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Population-wide emergence of antiviral resistance during pandemic influenza.

Moghadas SM, Bowman CS, Röst G, Wu J - PLoS ONE (2008)

Bottom Line: However, by changing treatment levels over the course of the pandemic, it is possible to reduce the final size of the pandemic below the minimum achieved at the optimal constant level.This reduction can occur with low treatment levels during the early stages of the pandemic, followed by a sharp increase in drug-use before the virus becomes widely spread.Our findings suggest that an adaptive antiviral strategy with conservative initial treatment levels, followed by a timely increase in the scale of drug-use, can minimize the final size of a pandemic while preventing large outbreaks of resistant infections.

View Article: PubMed Central - PubMed

Affiliation: Institute for Biodiagnostics, National Research Council Canada, Winnipeg, Manitoba, Canada. Seyed.Moghadas@nrc-cnrc.gc.ca

ABSTRACT

Background: The emergence of neuraminidase inhibitor resistance has raised concerns about the prudent use of antiviral drugs in response to the next influenza pandemic. While resistant strains may initially emerge with compromised viral fitness, mutations that largely compensate for this impaired fitness can arise. Understanding the extent to which these mutations affect the spread of disease in the population can have important implications for developing pandemic plans.

Methodology/principal findings: By employing a deterministic mathematical model, we investigate possible scenarios for the emergence of population-wide resistance in the presence of antiviral drugs. The results show that if the treatment level (the fraction of clinical infections which receives treatment) is maintained constant during the course of the outbreak, there is an optimal level that minimizes the final size of the pandemic. However, aggressive treatment above the optimal level can substantially promote the spread of highly transmissible resistant mutants and increase the total number of infections. We demonstrate that resistant outbreaks can occur more readily when the spread of disease is further delayed by applying other curtailing measures, even if treatment levels are kept modest. However, by changing treatment levels over the course of the pandemic, it is possible to reduce the final size of the pandemic below the minimum achieved at the optimal constant level. This reduction can occur with low treatment levels during the early stages of the pandemic, followed by a sharp increase in drug-use before the virus becomes widely spread.

Conclusions/significance: Our findings suggest that an adaptive antiviral strategy with conservative initial treatment levels, followed by a timely increase in the scale of drug-use, can minimize the final size of a pandemic while preventing large outbreaks of resistant infections.

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Related in: MedlinePlus

The effect of changing treatment level during a pandemic on the total number of clinical infections caused by all strains, with .Simulations were seeded with an initial treatment level of (a) 85%; (b) 78% (optimal level); (c) 50%; (d) 25%, and then changed to the level shown on the horizontal axis at the time displayed on the vertical axis (corresponding to the time-course of the epidemic). The color bars illustrate the total number of clinical cases due to all strains, relative to that generated when the optimal constant treatment level (78% in this case) is implemented.
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pone-0001839-g005: The effect of changing treatment level during a pandemic on the total number of clinical infections caused by all strains, with .Simulations were seeded with an initial treatment level of (a) 85%; (b) 78% (optimal level); (c) 50%; (d) 25%, and then changed to the level shown on the horizontal axis at the time displayed on the vertical axis (corresponding to the time-course of the epidemic). The color bars illustrate the total number of clinical cases due to all strains, relative to that generated when the optimal constant treatment level (78% in this case) is implemented.

Mentions: In the event of emerging drug-resistance, it has been suggested [1] that reducing treatment levels may permit the wild-type to outcompete the resistant strains due to its greater fitness, thereby preventing large resistant outbreaks. To investigate this strategy, we modified the model to allow for changing the population−level of treatment at a specified time (t*) during a pandemic. We define T as the total number of clinical infections when an antiviral strategy with varying level of treatment is implemented, and let Tc be the total number of clinical infections when treatment is maintained at the optimal constant level. The ratio T/Tc provides a criterion for identifying effective strategies for controlling the spread of disease. Assuming , we simulated the model when antiviral treatment is initiated at an 85% level (above the corresponding optimal constant level 78%). The results show that the final size of infections may be reduced only if treatment is scaled down to the optimal level during the early stages of the pandemic (Figures 5a), before outbreaks of compensated mutants can occur (Figure 6a). Further simulations (Figure 5b) with a 78% initial treatment level indicate that reducing antiviral use, at any time during a pandemic, below the optimal level would increase the number of clinical infections (T/Tc>1), suggesting that antiviral therapy at the optimal constant level will be more effective in mitigating a pandemic, and preventing resistant outbreaks (Figure 6b). However, the final size of a pandemic may be slightly reduced if the supply of drugs can afford a significant increase in the level of treatment at a later stage during the outbreak.


