Implications of Antiviral Resistance of Influenza Viruses

Abstract

Until very recently, concern about antiviral resistance was focused on only 1 of the 2 classes of drugs licensed for prophylaxis and treatment of influenza. The adamantanes, also called M2 inhibitors because of their principal mode of antiviral action, have been used intermittently for influenza A virus infection for >40 years. Amino acid substitutions in one of several positions in the M2 protein of the virus make both amantadine and rimantadine completely ineffective. These mutations are so closely associated with high levels of drug resistance that it is unnecessary to confirm drug resistance phenotypically in 50% inhibitory concentration assays [1]. Drug-resistant strains develop in ∼30% of patients treated with either adamantane, and these strains are easily transmitted [2]. Until 2003, nearly all community isolates of influenza A virus remained susceptible to the adamantanes [3]. This change likely resulted from a major increase in the overall use of amantadine that accompanied the spread of influenza A subtype H5N1 (influenza A/H5N1) virus. At present, in the United States, most influenza A subtype H3N2 (influenza A/H3N2) virus strains circulating are resistant to adamantanes, most influenza A subtype H1N1 (influenza A/H1N1) virus strains remain susceptible to adamantanes, and globally, resistance of influenza A/H5N1 virus to adamantanes varies by clade.