Triple Antiviral Drug Combination for Treatment of Influenza Fails to Provide Clinical Benefit

In what researchers refer to as the largest and most comprehensive study assessing combination antiviral therapy for the treatment of influenza, a triple antiviral drug combination significantly decreased viral shedding. However, the triple antiviral failed to provide more clinical benefit than a single agent with 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)’s 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.’”

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

In a commentary accompanying the study, Michael Ison, MD, Divisions of Infectious Diseases and Organ Transplantation, Northwestern University Feinberg School of Medicine, 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," Dr. Ison wrote. "Furthermore, newer antivirals are becoming available that have different mechanisms of actions."

The randomized study included 50 sites across the US, Thailand, Mexico, Argentina, and Australia, and included 633 participants seeking outpatient treatment for influenza; the participants received either the triple combination of oseltamivir, amantadine, and ribavirin or monotherapy with oseltamivir and 2 placebo formulations.

They found that 40% of those receiving the triple combination had detectable virus at day 3, compared with 50% of those in the monotherapy group. However, there was no benefit in multiple clinical secondary endpoints, 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 receiving monotherapy to feel as healthy as before the onset of influenza symptoms.

"In this double-blind, multicenter, randomized trial in multiple countries, virologic treatment benefit was observed without improved clinical outcomes," Dr. 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, Dr. 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.