Research Article: Hedging against Antiviral Resistance during the Next Influenza Pandemic Using Small Stockpiles of an Alternative Chemotherapy

Date Published: May 19, 2009

Publisher: Public Library of Science

Author(s): Joseph T. Wu, Gabriel M. Leung, Marc Lipsitch, Ben S. Cooper, Steven Riley, Cécile Viboud

Abstract: Mathematically simulating an influenza pandemic, Joseph Wu and colleagues predict that using a secondary antiviral drug early in local epidemics would reduce global emergence of resistance to the primary stockpiled drug.

Partial Text: Large-scale antiviral treatment and targeted prophylaxis may provide substantial public health benefits by slowing the spread of pandemic influenza [1]–[7]. Although it is not certain that existing antivirals will be effective against the eventual pandemic strain, many countries are investing in large stockpiles of a single drug (oseltamivir [Tamiflu]) [8]. Such massive use of a single antiviral will substantially increase the risk of emergence of resistant strains. For H3N2 strains, de novo emergence of resistance occurs in 0.4% of outpatient adults and 5.5% of outpatient children treated with oseltamivir [9]. If the rate of de novo emergence is similar for the pandemic strain, resistance will certainly emerge under large-scale antiviral intervention [5]. Although most oseltamivir-resistant H3N2 strains are less fit (i.e. less transmissible) than the wild type [10] and therefore cannot spread widely [11], there is no guarantee that this will be the case for the yet-to-be-observed pandemic strain. Indeed, the recent establishment of oseltamivir-resistant H1N1 viruses suggests that oseltamivir-resistant strains do not necessarily incur fitness costs [12]–[18]. The spread of antiviral resistance during a pandemic will substantially reduce the effectiveness of antiviral intervention [5],[19]–[21]. Despite this potential threat, countries stockpiling antivirals have not yet declared any strategies to hedge against the risk of antiviral resistance. Here, we test the hypothesis that a small stockpile of a secondary antiviral drug could be used to effectively mitigate the adverse consequences of the emergence of resistant influenza strains.

Our model predicts that the spread of treatment-induced antiviral resistance during an influenza pandemic can be effectively reduced by deploying a small stockpile of a secondary drug during the early phase of local epidemics. By investigating all potentially important regions of unknown parameter space we found that both ECC and SMC reduced the cumulative AR and the RAR unless the probability of emergence of resistance to the primary drug was so low that resistance was unlikely to be a problem or so high that resistance emerged as soon as primary drug monotherapy began. Using a global model of large cities, we found that as long as populations that were the main source of resistant strains employed these strategies (SMC or ECC), then those same strategies were also effective for populations far from the source even when some intermediate populations failed to control resistance.