Triple Combination of Oseltamivir, Amantadine, and Ribavirin Displays Synergistic Activity against Multiple Influenza Virus Strains In Vitro

Abstract

The recurring emergence of influenza virus strains that are resistant to available antiviral medications has become a global health concern, especially in light of the potential for a new influenza virus pandemic. Currently, virtually all circulating strains of influenza A virus in the United States are resistant to either of the two major classes of anti-influenza drugs (adamantanes and neuraminidase inhibitors). Thus, new therapeutic approaches that can be rapidly deployed and that will address the issue of recurring resistance should be developed. We have tested double and triple combinations of the approved anti-influenza drugs oseltamivir and amantadine together with ribavirin against three influenza virus strains using cytopathic effect inhibition assays in MDCK cells. We selected A/New Caledonia/20/99 (H1N1) and A/Sydney/05/97 (H3N2) as representatives of the wild-type versions of the predominant circulating seasonal influenza virus strains and A/Duck/ MN/1525/81 (H5N1) as a representative of avian influenza virus strains. Dose-response curves were generated for all drug combinations, and the degree of drug interaction was quantified using a model that calculates the synergy (or antagonism) between the drugs in double and triple combinations. This report demonstrates that a triple combination of antivirals was highly synergistic against influenza A virus. Importantly, the synergy of the triple combination was 2-to 13-fold greater than the synergy of any double combination depending on the influenza virus subtype. These data support the investigation of a novel combination of oseltamivir, amantadine, and ribavirin as an effective treatment for both seasonal and pandemic influenza virus, allowing the efficient use of the existing drug supplies.

Effect of Half-Life on the Pharmacodynamic Index of Zanamivir against Influenza Virus Delineated by a Mathematical Model

“…The emergence and spread of influenza viruses resistant to the available treatments have pushed combination chemotherapy to the forefront of antiviral research. Currently, there are several studies investigating the efficacy of antiviral agents when used in combination against influenza viruses (25,26,28). To use combination chemotherapy efficaciously, dosage regimens for antiviral combinations must be optimized.…”

Cyclopropavir Inhibits the Normal Function of the Human Cytomegalovirus UL97 Kinase

“…Results from combination studies were evaluated using a modified version of MacSynergy II (http://medicine.uab.edu/Peds /54568/infectious/79968/). This software was adapted to calculate statistically significant synergy using the genome copy number and is similar to methods we reported previously (26). The use of the genome copy number provided a greater dynamic range than traditional methods and facilitated the identification of synergistic interactions over a much wider range of compound concentrations.…”

Virological Clearance Rate of High-Dose Oseltamivir or Triple-Combination Antiviral Therapy in Complicated 2009 Pandemic Influenza A (H1N1) Infection

“…However, clinical data are lacking to substantiate this recommendation. The limitations of neuramidase inhibitor monotherapy for severe influenza illness have also renewed interest in combination antiviral therapy (5)(6)(7)(8). Previous studies have demonstrated that triple combination of antiviral drugs (TCAD)-amantadine, ribavirin, and oseltamivir-was highly and synergistically effective against influenza A virus in vitro, even for drugresistant strains (6).…”