Triple Antiviral Against Influenza Fails to Provide Clinical Benefit

John Beigel, MD

A triple antiviral drug combination significantly decreased viral shedding in what researchers characterize as the largest and most comprehensive study assessing combination antivirals for the treatment of influenza, but with no more clinical benefit than a single agent having less virological effect.

"The scarcity of evident clinical benefit despite enhanced viral clearance is both intriguing and disappointing," John Beigel, MD, Leidos Biomedical Research, Frederick, MD, wrote in support of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), and colleagues.

The results corroborate the Food and Drug Administration (FDA) stance on using virological primary endpoints for candidate antiviral studies. The FDA has previously indicated that "there is no established predictive relationship between the magnitude and timing of viral reductions and extent of clinical benefit of how a patient 'feels, functions, or survives'.”

Beigel and colleagues chose the primary endpoint of detectable virus in nasopharyngeal swabs at treatment day 3 from analyzing results of a pilot study before the full trial. They pointed out that when the study was conducted, there was no standardized, validated patient-reported outcome method for influenza.

In commentary accompanying the study, Michael Ison, MD, Divisions of Infectious Diseases and Organ Transplantation, Northwestern University Feinberg School of Medicine, Chicago, IL shared the researchers' disappointment, but suggested that such studies remain necessary.

"Although a scarcity of clinical benefit is frustrating, the improvement in viral shedding and the theoretical benefit in preventing resistance emergence (to single agent) suggest that studies of combination therapy should continue to be investigated," Ison wrote. "Furthermore, newer antivirals are becoming available that have different mechanisms of actions."

Beigel and colleagues in 50 sites across the US, Thailand, Mexico, Argentina and Australia randomized 633 participants seeking outpatient treatment for influenza to either the triple combination of oseltamivir, amantadine and ribavirin or monotherapy with oseltamivir and 2 placebo formulations.

They reported that 40% of those on the triple combination had detectable virus at day 3, compared with 50% of those in the monotherapy group. There was no benefit in multiple clinical secondary endpoints, however, including in median duration of symptoms, time to absence of fever, and time to resumption of pre-influenza level of physical activity.

In addition, patients in the combination antiviral efficacy population took longer than those on monotherapy to feel as healthy as before the onset of influenza symptoms.

"In this double-blind, multicenter, randomised trial in multiple countries, virologic treatment benefit was observed without improved clinical outcomes," Beigel and colleagues wrote. "This calls into question whether changes in viral shedding from an antiviral can be used to predict changes in clinical outcomes."

Despite the lack of advantage demonstrated in this study, Ison calls for additional studies of antiviral combinations.

"Combinations of two or more drugs with different mechanisms of action hold greater promise in enhancing the outcomes of influenza compared with monotherapy and should continue to be studied," he wrote.

The NIH-funded trial comparing a triple antiviral therapy against monotherapy for influenza was published in the December issue of The Lancet Infectious Diseases.