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Therapeutics

Oseltamivir once or twice daily safely prevented influenza

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ACP J Club. 2000 May-June;132:93. doi:10.7326/ACPJC-2000-132-3-093

Related Content in this Issue
• Companion Abstract and Commentary: Zanamivir speeds symptom relief in influenza


Source Citation

Hayden FG, Atmar RL, Schilling M, et al., and the Oseltamivir Study Group. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. N Engl J Med. 1999 Oct 28;341:1336-43. [PubMed ID: 10536125]


Abstract

Question

Is oral oseltamivir safe and effective in preventing naturally occurring influenzavirus infection?

Design

Two 6-week randomized (allocation concealed*), blinded (clinicians and patients),* placebo-controlled trials during influenza season.

Setting

3 centers in Virginia, 2 in Texas, and 1 in Kansas, USA.

Participants

1562 persons 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 immunization according to current (U.S.) 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).

Intervention

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 influenzavirus activity increased at the local study sites.

Main outcome measures

Laboratory-confirmed influenza-like illness (laboratory confirmation was culture of influenzavirus within 2 d of the onset of influenza symptoms or antibody titer on hemagglutination-inhibition testing ≥ 4 times the baseline titer or both). Adverse events were also assessed.

Main results

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).

Conclusion

Oseltamivir once or twice daily was effective and safe in preventing influenza.

*See Glossary.

Source of funding: Hoffmann-LaRoche.

For correspondence: Dr. F.G. Hayden, Department of Medicine, Box 473, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA. FAX 804-924-9065.


Table. Oseltamivir, 75 mg once (Osel qd) or twice (Osel bid) daily, vs placebo for preventing influenza†

Outcomes at 6 wk Comparison Event rates RRR (95% CI) NNT (CI)
Laboratory-confirmed influenza-like illness Osel qd vs placebo 1.2% vs 4.8% 76% (46 to 91) 27 (17 to 59)
Osel bid vs placebo 1.3% vs 4.8% 72% (40 to 89) 29 (17 to 69)
Combined groups vs placebo 1.3% vs 4.8% 74% (53 to 88) 28 (17 to 55)
RRI (CI) NNH (CI)
Nausea Osel qd vs placebo 12.1% vs 7.1% 70% (16 to 150) 20 (12 to 70)
Osel bid vs placebo 14.6% vs 7.1% 105% (42 to 198) 13 (9 to 27)
Vomiting Osel qd vs placebo 2.5% vs 0.8% 224% (12 to 840) 58 (28 to 479)
Osel bid vs placebo 2.7% vs 0.8% 249% (22 to 904) 52 (26 to 267)

†Abbreviations defined in Glossary; NNT and CI calculated from data in article; RRI and NNH calculated from data supplied by author.


Commentary

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 (e.g., 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 persons, nursing-home residents, and other high-risk groups are needed.

How should the neuraminidase inhibitors be used? Immunization 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 persons 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.

Kristin L. Nichol, MD, MPH
Veterans Affairs Medical Center
Minneapolis, Minnesota, USA


References

1. Neuraminidase inhibitors for treatment of influenza A and B infections. MMWR Morb Mortal Wkly Rep. 1999;48(RR14):1-9.

2. Hayden FG, Osterhaus AD, Treanor JJ, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenzavirus infections. GG167 Influenza Study Group. N Engl J Med. 1997;337:874-80.

3. The MIST (Management of Influenza in the Southern Hemisphere Trialists) Study Group. Randomised trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections. Lancet. 1998;352:1877-81.

4. Treanor JJ, Hayden FG, Vrooman PS, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza. A randomized controlled trial. JAMA. 2000;283:1016-24.

5. Monto AS, Robinson DP, Herlocher ML, et al. Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial. JAMA. 1999;282:31-5.