Limits...
Modeling the effects of drug resistant influenza virus in a pandemic.

Brockmann SO, Schwehm M, Duerr HP, Witschi M, Koch D, Vidondo B, Eichner M - Virol. J. (2008)

Bottom Line: If a resistant infection is introduced into the population after three weeks, the outcome dramatically deteriorates.Wide-spread use of NI treatment makes it highly likely that the resistant strain will spread if its fitness is high.This situation is further aggravated if a resistant virus is imported into a country in the early phase of an outbreak.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Epidemiology and Health Reporting, Baden-Württemberg State Health Office, District Government Stuttgart, Germany. stefan.brockmann@rps.bwl.de

ABSTRACT
Neuraminidase inhibitors (NI) play a major role in plans to mitigate future influenza pandemics. Modeling studies suggested that a pandemic may be contained at the source by early treatment and prophylaxis with antiviral drugs. Here, we examine the influence of NI resistant influenza strains on an influenza pandemic. We extend the freely available deterministic simulation program InfluSim to incorporate importations of resistant infections and the emergence of de novo resistance. The epidemic with the fully drug sensitive strain leads to a cumulative number of 19,500 outpatients and 258 hospitalizations, respectively, per 100,000 inhabitants. Development of de novo resistance alone increases the total number of outpatients by about 6% and hospitalizations by about 21%. If a resistant infection is introduced into the population after three weeks, the outcome dramatically deteriorates. Wide-spread use of NI treatment makes it highly likely that the resistant strain will spread if its fitness is high. This situation is further aggravated if a resistant virus is imported into a country in the early phase of an outbreak. As NI-resistant influenza infections with high fitness and pathogenicity have just been observed, the emergence of drug resistance in treated populations and the transmission of drug resistant strains is an important public health concern for seasonal and pandemic influenza.

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Prevalence of infection with the drug sensitive virus (solid lines in black), the drug resistant one (dashed lines) and the sum of both (dotted lines). All cases who seek medical help ('outpatients') receive antiviral treatment. The grey curves indicate the fractions of resistant infections among all infections. In all 3 graphs, resistance develops de novo in 4.1% of children and 0.32% of adults who receive treatment. (a) Drug-sensitive infections are imported on day 0 and 21; (b) Drug sensitive infection is imported on day 0, followed by a drug-resistant one on day 21; (c) Drug resistant infection is imported on day 0, followed by a drug-sensitive one on day 21. Further assumptions: (1) Swiss population of 100,000 individuals. (2) R0 = 2.5 for the drug sensitive and the drug resistant virus. Both strains are assumed to have the same transmissibility. (3) One third of all infected individuals become severely sick and seek medical help. Antiviral treatment reduces their contagiousness by 80% and their duration of sickness by 25% if they are infected with the drug sensitive virus. (4) General social distancing reduces the number of contacts by 10% for all individuals; isolation additionally prevents 10%, 20% and 30% of contacts of moderately sick cases, severely sick cases at home, and hospitalized cases, respectively. For references about assumptions and parameter values see text.
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Figure 1: Prevalence of infection with the drug sensitive virus (solid lines in black), the drug resistant one (dashed lines) and the sum of both (dotted lines). All cases who seek medical help ('outpatients') receive antiviral treatment. The grey curves indicate the fractions of resistant infections among all infections. In all 3 graphs, resistance develops de novo in 4.1% of children and 0.32% of adults who receive treatment. (a) Drug-sensitive infections are imported on day 0 and 21; (b) Drug sensitive infection is imported on day 0, followed by a drug-resistant one on day 21; (c) Drug resistant infection is imported on day 0, followed by a drug-sensitive one on day 21. Further assumptions: (1) Swiss population of 100,000 individuals. (2) R0 = 2.5 for the drug sensitive and the drug resistant virus. Both strains are assumed to have the same transmissibility. (3) One third of all infected individuals become severely sick and seek medical help. Antiviral treatment reduces their contagiousness by 80% and their duration of sickness by 25% if they are infected with the drug sensitive virus. (4) General social distancing reduces the number of contacts by 10% for all individuals; isolation additionally prevents 10%, 20% and 30% of contacts of moderately sick cases, severely sick cases at home, and hospitalized cases, respectively. For references about assumptions and parameter values see text.

Mentions: If a resistant strain emerges only de novo, its prevalence may remain low, implying little epidemiological consequences (Figure 1a). Importation of resistance, however, increasingly replaces the drug sensitive strain because the latter is continuously eliminated by treatment. The dominance of the resistant strain depends on when its importation starts. E. g. if a drug resistant strain is imported 21 days after seeding the epidemic (with a sensitive strain), the prevalence curve for the resistant strain mimics in a delayed shape the prevalence of the sensitive strain (Figure 1b). If the time point for the importation of the resistant strain is shifted towards the initial phase of the epidemic, the resistant strain increasingly replaces the sensitive strain (Figure 1c). Early importation of resistant infection increases the number of treatment failures and thus, increases the overall number of infections emerging from the epidemic (Figure 1a–c). A sensitivity analysis which addresses the influence of the non-pharmaceutical interventions on these results is presented as an additional file (Additional file 1). Figure 2 illustrates the total numbers of (a) outpatients, (b) hospitalizations, and (c) deaths in dependence of a given time delay between the importation of the drug sensitive and the drug resistant infection (0–30 days).


