The rapid emergence and subsequent spread of the novel 2009
Influenza A/H1N1 virus (2009 H1N1) has prompted the World Health Organization to declare the first pandemic of the 21st century, highlighting the threat of
influenza to public health and healthcare systems. Widespread resistance to both classes of
influenza antivirals (adamantanes and
neuraminidase inhibitors) occurs in both pandemic and seasonal viruses, rendering these drugs to be of marginal utility in the treatment modality. Worldwide, virtually all 2009 H1N1 and seasonal H3N2 strains are resistant to the adamantanes (
rimantadine and
amantadine), and the majority of seasonal H1N1 strains are resistant to
oseltamivir, the most widely prescribed
neuraminidase inhibitor (NAI). To address the need for more effective
therapy, we evaluated the in vitro activity of a triple combination
antiviral drug (
TCAD) regimen composed of drugs with different mechanisms of action against
drug-resistant seasonal and 2009 H1N1 influenza viruses.
Amantadine,
ribavirin, and
oseltamivir, alone and in combination, were tested against
amantadine- and
oseltamivir-resistant influenza A viruses using an in vitro
infection model in MDCK cells. Our data show that the triple combination was highly synergistic against
drug-resistant viruses, and the synergy of the triple combination was significantly greater than the synergy of any double combination tested (P<0.05), including the combination of two NAIs. Surprisingly,
amantadine and
oseltamivir contributed to the
antiviral activity of the
TCAD regimen against
amantadine- and
oseltamivir-resistant viruses, respectively, at concentrations where they had no activity as single agents, and at concentrations that were clinically achievable. Our data demonstrate that the
TCAD regimen composed of
amantadine,
ribavirin, and
oseltamivir is highly synergistic against resistant viruses, including 2009 H1N1. The
TCAD regimen overcomes baseline drug resistance to both classes of approved
influenza antivirals, and thus may represent a highly active
antiviral therapy for seasonal and pandemic
influenza.