (95% BCrI 1.00 to 5.50)
Adverse events
- Vomiting or nausea was increased in the oseltamivir group

Overall, patients in the primary care setting with influenza-like symptoms recovered one day sooner using oseltamivir vs usual care
For older, sicker patients, oseltamivir resulted in faster recovery by 2 to 3 days
Benefit seen even when medication started after 48 hours and regardless of whether a patient tested positive for influenza

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