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Triple-Drug Cocktails for Influenza?
In vitro studies showed that a triple-drug combination provided synergistic activity against influenza A virus.
Nearly all strains of influenza A virus currently circulating in the U.S. are resistant to either adamantanes or neuraminidase inhibitors. Concern about the potential development of multidrug resistance and the suboptimal efficacy of individual drugs led researchers (several of them employees of a pharmaceutical company) to test the interactions of three antiviral drugs that have different mechanisms of action and act at different stages in the viral life cycle.
Various concentrations of oseltamivir, amantadine, and ribavirin were used alone or in combination in several in vitro tests involving three strains of influenza A virus. The tested viruses — wild-type versions of seasonal H1N1 and H3N2 strains and an avian strain of H5N1 — did not contain mutations known to confer resistance to oseltamivir or amantadine. Dose-response curves were generated, and synergy (or antagonism) between the drugs in dual and triple combinations was determined.
For dual combinations, synergistic activity varied depending on the drugs involved and the influenza strain tested. However, the triple combination was consistently synergistic against all tested strains and was more active than the drugs alone or in dual combinations. Synergistic activity of triple therapy occurred at concentrations that were achievable in human plasma with currently recommended doses of the individual drugs.
Comment: Combination therapies for HIV infection are effective in suppressing viral load and preventing the emergence of resistance. These researchers extrapolated from HIV to the influenza virus, another pathogen with high mutation capability. Using three influenza A strains, they demonstrated the superiority of triple-combination therapy over double-combination or single therapy. Of note, the outbreak strain of swine-origin influenza A (H1N1) virus, strains with resistance mutations, and influenza B strains were not included in this study.
Published in Journal Watch Infectious Diseases July 29, 2009
Citation(s):
Nguyen JT et al. Triple combination of oseltamivir, amantadine, and ribavirin displays synergistic activity against multiple influenza strains in vitro. Antimicrob Agents Chemother 2009 Jul 20; [e-pub ahead of print]. (http://dx.doi.org/10.1128/AAC.00476-09)
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