The global spread of drug-resistant influenza

Abstract

Resistance to oseltamivir, the most widely used influenza antiviral drug, spread to fixation in seasonal influenza A(H1N1) between 2006 and 2009. This sudden rise in resistance seemed puzzling given the low overall level of the oseltamivir usage and the lack of a correlation between local rates of resistance and oseltamivir usage. We used a stochastic simulation model and deterministic approximations to examine how such events can occur, and in particular to determine how the rate of fixation of the resistant strain depends both on its fitness in untreated hosts as well as the frequency of antiviral treatment. We found that, for the levels of antiviral usage in the population, the resistant strain will eventually spread to fixation, if it is not attenuated in transmissibility relative to the drugsensitive strain, but not at the speed observed in seasonal H1N1. The extreme speed with which the resistance spread in seasonal H1N1 suggests that the resistant strain had a transmission advantage in untreated hosts, and this could have arisen from genetic hitchhiking, or from the mutations responsible for resistance and compensation. Importantly, our model also shows that resistant virus will fail to spread if it is even slightly less transmissible than its sensitive counterpart-a finding of relevance given that resistant pandemic influenza (H1N1) 2009 may currently suffer from a small, but nonetheless experimentally perceptible reduction in transmissibility.

Enhanced Mammalian Transmissibility of Seasonal Influenza A/H1N1 Viruses Encoding an Oseltamivir-Resistant Neuraminidase

“…Our data are consistent with, but do not discriminate between, stochastic models demonstrating that the rapid strain replacement observed among sH1N1 viruses can occur whether the resistance mutation itself (i.e., H275Y) provides a small transmission advantage or whether it arises coincidentally with a second mutation that confers a transmission advantage of similar magnitude (12). Improved mammalian transmissibility can also explain the emergence and persistence of oseltamivir-resistant sH1N1 viruses, even in the absence of widespread oseltamivir use.…”

“…Both HA-NA balance and genetic "hitchhiking" have been proposed as evolutionary mechanisms that would explain the rapid surge in prevalence undergone by oseltamivir-resistant Brisbane/59-like sH1N1 viruses. The "hitchhiking" hypothesis posits that the H275Y substitution arose coincidentally with some other advantageous mutation(s) in the viral genome; thus, the H275Y mutation did not necessarily confer a fitness advantage upon sH1N1 viruses, but rather became dominant by assorting with another gene(s) that did (12,56). Our data suggest that the oseltamivir-resistant NA (inclusive of both H275Y and D354G substitutions) accounts for most, if not all, of the enhancement in transmission efficiency seen in these oseltamivir-resistant Brisbane/ 59-like viruses.…”

“…However, the relative fitness and transmissibility of sH1N1 viruses might instead have been modulated by other viral genes. Phylogenetic analysis (56) and stochastic models (12) have suggested that the H275Y substitution could have occurred coincidentally with some other advantageous mutation(s) in the viral genome and simply "hitchhiked" to fixation along with them. To our knowledge, no in vivo data conclusively support either of these hypotheses.…”

Preclinical Activity of VX-787, a First-in-Class, Orally Bioavailable Inhibitor of the Influenza Virus Polymerase PB2 Subunit

“…In addition to the limited treatment window, another concern for this class of antivirals is the possibility of neuraminidase inhibitor resistance, as occurred during the 2008 to 2009 season when oseltamivir-resistant H1N1 was prevalent (22,23). This highlights the need for new classes of antiviral agents with novel mechanisms of action (24)(25)(26)(27).In order to provide alternative therapeutic options for patients with influenza infection, we initiated a phenotypic-assay-based drug discovery effort. Subsequently, the molecular target of a series of azaindole hits resulting from these screening efforts was determined to be the PB2 cap-binding domain of the influenza viral polymerase complex (28).…”

Bayesian hierarchical statistical SIRS models

“…Some more recent stochastic models involve complex networks (e.g., Halloran et al, 2002;Zhou et al, 2006;Volz, 2008) or drug resistance (e.g., Chao et al, 2012) to avoid the assumption of homogenous mixing. However, these stochastic models ignore the noisy nature of data, and they apply mass balance to the observed counts rather than the true counts.…”