Intermittent treatment of severe influenza.

Severe, long-lasting influenza infections are often caused by new strains of the virus. The long duration of these infections leads to an increased opportunity for the emergence of drug resistant mutants. This is particularly problematic since for new strains there is often no vaccine, so drug treatment is the first line of defense. One strategy for trying to minimize drug resistance is to apply drugs periodically. During treatment phases the wild-type virus decreases, but resistant virus might increase; when there is no treatment, wild-type virus will hopefully out-compete the resistant virus, driving down the number of resistant virus. A stochastic model of severe influenza is combined with a model of drug resistance to simulate long-lasting infections and intermittent treatment with two types of antivirals: neuraminidase inhibitors, which block release of virions; and adamantanes, which block replication of virions. Each drug's ability to reduce emergence of drug resistant mutants is investigated. We find that cell regeneration is required for successful implementation of intermittent treatment and that the optimal cycling parameters change with regeneration rate.