CLINICAL QUESTION: Can oseltamivir be used to prevent influenza infection?
BACKGROUND: Oseltamivir reduces the replication of influenza A and B by inhibiting influenza neuraminidase, an essential enzyme involved in the final packaging of new viral particles. Rimantadine and amantadine have been used for prophylaxis but are only effective against influenza A; adverse effects and cost limit their use. Oseltamivir is currently indicated to treat acute influenza infection if given within the first 2 days of symptoms. The present study evaluated oseltamivir for the prevention of influenza in healthy persons.
POPULATION STUDIED: The researchers studied 1562 healthy subjects with a mean age of 35 years (range = 18 to 65 years); 63% were women. Key exclusion criteria included having had an influenza vaccination in the previous year or an acute respiratory illness accompanied by a fever in the week before drug administration. Patients with any indication for influenza immunization according to 1998 Centers for Disease Control (CDC) and Prevention guidelines were also excluded.
STUDY DESIGN AND VALIDITY: Two identical randomized placebo-controlled double-blinded multicenter studies were conducted. Because of a low incidence of influenza infection (38/1559, 2.4%), the investigators combined the data before unblinding. Subjects were started on oseltamivir or placebo following an increase in influenzavirus activity at the clinical site. They received either oseltamivir 75 mg once daily, 75 mg twice daily, or placebo for 6 weeks. Return visits occurred at weeks 3, 6, and 8. Participants were instructed to return to the clinic for influenzalike symptoms. Nasal and pharyngeal swabs were collected for influenzavirus culture when patients presented with illness. Influenza antibody testing was done at baseline and 8 weeks.
OUTCOMES MEASURED: The primary end point was laboratory-confirmed influenzalike illness during the 6-week period of drug administration. Influenzalike illness was defined as an oral temperature of Ž37.2°C, with at least one respiratory symptom (cough, sore throat, or nasal congestion) and at least one constitutional symptom (aches, fatigue, headache, or chills or sweats). Laboratory confirmation was defined as culture of influenzavirus or 4-fold increase in antibody titer.
RESULTS: The rates of laboratory-confirmed clinical influenza were significantly lower in the oseltamivir once-daily (6/520, 1.2%) and twice-daily (7/520, 1.3%) groups than in the placebo group (25/519, 4.8%). These differences were statistically significant (P <.001 and P = .001, respectively). The relative risk reduction for influenza of once and twice daily dosing were 76% (95% confidence interval [CI], 46-91) and 72% (95% CI, 40-89), respectively. The number needed to treat (NNT) to prevent one case of influenza is 29. Drop-out rates were low and did not differ between the groups (3.1% to 4.0%), suggesting that the medication was well tolerated. Compliance between the groups did not differ.
Oseltamivir has the ability to prevent influenza infection, but the real world utility of this agent for prophylaxis is limited. Using an estimate of $225 per 6-week course of 75 mg once daily and an NNT of 29, the cost of preventing one case of influenza with oseltamivir is $6525. In a similar unvaccinated healthy population, the average cost per person attributed to respirato ry illness (including influenza) has been estimated at $152.18 (1994 dollars) per flu season.1 This estimate includes time lost from work and physician visits. In the same study, it was found that the vaccination of healthy working adults saved $46.85 per person vaccinated. In a low-risk population, oseltamivir is unlikely to be cost-effective. Recent CDC guidelines state that all persons interested in decreasing their likelihood of becoming ill with influenza may be vaccinated.2 Whether oseltamivir is the agent of choice for rare instances requiring prophylaxis will require comparison with rimantadine. In an unvaccinated population at high risk during an influenza B outbreak, oseltamivir may offer protection. However this study only documented one case of influenza B in the 1559 study participants.