Emerging Influenza Antiviral Resistance Threats

Abstract

Antiviral resistance in influenza may not only develop during treatment but also sometimes transmit widely to replace susceptible strains in the absence of drug pressure. This transmission is exemplified by the global spread of adamantane-resistant A(H3N2) viruses since 2003, oseltamivir-resistant seasonal A(H1N1) viruses since 2007, and adamantane-resistant pandemic A(H1N1) viruses in 2009, events that emphasize the unpredictability of influenza viruses and the increasing challenges of clinical management of influenza, especially given the current paucity of therapeutic choices. Three articles in this issue of The Journal of Infectious Diseases extend these observations, describing the plasticity of seasonal A(H1N1) viruses in developing dual adamantane-oseltamivir resistance [1], the effects on drug susceptibility and viral fitness of various neuraminidase (NA) mutations in pandemic A(H1N1) viruses [2], and the risk of nosocomial spread of oseltamivir-resistant pandemic A(H1N1) virus [3]. Together, these findings illustrate that single reassortment events or mutations can lead to the emergence of transmissible variants of pandemic 2009 or seasonal A(H1N1) viruses unresponsive to most, if not all, of our currently available drugs. This raises multiple questions regarding patient management and preparations for future influenza outbreaks. High-level adamantane resistance rapidly develops during treatment and is conferred by single amino acid changes in the M2 ion channel, most notably at S31N, that do not diminish viral replication or transmissibility [4, 5]. Until several years ago, wide-scale spread of oseltamivir-resistant viruses associated with NA mutations, such as the H275Y change that causes marked loss of oseltamivir susceptibility in N1-containing viruses [6], was deemed unlikely in view of observed reductions in viral infectivity and virulence associated with the H275Y change in earlier seasonal H1N1 viruses [7, 8]. However, this was clearly not the case for the oseltamivir-resistant A/Brisbane/59/07(H1N1) virus, which transmitted very efficiently from person to person, ultimately replaced susceptible viruses in the absence of selective drug pressure in much of the world, and caused illness similar to that caused by susceptible viruses, including severe disease in at-risk patients [9–11]. The mechanisms for the undiminished fitness of oseltamivir-resistant A/Brisbane/59/07(H1N1) virus are incompletely understood, but the reduced substrate affinity of the NA with H275Y may have restored a balance between hemagglutinin (HA) receptor-binding and NA receptor-cleaving functionalities altered by earlier NA mutations that increased substrate affinity [12–14]. Further evidence of this hypothesis was provided by recent studies showing that NA mutations at sites outside of the active enzyme site enhanced surface expression of properly folded NA and appeared to facilitate the subsequent emergence of the H275Y mutation, possibly by restoring the functional balance between HA and NA [15]. Worryingly, these observations suggest the emergence of drug-resistant influenza virus variants with higher transmission fitness than that of the corresponding susceptible virus by selective pressures apparently unrelated to antiviral exposure. Of concern in this respect is the finding by Pizzorno and colleagues [2] that an I223V NA change not only increased oseltamivir and peramivir resistance of pandemic A(H1N1) virus conferred by the H275Y NA change, similar to previous findings for seasonal A(H1N1) and avian A(H5N1) viruses [16], but also restored NA substrate affinity and replication fitness in vitro. Of note, Garrison and coauthors identified pandemic A(H1N1) virus infections with dual H275Y and I223V NA mutations in a pair of campers [17], and it is tempting to speculate whether the I223V change fostered transmission in this event. An I223R mutation in pandemic N1 is associated with 7- to 10-fold decreased susceptibility to zanamivir and up to 45-fold decreased susceptibility to oseltamivir [18–20]; the same mutation in conjunction with H275Y causes further reductions in NA inhibitor (NAI) susceptibility, especially for oseltamivir and peramivir [19, 21, 22]. Variants harboring the I223R change emerged and replicated to high titers during intravenous zanamivir treatment in 1 severely immunocompromised patient in whom H275Y had developed during a previous course of oseltamivir treatment [18]. In another immunocompromised host, the I223R mutation emerged during oseltamivir therapy but became predominant after subsequent inhaled administration of zanamivir [19]. Further studies of the fitness effects of I223 mutations, alone and in conjunction with H275Y in animal models, and close monitoring of changes in the I223 residue in N1 viruses are clearly needed. In addition, because other mutations may confer reduced susceptibility to 1 or more NAIs in N1-containing [21–26] and other influenza viruses, continued surveillance u