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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

Time-courses of clinical infections with one day delay in onset of treatment of indexed cases, with .Simulations were run, when a single case infected with the wild-type virus is introduced into the susceptible population of size S0 = 100 000. Treatment levels are: (a) 50%; (b) 78%; (c) 90%; and (d) 95%. The corresponding reproduction numbers of the wild-type strain are: (a) ; (b) ; (c) ; and (d) .
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pone-0001839-g002: Time-courses of clinical infections with one day delay in onset of treatment of indexed cases, with .Simulations were run, when a single case infected with the wild-type virus is introduced into the susceptible population of size S0 = 100 000. Treatment levels are: (a) 50%; (b) 78%; (c) 90%; and (d) 95%. The corresponding reproduction numbers of the wild-type strain are: (a) ; (b) ; (c) ; and (d) .

Mentions: Assuming and , Figure 2 shows the occurrence of disease outbreaks for constant treatment levels during the entire course of the pandemic. For 50% treatment level of clinical cases, the wild-type strain spreads quickly and depletes the susceptible population, and therefore a limited number of resistant cases is generated (Figure 2a). Increasing treatment level to 78% leads to a reduction in the clinical attack rate of the wild-type virus from 22% (at 50% treatment level) to 16%, and lowers from 1.38 to 1.25 (Figure 2b). In this case, however, the emergent resistant mutants begin to invade the susceptible hosts and establish a self-sustaining epidemic. Further increase in the treatment level to 90% enhances the spread of resistant mutants and leads to the co-existence of outbreaks (Figure 2c). With higher treatment level (95%), is reduced considerably below , and the resistant outbreak substantially dominates that of the wild-type strain (Figure 2d). Transmission of wild-type infections is dramatically reduced, resulting in a 4% clinical attack rate. However, the wide-spread presence of resistant strains results in a higher overall attack rate than would have been the case if treatment were administered at a lower rate. We observed similar patterns for outbreaks of wild-type and resistant infections with higher values of . However, in these cases, wide-spread drug-resistance is less probable and requires higher levels of treatment to significantly interrupt the transmission of wild-type infections.


Population-wide emergence of antiviral resistance during pandemic influenza.

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

Time-courses of clinical infections with one day delay in onset of treatment of indexed cases, with .Simulations were run, when a single case infected with the wild-type virus is introduced into the susceptible population of size S0 = 100 000. Treatment levels are: (a) 50%; (b) 78%; (c) 90%; and (d) 95%. The corresponding reproduction numbers of the wild-type strain are: (a) ; (b) ; (c) ; and (d) .
© Copyright Policy
Related In: Results  -  Collection

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

pone-0001839-g002: Time-courses of clinical infections with one day delay in onset of treatment of indexed cases, with .Simulations were run, when a single case infected with the wild-type virus is introduced into the susceptible population of size S0 = 100 000. Treatment levels are: (a) 50%; (b) 78%; (c) 90%; and (d) 95%. The corresponding reproduction numbers of the wild-type strain are: (a) ; (b) ; (c) ; and (d) .
Mentions: Assuming and , Figure 2 shows the occurrence of disease outbreaks for constant treatment levels during the entire course of the pandemic. For 50% treatment level of clinical cases, the wild-type strain spreads quickly and depletes the susceptible population, and therefore a limited number of resistant cases is generated (Figure 2a). Increasing treatment level to 78% leads to a reduction in the clinical attack rate of the wild-type virus from 22% (at 50% treatment level) to 16%, and lowers from 1.38 to 1.25 (Figure 2b). In this case, however, the emergent resistant mutants begin to invade the susceptible hosts and establish a self-sustaining epidemic. Further increase in the treatment level to 90% enhances the spread of resistant mutants and leads to the co-existence of outbreaks (Figure 2c). With higher treatment level (95%), is reduced considerably below , and the resistant outbreak substantially dominates that of the wild-type strain (Figure 2d). Transmission of wild-type infections is dramatically reduced, resulting in a 4% clinical attack rate. However, the wide-spread presence of resistant strains results in a higher overall attack rate than would have been the case if treatment were administered at a lower rate. We observed similar patterns for outbreaks of wild-type and resistant infections with higher values of . However, in these cases, wide-spread drug-resistance is less probable and requires higher levels of treatment to significantly interrupt the transmission of wild-type infections.

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