Population-wide emergence of antiviral resistance during pandemic influenza.

Moghadas SM, Bowman CS, Röst G, Wu J - PLoS ONE (2008)

The effect of changing treatment level during a pandemic on the total number of clinical infections caused by all strains, with .Simulations were seeded with an initial treatment level of (a) 85%; (b) 78% (optimal level); (c) 50%; (d) 25%, and then changed to the level shown on the horizontal axis at the time displayed on the vertical axis (corresponding to the time-course of the epidemic). The color bars illustrate the total number of clinical cases due to all strains, relative to that generated when the optimal constant treatment level (78% in this case) is implemented.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2266801&req=5

pone-0001839-g005: The effect of changing treatment level during a pandemic on the total number of clinical infections caused by all strains, with .Simulations were seeded with an initial treatment level of (a) 85%; (b) 78% (optimal level); (c) 50%; (d) 25%, and then changed to the level shown on the horizontal axis at the time displayed on the vertical axis (corresponding to the time-course of the epidemic). The color bars illustrate the total number of clinical cases due to all strains, relative to that generated when the optimal constant treatment level (78% in this case) is implemented.
Mentions: In the event of emerging drug-resistance, it has been suggested [1] that reducing treatment levels may permit the wild-type to outcompete the resistant strains due to its greater fitness, thereby preventing large resistant outbreaks. To investigate this strategy, we modified the model to allow for changing the population−level of treatment at a specified time (t*) during a pandemic. We define T as the total number of clinical infections when an antiviral strategy with varying level of treatment is implemented, and let Tc be the total number of clinical infections when treatment is maintained at the optimal constant level. The ratio T/Tc provides a criterion for identifying effective strategies for controlling the spread of disease. Assuming , we simulated the model when antiviral treatment is initiated at an 85% level (above the corresponding optimal constant level 78%). The results show that the final size of infections may be reduced only if treatment is scaled down to the optimal level during the early stages of the pandemic (Figures 5a), before outbreaks of compensated mutants can occur (Figure 6a). Further simulations (Figure 5b) with a 78% initial treatment level indicate that reducing antiviral use, at any time during a pandemic, below the optimal level would increase the number of clinical infections (T/Tc>1), suggesting that antiviral therapy at the optimal constant level will be more effective in mitigating a pandemic, and preventing resistant outbreaks (Figure 6b). However, the final size of a pandemic may be slightly reduced if the supply of drugs can afford a significant increase in the level of treatment at a later stage during the outbreak.

Bottom Line: However, by changing treatment levels over the course of the pandemic, it is possible to reduce the final size of the pandemic below the minimum achieved at the optimal constant level.This reduction can occur with low treatment levels during the early stages of the pandemic, followed by a sharp increase in drug-use before the virus becomes widely spread.Our findings suggest that an adaptive antiviral strategy with conservative initial treatment levels, followed by a timely increase in the scale of drug-use, can minimize the final size of a pandemic while preventing large outbreaks of resistant infections.

View Article: PubMed Central - PubMed

Affiliation: Institute for Biodiagnostics, National Research Council Canada, Winnipeg, Manitoba, Canada. Seyed.Moghadas@nrc-cnrc.gc.ca

ABSTRACT

Background: The emergence of neuraminidase inhibitor resistance has raised concerns about the prudent use of antiviral drugs in response to the next influenza pandemic. While resistant strains may initially emerge with compromised viral fitness, mutations that largely compensate for this impaired fitness can arise. Understanding the extent to which these mutations affect the spread of disease in the population can have important implications for developing pandemic plans.

Methodology/principal findings: By employing a deterministic mathematical model, we investigate possible scenarios for the emergence of population-wide resistance in the presence of antiviral drugs. The results show that if the treatment level (the fraction of clinical infections which receives treatment) is maintained constant during the course of the outbreak, there is an optimal level that minimizes the final size of the pandemic. However, aggressive treatment above the optimal level can substantially promote the spread of highly transmissible resistant mutants and increase the total number of infections. We demonstrate that resistant outbreaks can occur more readily when the spread of disease is further delayed by applying other curtailing measures, even if treatment levels are kept modest. However, by changing treatment levels over the course of the pandemic, it is possible to reduce the final size of the pandemic below the minimum achieved at the optimal constant level. This reduction can occur with low treatment levels during the early stages of the pandemic, followed by a sharp increase in drug-use before the virus becomes widely spread.

Conclusions/significance: Our findings suggest that an adaptive antiviral strategy with conservative initial treatment levels, followed by a timely increase in the scale of drug-use, can minimize the final size of a pandemic while preventing large outbreaks of resistant infections.

Show MeSH
Related in: MedlinePlus