Session: Slide Session: Influenza
Sunday, October 26, 2008: 12:00 AM
Room: Room 202B
Background: Influenza A viruses are associated with mortality and morbidity in seasonal epidemics and pandemics. The biggest obstacles in the fight against influenza are poor efficacy and resistance. To date, only double combinations have been tested against influenza, and with variable success. We report in vitro and in vivo data of a triple combination of antivirals against influenza A, showing that the triple combination is synergistic and effective at reducing viral load and preventing resistance. Methods: Triple combinations composed of amantadine, ribavirin, and a neuraminidase inhibitor (zanamivir or oseltamivir) were tested against influenza A viruses from different subtypes in MDCK cells. The drugs were tested as single agents, and in double and triple combinations. For mouse challenge models, Balb/C mice were infected with a LD100 dose of influenza A. Infected animals were treated with each drug as a single agent or the triple combination at various times pre- and post-infection. Results: Triple combination therapy was highly synergistic, reducing the EC50 of the drugs by 10 to 100 fold compared to monotherapy. The synergy was seen against multiple influenza A subtypes. Furthermore, efficacy of the triple combination was superior to the double combinations and monotherapy. In an in vitro kinetic model of influenza infection, the triple combination was effective at reducing viral load and preventing the emergence of resistance. In mouse challenge models, the triple combination was superior to monotherapy in protection against mortality and weight loss in both prophylaxis and delayed treatment models. Conclusions: Our data provide evidence to support the development of triple combinations against influenza A infection. We have shown that the triple combination has a great advantage over double combinations and monotherapies in terms of efficacy and preventing resistance.