Low Dose Oral Combination Chemoprophylaxis with Oseltamivir and Amantadine for Influenza a Virus Infections in Mice

In the present study, the effect of combining anti-influenza drugs active at different steps of the influenza virus replication cycle, oseltamivir as a neuraminidase (NA) inhibitor and amantadine targeting M2 protein, was investigated in vivo by oral administration in a mouse model of aerosol influenza virus infection and in vitro in MDCK cells. In mice, doses of oseltamivir and amantadine providing 50-60% survival against A/Hongkong/1/68 (H3N2) or A/PR/8/34 (H1N1) were capable of conferring complete protection when used simultaneously, suggesting that increased inhibition of influenza virus replication by combining oseltamivir and amantadine in vitro translates into protection from lethal infection of mice. The combination of amantadine with oseltamivir required 15-fold less oseltamivir than monotherapy to confer complete protection against lethal aerosol influenza virus infection. Remarkably, amantadine-based combination chemoprophylaxis was even effective against amantadine-resistant A/PR/8/34 influenza virus. Thus, combination chemotherapy may be more efficacious than monotherapy against newly emerging Influenza A subtypes.