Modeling the effects of drug resistant influenza virus in a pandemic.

Brockmann SO, Schwehm M, Duerr HP, Witschi M, Koch D, Vidondo B, Eichner M - Virol. J. (2008)

Prevalence of infection with the drug sensitive virus (solid lines in black), the drug resistant one (dashed lines) and the sum of both (dotted lines). All cases who seek medical help ('outpatients') receive antiviral treatment. The grey curves indicate the fractions of resistant infections among all infections. In all 3 graphs, resistance develops de novo in 4.1% of children and 0.32% of adults who receive treatment. (a) Drug-sensitive infections are imported on day 0 and 21; (b) Drug sensitive infection is imported on day 0, followed by a drug-resistant one on day 21; (c) Drug resistant infection is imported on day 0, followed by a drug-sensitive one on day 21. Further assumptions: (1) Swiss population of 100,000 individuals. (2) R0 = 2.5 for the drug sensitive and the drug resistant virus. Both strains are assumed to have the same transmissibility. (3) One third of all infected individuals become severely sick and seek medical help. Antiviral treatment reduces their contagiousness by 80% and their duration of sickness by 25% if they are infected with the drug sensitive virus. (4) General social distancing reduces the number of contacts by 10% for all individuals; isolation additionally prevents 10%, 20% and 30% of contacts of moderately sick cases, severely sick cases at home, and hospitalized cases, respectively. For references about assumptions and parameter values see text.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2590604&req=5

Figure 1: Prevalence of infection with the drug sensitive virus (solid lines in black), the drug resistant one (dashed lines) and the sum of both (dotted lines). All cases who seek medical help ('outpatients') receive antiviral treatment. The grey curves indicate the fractions of resistant infections among all infections. In all 3 graphs, resistance develops de novo in 4.1% of children and 0.32% of adults who receive treatment. (a) Drug-sensitive infections are imported on day 0 and 21; (b) Drug sensitive infection is imported on day 0, followed by a drug-resistant one on day 21; (c) Drug resistant infection is imported on day 0, followed by a drug-sensitive one on day 21. Further assumptions: (1) Swiss population of 100,000 individuals. (2) R0 = 2.5 for the drug sensitive and the drug resistant virus. Both strains are assumed to have the same transmissibility. (3) One third of all infected individuals become severely sick and seek medical help. Antiviral treatment reduces their contagiousness by 80% and their duration of sickness by 25% if they are infected with the drug sensitive virus. (4) General social distancing reduces the number of contacts by 10% for all individuals; isolation additionally prevents 10%, 20% and 30% of contacts of moderately sick cases, severely sick cases at home, and hospitalized cases, respectively. For references about assumptions and parameter values see text.
Mentions: If a resistant strain emerges only de novo, its prevalence may remain low, implying little epidemiological consequences (Figure 1a). Importation of resistance, however, increasingly replaces the drug sensitive strain because the latter is continuously eliminated by treatment. The dominance of the resistant strain depends on when its importation starts. E. g. if a drug resistant strain is imported 21 days after seeding the epidemic (with a sensitive strain), the prevalence curve for the resistant strain mimics in a delayed shape the prevalence of the sensitive strain (Figure 1b). If the time point for the importation of the resistant strain is shifted towards the initial phase of the epidemic, the resistant strain increasingly replaces the sensitive strain (Figure 1c). Early importation of resistant infection increases the number of treatment failures and thus, increases the overall number of infections emerging from the epidemic (Figure 1a–c). A sensitivity analysis which addresses the influence of the non-pharmaceutical interventions on these results is presented as an additional file (Additional file 1). Figure 2 illustrates the total numbers of (a) outpatients, (b) hospitalizations, and (c) deaths in dependence of a given time delay between the importation of the drug sensitive and the drug resistant infection (0–30 days).

Bottom Line: If a resistant infection is introduced into the population after three weeks, the outcome dramatically deteriorates.Wide-spread use of NI treatment makes it highly likely that the resistant strain will spread if its fitness is high.This situation is further aggravated if a resistant virus is imported into a country in the early phase of an outbreak.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Epidemiology and Health Reporting, Baden-Württemberg State Health Office, District Government Stuttgart, Germany. stefan.brockmann@rps.bwl.de

ABSTRACT
Neuraminidase inhibitors (NI) play a major role in plans to mitigate future influenza pandemics. Modeling studies suggested that a pandemic may be contained at the source by early treatment and prophylaxis with antiviral drugs. Here, we examine the influence of NI resistant influenza strains on an influenza pandemic. We extend the freely available deterministic simulation program InfluSim to incorporate importations of resistant infections and the emergence of de novo resistance. The epidemic with the fully drug sensitive strain leads to a cumulative number of 19,500 outpatients and 258 hospitalizations, respectively, per 100,000 inhabitants. Development of de novo resistance alone increases the total number of outpatients by about 6% and hospitalizations by about 21%. If a resistant infection is introduced into the population after three weeks, the outcome dramatically deteriorates. Wide-spread use of NI treatment makes it highly likely that the resistant strain will spread if its fitness is high. This situation is further aggravated if a resistant virus is imported into a country in the early phase of an outbreak. As NI-resistant influenza infections with high fitness and pathogenicity have just been observed, the emergence of drug resistance in treated populations and the transmission of drug resistant strains is an important public health concern for seasonal and pandemic influenza.

Show MeSH
Related in: MedlinePlus