Elsevier

The Lancet

Volume 355, Issue 9218, 27 May 2000, Pages 1845-1850
The Lancet

Articles
Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial

https://doi.org/10.1016/S0140-6736(00)02288-1Get rights and content

Summary

Background

Use of some antiviral drugs for influenza infection is limited by potential rapid emergence of resistance. We studied the efficacy and safety of oseltamivir, the oral prodrug of the neuraminidase inhibitor GS4071, in adults with naturally acquired laboratory-confirmed influenza.

Methods

We did a randomised controlled trial of 726 previously healthy non-immunised adults with febrile influenza-like illness of up to 36 h duration. Patients were assigned oral oseltamivir 75 mg (n=243), oseltamivir 150 mg (n=245), or placebo (n=238) twice daily for 5 days. We assessed recovery by questionnaire and temperature recordings. The primary endpoint was time to resolution of illness in influenza-infected patients.

Findings

475 (66%) patients had confirmed infection. Duration of illness was significantly shorter by 29 h (25% reduction, median duration 87·4 h [95% Cl 73·3–104·7], p=0·02) with oseltamivir 75 mg and by 35 h (30%, 81·8 h [68·2–100·0], p=0·01) with oseltamivir 150 mg than with placebo (116·5 h [101·5–137·8]). The effect of oseltamivir was apparent within 24 h of the start of treatment. In patients treated within 24 h of symptom onset, symptoms were alleviated 43 h (37% reduction) and 47 h (40%) earlier with oseltamivir 75 mg and 150 mg, respectively, compared with placebo (75 mg 74·5 h [68·2–98·0], p=0·02; 150 mg 70·7 h [54·0–89·4], p=0·01; placebo 117·5 h [103·0–143·8]). Oseltamivir was associated with higher symptom scores, less viral shedding, and improved health, activity, and sleep quality, and was well tolerated.

Interpretation

Oseltamivir was effective and well tolerated in the treatment of natural influenza infection in adults. The efficacy, tolerability, and ease of administration warrant further investigation in children, elderly patients, and at-risk patients.

Introduction

Influenza continues to inflict an important burden on health-care systems, filling hospital beds during winter months and causing misery to millions of people worldwide. As well as the individual and direct healthcare burden, work absenteeism during epidemics can have a substantial economic impact.1, 2, 3 Although vaccination can lessen the impact of the disease in high-risk groups,4, 5 efficacy can be variable and unvaccinated populations remain vulnerable to disease. Antivirals represent a rational approach to influenza control but only the M2 inhibitors, amantadine and rimantadine, have been available. The use of these two drugs is limited by the potential for rapid emergence of resistant viruses capable of transmission to and causing disease in close contacts. Neither treatment is effective against influenza B, and amantadine has a side-effect profile that limits its use in frail elderly patients.6 The goal of achieving broad activity against influenza viruses became possible with the discovery that one of the virus's surface proteins, the neuraminidase, possesses a highly conserved active site.7

Influenza neuraminidase is essential for viral replication. Through cleaving of terminal sialic-acid residues from glycoproteins, this enzyme facilitates the release of new virus particles from infected cells, prevents virus aggregation, and promotes viral passage through respiratory mucus.8 Inhibition of the enzyme has become possible with the development of the neuraminidase inhibitors zanamivir9 and GS4071 ([3R, 4R, 5S]-4-acetamido-5-amino-3-[1-ethylpropoxy]-1-cyclohexane-1-carboxylic acid),10 which show potent and specific activity against a wide range of influenza-virus neuraminidases in vitro.11, 12 Zanamivir has poor oral bioavailability and has been developed for administration by inhalation,13 a route that requires specific instructions to ensure adequacy of delivery. The oral prodrug of GS4071, oseltamivir, is highly bioavailable and undergoes rapid conversion to the active form after gastrointestinal absorption.14

Oral oseltamivir was effective in studies of experimental influenza in animals and human beings.12, 15, 16 We did a double-blind randomised placebo-controlled study to investigate the efficacy and safety of oseltamivir in the treatment of naturally acquired influenza in human beings.

Section snippets

Patients

Eligible patients were aged 18–65 years and presented within 36 h of onset of influenza-like illness with fever of at least 38°C, with at least one respiratory symptom (cough, sore throat, or nasal symptom) and at least one constitutional symptom (headache, malaise, myalgia, sweats or chills, or fatigue). All patients had to provide written informed consent and women had to have a negative urine pregnancy test. We excluded patients who had been vaccinated against influenza in the previous 12

Discussion

The administration of oral oseltamivir 75 mg or 150 mg twice daily was associated with significant clinical and antiviral effects is healthy adults with naturally occurring influenza and was generally well tolerated. For patients with documented influenza, the median time to resolution of illness was reduced by 25% in the 75 mg group and by 30% in the 150 mg group.

The shorter duration of illness in oseltamivir recipients was associated with similar improvements in the severity of illness and

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