Combination oseltamivir therapy for influenza improves viral shedding, but not clinical benefit

Although combination therapy with oseltamivir, amantadine and ribavirin demonstrated significantly increased viral shedding in patients with influenza, it did not show any clinical benefit compared with oseltamivir monotherapy, according to findings recently published in Lancet Infectious Diseases.

“The theory of using a combination of antivirals to more effectively control viral replication was explored in influenza even before it became an established method in the treatment of HIV,” John H. Beigel, MD, of the National Institute of Allergy and Infectious Diseases at NIH, and colleagues wrote. “The combination of amantadine, oseltamivir and ribavirin has been shown to increase the antiviral activity in vitro (reduction in the EC₅₀, or the half maximal effective drug concentration) of each drug compared with its activity in double combinations or as single agents.”

The researchers performed a randomized, double-blind, multicenter phase 2 trial of 633 adults at sites in the U.S., Mexico, Argentina, Australia and Thailand. Patients were randomly assigned to either combination therapy (n = 316) with oseltamivir (75 mg), amantadine (100 mg) and ribavirin (600 mg) or monotherapy with oseltamivir and matching placebos (n = 317). The participants took the drugs twice daily for 5 days, and were followed for 28 days. The main outcome was the percentage of patients who had detectable influenza in nasopharyngeal swabs at 3 days.

Three hundred ninety-four patients were included in the primary analysis, which excluded 47 patients from the pilot phase, 13 without an endpoint sample and 172 patients without confirmed influenza infection. Fewer than half of the 200 patients assigned to combination therapy (40%; n = 80) demonstrated detectable virus at day 3, whereas 50% (n = 97) of 194 patients in the monotherapy group (mean difference, 10; 95% CI, 0.2-19.8), the researchers reported.

Gastrointestinal disorders were the most common adverse events, Beigel and colleagues wrote, specifically nausea (12% of 556 adverse events in the combination therapy group vs. 11% of 585 reported events in the monotherapy group), diarrhea (10% vs. 11%) and vomiting (7% vs. 4%).

Combination therapy did not demonstrate any benefit for secondary endpoints including median duration of symptoms (4.5 days for combination group vs. 4 days for monotherapy). One patient, an elderly patient assigned to the monotherapy group, died of cardiovascular failure at day 13 after being assigned, Beigel and colleagues reported.

“Although a scarcity of clinical benefit is frustrating, the improvement in viral shedding and the theoretical benefit in preventing resistance emergence suggest that studies of combination therapy should continue to be investigated,” Michael G. Ison, MD, of Northwestern University Feinberg School of Medicine, wrote in an accompanying editorial. “Furthermore, newer antivirals are becoming available that have different mechanisms of actions. 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.” – by Andy Polhamus

Disclosures: Ison reports research support to Northwester University from Beckman Coulter, Cepheid, Chimerix, Gilead, Janssen and Shire; consulting fees from Celltrion, Chimerix, Farmark, Genentech/Roche, Toyama Medivector, Seqirus and Shionogi; unpaid consultation for BioCryst, Cellex, GlaxoSmithKline, NexBio, Romark, Unither Virology and Vertex; and paid data and safety roles with GlaxoSmithKline and Shionogi. Beigel reports no relevant financial disclosures. Please see the study for a complete list of all other authors’ relevant financial disclosures.