Emergence of drug resistance: implications for antiviral control of pandemic influenza

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Abstract
Given the danger of an unprecedented spread of the highly pathogenic avian influenza strain H5N1 in humans, and great challenges to the development of an effective influenza vaccine, antiviral drugs will probably play a pivotal role in combating a novel pandemic strain. A critical limitation to the use of these drugs is the evolution of highly transmissible drug-resistant viral mutants. Here, we develop a mathematical model to evaluate the potential impact of an antiviral treatment strategy on the emergence of drug resistance and containment of a pandemic. The results show that elimination of the wild-type strain depends crucially on both the early onset of treatment in indexed cases and population-level treatment. Given the probable delay of 0.5–1 day in seeking healthcare and therefore initiating therapy, the findings indicate that a single strategy of antiviral treatment will be unsuccessful at controlling the spread of disease if the reproduction number of the wild-type strain exceeds 1.4. We demonstrate the possible occurrence of a self-sustaining epidemic of resistant strain, in terms of its transmission fitness relative to the wild-type, and the reproduction number . Considering reproduction numbers estimated for the past three pandemics, the findings suggest that an uncontrollable pandemic is likely to occur if resistant viruses with relative transmission fitness above 0.4 emerge. While an antiviral strategy is crucial for containing a pandemic, its effectiveness depends critically on timely and strategic use of drugs.