Hedging against Antiviral Resistance During the Next Current Influenza Pandemic

Commentary on: J.T. Wu, G.M. Leung, M. Lipsitch, B. S. Cooper, and S. Riley  2009. Hedging against Antiviral Resistance during the Next Influenza Pandemic Using Small Stockpiles of an Alternative Chemotherapy. PloS Medicine. Online ahead of print 4/30/09. http://www.plos.org/press/plme-06-05-wu.pdf

Eight days ago we received the first reports of a half-dozen infections in Texas and California patients by a swine-derived strain of influenza A H1N1; these reports were accompanied by speculation that these case might be related to a cluster of atypical pneumonia cases in Mexico City. Only eight days later, we now are looking at hundreds of confirmed cases, and presumably thousands of total cases, distributed throughout the US and Mexico, with additional confirmed cases in multiple regions of Europe, Asia, and Oceana. The World Health Organization has raised the pandemic alert level from phase 3 to phase 5 (widespread human infection), and pandemic plans are being put into operation around the globe.

The point is that things move extremely fast in the early phases of an epidemic – and at the same, early decisions about plans to control or mitigate the epidemic can cast a very long shadow with respect to the ultimate trajectory that the epidemic takes. Yesterday, PloS Medicine released an advance copy of a paper by Wu et al., written prior to the current situation but uncannily relevant to the current pandemic control process.

Using a set of simulation models, the authors show that the choice of which antivirals to use early in an influenza pandemic can have dramatic consequences for the evolution and spread of antiviral resistance later in the pandemic. Given our arsenal of multiple antiviral agents that can potentially limit the transmissibility and mortality associated with pandemic influenza, the antiviral susceptibility or resistance of circulating influenza strains can have an enormous impact on the trajectory and severity of an influenza pandemic. In particular, the authors argue that the early use of an antiviral agent that is in short supply (e.g. zanamivir / Relenza) can substantially prolong the effective life of another agent for which we have larger stockpiles (e.g. oseltamivir / Tamiflu).

The basic intuition behind these results is that, early in an epidemic, the number of cases increases exponentially. Thus, if resistance to the stockpiled antiviral evolves early in an epidemic, large resistant clades are produced and resistance becomes widespread. If we could delay the evolution of resistance to the stockpiled antiviral even slightly, by using the alternative therapy first, or in combination with the more widely available therapy, resistant clades would be much smaller and resistance would be more localized.

By limiting resistance, we benefit in two ways. First, fewer resistant cases means fewer treatment failures and, thus, fewer deaths. Second, lowering the rate of spread later in an epidemic with effective antivirals will reduce the total number of cases. This occurs because a low rate of spread late in the epidemic minimizes the degree to which the epidemic “overshoots” the number of cases required to confer herd immunity (Handel et al 2007).

Wu et al. have revealed a new principle in the evolutionary management of antimicrobial agents, and an extremely important one for the current influenza outbreak. Wu et al. have provided not only a key insight in dealing with the present situation, but also another powerful illustration of need for evolutionary biology in public health decision-making.

Reference: A. Handel, I. M. Longini Jr., and R. Antia (2007) What is the best control strategy for multiple infectious disease outbreaks? Proc. R. Soc. B. 274(1611):833-7