The fever, fatigue, muscle and headache caused by influenza (flu) can make even the healthiest person feel miserable for days. For more vulnerable people, such as the very young or the elderly, flu can be fatal. Although vaccination is recommended and can help protect against flu infection, there is a need for effective therapies to combat illness caused by the flu virus.
NIAID researchers and their co-investigators recently concluded a five-year international clinical trial that compared outcomes when flu patients were treated with a single antiviral drug (oseltamivir) versus a regimen of three flu drugs (oseltamivir, amantadine and ribavirin). The study results were published in The Lancet Infectious Diseases on September 22. Earlier research in animals and in cells grown in the lab suggested that combination therapy was better than single drug therapy. For example, in mice, the triple therapy prevented death from flu infection even when drug administration was delayed for three days after the animals were exposed to flu virus.
Between March 2011 and April 2016, 633 adult volunteers with moderate flu symptoms enrolled at trial sites in the United States, Thailand, Mexico, Argentina and Australia. Enrollees, who were at a heightened risk of developing serious influenza disease due to such conditions as asthma or diabetes, were randomized to receive either single or triple antiviral drug therapy.
At enrollment, participants scored themselves on the severity of such flu symptoms as feeling feverish, achy or tired on a zero to 3 scale. The median score among all participants was 15 points in the 11-symptom survey. For the first week of their participation, volunteers recorded self-scored symptom severity (the same 11 symptoms scored at enrollment) twice a day, then once a day for the next week. They also recorded whether they perceived themselves to be limited by flu “a lot, a little or not at all” each day. Study staff collected nasal swabs from participants on study days 3 and 7 and also asked participants to characterize whether they were functioning as well as they had prior to getting flu.
All the study drugs were formulated into identical-appearing capsules that volunteers took twice a day for five days. The treatment kits were disguised so that neither the volunteers nor the study staff knew who was in which group.
At enrollment, nasal swabs were taken from the volunteers and any that did not test positive for influenza virus were excluded from the preliminary analysis. Ultimately, 205 volunteers in the combination therapy group and 202 volunteers in the monotherapy group were assessed for two key outcomes: how long flu virus continued to be detectable in nasal secretions and how long it took for volunteers to report feeling as healthy as they had prior to getting flu. Earlier, smaller studies, including ones in which volunteers were exposed to flu virus under controlled conditions, found that a decrease in virus levels tracked with a decrease in clinical symptoms.
Among those receiving triple therapy, the team found a modest, but statistically significant, decrease in the proportion of volunteers who were shedding virus in nasal secretions at day 3 after beginning treatment relative to those on monotherapy. However, this advantage for triple therapy disappeared by day 7.
Contrary to expectations, participants on triple antiviral therapy did not experience any reduction in clinical symptoms, and triple therapy did not shorten the duration of illness (median duration in the triple therapy group was 4.5 days and in the monotherapy group was 4.0 days.)
The researchers point to several possible reasons for what they called the “intriguing and disappointing” absence of noticeable clinical benefits in the triple therapy group. For example, when the trial began, few antiviral flu drugs other than the ones chosen for the trial were available. Two, amantadine and ribavirin, are known to cause gastrointestinal upset and could account for some of the persistence of clinical symptoms and unwell feeling in those who received the triple therapy. Although this trial did not show a clinical benefit of combination therapy among those with moderate flu symptoms, it may be, note the researchers, that patients with severe flu would fare better on a combination regimen or that moderately ill patients taking a different combination of newer antivirals with fewer side effects could experience clinical benefits.
Finally, they observe, the lowering of viral shedding could have benefits besides improved clinical signs. For example, shortening the time that a sick person sheds flu virus in nasal secretions could aid the broader community because the spread of illness would be slowed. “More work is needed,” the investigators conclude, “to explore and hopefully better understand this outcome[.]”
Reference: JH Beigel et al. Oseltamivir, amantadine, and ribavirin combination antiviral therapy versus oseltamivir monotherapy for the treatment of influenza: a multicenter, double-blind randomized phase 2 trial. The Lancet Infectious Diseases. DOI: 10.1016/S1473-3099(17)30476-0 (2017).