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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

Model structure for the emergence of drug-resistance during treatment of symptomatic infections.The clinical course of disease is divided into three stages: pre-symptomatic; primary; and secondary stages of symptomatic infections. Drug-resistance with low transmission fitness can emerge during treatment of individuals infected with the wild-type virus. It is assumed that compensatory mutations may result in generation of resistant mutants with high transmission fitness during the secondary stage of treated symptomatic infection. The compartments of untreated and treated individuals infected with the wild-type strain are represented by IU and IT, respectively. The corresponding compartments for the resistant strain with low (high) transmission fitness are denoted by sub-index r (rH).
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pone-0001839-g001: Model structure for the emergence of drug-resistance during treatment of symptomatic infections.The clinical course of disease is divided into three stages: pre-symptomatic; primary; and secondary stages of symptomatic infections. Drug-resistance with low transmission fitness can emerge during treatment of individuals infected with the wild-type virus. It is assumed that compensatory mutations may result in generation of resistant mutants with high transmission fitness during the secondary stage of treated symptomatic infection. The compartments of untreated and treated individuals infected with the wild-type strain are represented by IU and IT, respectively. The corresponding compartments for the resistant strain with low (high) transmission fitness are denoted by sub-index r (rH).

Mentions: To develop a population dynamical model, we followed previous work [8], [15] and divided the population into several compartments comprising susceptible, exposed, asymptomatic, and symptomatic infected individuals. In our model, exposed individuals undergo a latent period, during which viral titers increase to detectable and transmissible levels [16]. An exposed individual may become infectious after the latent period and shed virus without showing clinical symptoms; this is referred to as asymptomatic infection. Considering the kinetics of influenza infection in humans [16], we divided the clinical course of infection into three stages: (i) pre-symptomatic infection, (ii) primary stage of symptomatic infection (referred to as the window of opportunity for start of treatment); and (iii) secondary stage of symptomatic infection (Figure 1). The relative transmissibility of the virus at each stage is estimated by superposing a step-function on the log-normal curve fitted to household longitudinal data on influenza viral shedding [1], [17]. Antiviral treatment, as a single containment strategy, may be initiated upon diagnosis of a clinical case within the window of opportunity; however, those who have not started treatment in this window will receive no antiviral therapy during the secondary stage of symptomatic infection. The probability of an individual receiving treatment decreases with the time elapsed since the onset of symptoms, which is reflected in the functional form of the treatment rate with delay in seeking healthcare [8], [15]. We assumed that treatment reduces the infectiousness level of the wild-type disease by 60% (reflected as a reduced transmission rate in the model since initiation of treatment), but has no effect on individuals infected with resistant viruses.


Population-wide emergence of antiviral resistance during pandemic influenza.

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

Model structure for the emergence of drug-resistance during treatment of symptomatic infections.The clinical course of disease is divided into three stages: pre-symptomatic; primary; and secondary stages of symptomatic infections. Drug-resistance with low transmission fitness can emerge during treatment of individuals infected with the wild-type virus. It is assumed that compensatory mutations may result in generation of resistant mutants with high transmission fitness during the secondary stage of treated symptomatic infection. The compartments of untreated and treated individuals infected with the wild-type strain are represented by IU and IT, respectively. The corresponding compartments for the resistant strain with low (high) transmission fitness are denoted by sub-index r (rH).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0001839-g001: Model structure for the emergence of drug-resistance during treatment of symptomatic infections.The clinical course of disease is divided into three stages: pre-symptomatic; primary; and secondary stages of symptomatic infections. Drug-resistance with low transmission fitness can emerge during treatment of individuals infected with the wild-type virus. It is assumed that compensatory mutations may result in generation of resistant mutants with high transmission fitness during the secondary stage of treated symptomatic infection. The compartments of untreated and treated individuals infected with the wild-type strain are represented by IU and IT, respectively. The corresponding compartments for the resistant strain with low (high) transmission fitness are denoted by sub-index r (rH).
Mentions: To develop a population dynamical model, we followed previous work [8], [15] and divided the population into several compartments comprising susceptible, exposed, asymptomatic, and symptomatic infected individuals. In our model, exposed individuals undergo a latent period, during which viral titers increase to detectable and transmissible levels [16]. An exposed individual may become infectious after the latent period and shed virus without showing clinical symptoms; this is referred to as asymptomatic infection. Considering the kinetics of influenza infection in humans [16], we divided the clinical course of infection into three stages: (i) pre-symptomatic infection, (ii) primary stage of symptomatic infection (referred to as the window of opportunity for start of treatment); and (iii) secondary stage of symptomatic infection (Figure 1). The relative transmissibility of the virus at each stage is estimated by superposing a step-function on the log-normal curve fitted to household longitudinal data on influenza viral shedding [1], [17]. Antiviral treatment, as a single containment strategy, may be initiated upon diagnosis of a clinical case within the window of opportunity; however, those who have not started treatment in this window will receive no antiviral therapy during the secondary stage of symptomatic infection. The probability of an individual receiving treatment decreases with the time elapsed since the onset of symptoms, which is reflected in the functional form of the treatment rate with delay in seeking healthcare [8], [15]. We assumed that treatment reduces the infectiousness level of the wild-type disease by 60% (reflected as a reduced transmission rate in the model since initiation of treatment), but has no effect on individuals infected with resistant viruses.

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