Antiviral Therapy for Influenza: To Combine or Not to Combine?

To combine or not to combine?

That is the question when it comes to antiviral therapy for influenza. And a multi-national team of researchers may have come up with at least a partial answer—although it’s clear further research is needed.

In an article published in the September 22nd issue of The Lancet Infectious Diseases, the researchers described their findings in a multicenter, phase 2 trial comparing outcomes with combination therapy using oseltamivir/amantadine/ribavirin with oseltamivir monotherapy. To date, preclinical data have suggested that combination therapy may be more effective than monotherapy; however, this most recent analysis determined that “although combination treatment showed a significant decrease in viral shedding at day 3”—the primary endpoint of the study—it was not associated with a clinical benefit based on multiple parameters.

Study co-author John Beigel, MD, Medical Affairs Scientist, Clinical Monitoring Research Program, Leidos Biomedical Research, and Support to National Institute of Allergy and Infectious Diseases (NIAID), described this as “one of the most surprising findings from our study” told Contagion^® via email correspondence. “We are planning further analyses of the study data in an effort to understand why reductions in viral shedding do not appear to translate into a shorter period of illness and more rapid return to baseline health,” he added. “Because our study was limited to outpatients, we also cannot say whether these same findings would hold true for a more seriously ill population such as those hospitalized for influenza or its complications. This, too, likely warrants further investigation…”

The randomized, double-blind trial chronicled Dr. Beigel and colleagues in The Lancet ID looked at results in patients treated with combination therapy versus monotherapy with matching placebo in 50 study sites, including academic medical center clinics, emergency rooms, and private physician offices in the US, Thailand, Mexico, Argentina, and Australia. All study participants were adults (≥18 years of age) with influenza who were at increased risk of complications; they were randomized (1:1) using an online system.

The 316 patients in the combination therapy group received oseltamivir (75 mg), amantadine (100 mg), and ribavirin (600 mg), while the 317 participants in the monotherapy group were given oseltamivir (75 mg) twice daily for 5 days. Study participants were monitored for 28 days. In all, 394 of the enrolled patients were included in the final analysis.

The authors found that 80 of the 200 participants included in the final analysis from the combination group had detectable virus (via PCR of nasopharyngeal swab) at day 3 compared with 97 of the 194 from the monotherapy group (P=0·046). Adverse events were similar between the two groups, with nausea (65 of 556 reported adverse events in the combination group vs 63 of 585 reported adverse events in the monotherapy group), diarrhea (56 of 556 vs 64 of 585, respectively), and vomiting (39 of 556 vs 23 of 585, respectively) the most common.

Interestingly, although fewer study participants in the combination group had detectable virus at day 3, the authors of The Lancet ID study were unable to identify a clinical benefit for the multidrug approach based on multiple secondary endpoints, including median duration of symptoms (4.5 days in the combination group vs. 4.0 days in the monotherapy group).

“Our study showed combination therapy was better at eliminating the virus in outpatients as compared to oseltamivir monotherapy; however, by standard measurements, people on combination therapy did not appear to improve any faster,” Dr. Beigel explained. “That is, they had a similar duration of symptoms and didn’t return to their normal state of health any sooner despite having cleared the virus more quickly. Based on these data we were unable to establish a clinical benefit of combination therapy over oseltamivir monotherapy in the outpatient population.”

Brian P. Dunleavy is a medical writer and editor based in New York. His work has appeared in numerous healthcare-related publications. He is the former editor of Infectious Disease Special Edition.