The primary method of preventing influenza is through annual active immunization with the vaccine. In some situations, the infection can spread quite rapidly among institutionalized persons at high risk for infection. The antiviral agents amantadine or rimantidine have been used for prophylactic treatment, but these agents are effective only against strains of influenza type A virus. The influenza neuraminidase inhibitors represent a new class of drugs that show efficacy against influenza A and B viruses. Oseltamivir is an orally-administered neuraminidase inhibitor that has been found to be effective in treating acute influenza. Hayden and colleagues conducted two placebo-controlled, double-blind trials at different U.S. sites to evaluate the efficacy of this drug for long-term prophylactic treatment against influenza.
Healthy adults between 18 and 65 years of age were enrolled at several centers in the states of Virginia, Texas and Kansas. Exclusion criteria included receiving influenza vaccine during the previous year or meeting any of the recommended criteria for influenza vaccine according to current guidelines. Two to three months before the anticipated start of the peak influenza season, eligible persons underwent routine physical examination and laboratory screening to confirm eligibility. Participants were instructed to return when a local increase in influenza activity was noted and were then randomly assigned to one of three treatment groups to receive 75 mg of oseltamivir once a day; 75 mg of oseltamivir twice a day; or placebo, for a total of six weeks. Before the drug was started, blood was drawn to obtain influenza antibody titers. The patients were instructed to keep symptom cards to record their oral temperature, time of drug administration and occurrence of seven influenza symptoms (chills or sweats, aches, fatigue, headache, cough, sore throat or nasal congestion). Participants were instructed to return to the study centers for medical evaluation if they became ill. Otherwise, all participants were routinely seen at weeks 3, 6 and 8 after the initiation of therapy. At the last visit, influenza antibody testing was again performed.
A total of 1,562 persons was enrolled in the study. The mean age was 35 years, and women accounted for 63 percent of the study participants. During the six-week treatment period, 38 participants exhibited an influenza-like illness; 19 had cultures positive for influenza. Only 1.2 and 1.3 percent of those with confirmed influenza were in the oseltamivir-treatment groups compared with 4.8 percent in the placebo group. The overall efficacy of the drug given once daily for prophylaxis was 76 percent compared with 72 percent efficacy when given twice daily. At the three sites in Virginia where the incidence of influenza was highest, the protective efficacy of oseltamivir was 84 percent in the once-daily treatment group and 79 percent in the twice-daily treatment group. Among participants with culture-proven influenza in whom illness was directly linked to viral replication, there were only four cases from the treatment groups compared with 15 from the placebo group.
Headache was the most commonly reported adverse effect, but this occurred in a similar number of participants in all three groups (range: 39 to 47 percent). The most common side effects associated with oseltamivir treatment were upper gastrointestinal in nature: 12.1 percent of the participants in the once-daily treatment group and 15 percent of the those in the twice-daily treatment group reported gastrointestinal symptoms. Overall, only 0.6 percent of participants in both oseltamivir-treatment groups discontinued therapy.
The authors conclude that oral oseltamivir is effective for the prevention of influenza when taken once or twice daily for six weeks. It is well tolerated during long-term administration and can be effectively dosed once daily. These findings are consistent with those from a previously published study showing that 100 mg of oseltamivir given once daily was effective against experimentally-induced influenza.
editor's note: This is the second neuraminidase inhibitor labeled by the U.S. Food and Drug Administration for the treatment of influenza virus. The question remains as to what the role of these new antiviral agents will be. Clinical trial data support their efficacy, but whether these new agents are more effective for primary treatment or prevention of influenza virus than amantadine or rimantidine remains to be seen. Cost issues must also be addressed.—j.t.k.