Adamantane-Resistant Influenza A Viruses in the World (1902–2013): Frequency and Distribution of M2 Gene Mutations

Adamantanes (amantadine and rimantadine) have been used to prevent and treat influenza A virus infections for many years; however, resistance to these drugs has been widely reported in the world. To investigate the frequency and distribution of M2 gene mutations in adamantane-resistant influenza variants circulated in the world between 1902 and 2013, 31251 available M2 protein sequences from different HA-subtype influenza A viruses (H1–H17) were analyzed and adamantane resistance-associated mutations were compared (L26F, V27A, A30T, A30V, S31N, G34E, and L38F). We find that 45.2% (n = 14132) of influenza A (H1–H17) viruses circulating globally were resistant to adamantanes, and the vast majority of resistant viruses (95%) bear S31N mutations. Whereas, only about 1% have V27A mutations and other mutations (L26F, A30T, G34E, and L38F) were extremely rare (their prevalence appeared to be