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QUESTION: Is oral oseltamivir safe and effective in preventing naturally occurring influenza virus infection?
Two 6 week randomised (allocation concealed*), blinded (clinicians and patients),* placebo controlled trials during influenza season.
3 centres in Virginia, 2 in Texas, and 1 in Kansas, USA.
1562 people who were 18 to 65 years of age (mean age 35 y, 63% women) and were recruited by advertisement. Exclusion criteria were influenza vaccination in the previous year, meeting ≥1 criterion for influenza immunisation according to current (US) guidelines, acute respiratory illness with fever in the previous week, pregnancy, or potential for pregnancy. 1559 participants took ≥1 dose of the assigned study medication and were included in the analysis (intention to treat).
Participants were allocated to oral oseltamivir, 75 mg once (n=520) or twice (n=520) daily, or to placebo (n=519) for 6 weeks, beginning when influenza virus activity increased at the local study sites.
Main outcome measures
Laboratory confirmed influenza-like illness (laboratory confirmation was culture of influenza virus within 2 d of the onset of influenza symptoms or antibody titer on haemagglutination inhibition testing ≥4 times the baseline titer or both). Adverse events were also assessed.
Fewer patients receiving oseltamivir developed laboratory confirmed influenza than did patients receiving placebo (once daily p<0.001, twice daily p=0.001) (table). Rates of influenza were higher at the 3 Virginia sites than at the Texas and Kansas sites. Oseltamivir reduced influenza in Virginia (protective efficacy 82%, 95% CI 60% to 93%; p<0.001) but showed no significant reduction in Texas and Kansas (protective efficacy 50%, CI –23% to 93%; p=0.39). Nausea and vomiting were reported by more oseltamivir recipients than placebo recipients but did not contribute to discontinuation of treatment (table).
Oseltamivir once or twice daily was effective and safe in preventing influenza.
Influenza remains a major cause of morbidity and mortality each year. Although vaccination is the primary method for preventing influenza, antiviral agents play an important complementary role for preventing and treating the disease.
In 1999, zanamivir and oseltamivir were approved for the treatment of influenza A and B.1 Before 1999, amantadine and rimantadine were the only antiviral agents available and were active only against influenza A viruses. Their use has been limited by side effects (especially related to the central nervous system) and the rapid emergence of resistant viruses. The neuraminidase inhibitors appear to be much less likely to induce resistance. They are also generally well tolerated, as shown in these studies by Monto and Hayden and their colleagues, although zanamivir has been reported to induce bronchospasm and oseltamivir has been associated with gastrointestinal symptoms.1
Zanamivir and oseltamivir are effective for the treatment of influenza A or B among adults when started within 2 days of onset of symptoms. Monto and colleagues administered zanamivir by nasal spray and in its currently available form of orally inhaled powder.
Duration of influenza was reduced by about 1 day, with greater benefits for patients with more severe (eg, febrile) illness and when started within 30 hours of onset of symptoms. 2 other trials reported similar findings: zanamivir relieved symptoms 1 to 1.5 days earlier.2, 3 Oral oseltamivir also reduces the duration of influenza illness among healthy adults by about 30 hours when started within 1.5 days of the onset of symptoms.4
Most of the available data on the efficacy of the neuraminidase inhibitors are from healthy adults <65 years of age. 13% of participants in the study by Monto and colleagues were high risk (age ≥65 y or with stable chronic medical conditions). The study findings suggested that zanamivir was also effective in this subgroup, but the sample size was too small to detect a statistically significant benefit. More data are needed to define clearly the role of the neuraminidase inhibitors in high-risk groups.
Although not approved for prophylaxis, zanamivir and oseltamivir have also been shown to prevent influenza in healthy adults. Hayden and colleagues found oseltamivir given for 6 weeks was 74% effective in preventing influenza. Furthermore, a trial of a 4 week course of zanamivir in 1107 adults showed a 67% efficacy in preventing influenza and an 84% efficacy in preventing febrile influenza.5 Of note, Hayden and colleagues reported that 7 participants developed influenza within 2 weeks of completing the 6 week prophylaxis period, including 5 participants who had received oseltamivir. The neuraminidase inhibitors may protect against illness only for as long as the medication is actually taken. More data on the effectiveness of the neuraminidase inhibitors for the prevention of influenza among elderly people, nursing home residents, and other high risk groups are needed.
How should the neuraminidase inhibitors be used? Immunisation remains the mainstay of efforts for the prevention and control of influenza. However, antiviral agents, including the neuraminidase inhibitors, are important adjuncts to vaccination for prevention and treatment during interpandemic periods for people who have not been vaccinated, who develop influenza even if they have been vaccinated, and who travel between May and September to areas of the world with influenza activity. Decisions about which antiviral agent to use should be based on the relative importance of spectrum of activity, side effects, risk for emergence of resistance, and cost. Given the need to start treatment within 2 days of the onset of symptoms, providers will have to develop efficient processes for accurate diagnosis and timely prescribing of these agents if they are to be used widely. The antirivals will also play an important role during the next pandemic, providing critical protection during times when sufficient supplies of vaccine may not be available.
Source of funding: Hoffmann-LaRoche.
For correspondence: Dr FG Hayden, Department of Medicine, Box 473, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA. Fax +1 804 924 9065.