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Antiviral prophylaxis during pandemic influenza may increase drug resistance.

Eichner M, Schwehm M, Duerr HP, Witschi M, Koch D, Brockmann SO, Vidondo B - BMC Infect. Dis. (2009)

Bottom Line: Neuraminidase inhibitors (NI) and social distancing play a major role in plans to mitigate future influenza pandemics.Although NI drug resistance may emerge in treated patients in such a late state of their disease that passing on the newly developed resistant viruses is unlikely, resistant strains quickly become highly prevalent in the population if their fitness is high.The authors show scenarios where pre-exposure antiviral prophylaxis even increases the number of influenza cases and deaths.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Biometry, University of Tübingen, Tübingen, Germany. martin.eichner@uni-tuebingen.de

ABSTRACT

Background: Neuraminidase inhibitors (NI) and social distancing play a major role in plans to mitigate future influenza pandemics.

Methods: Using the freely available program InfluSim, the authors examine to what extent NI-treatment and prophylaxis promote the occurrence and transmission of a NI resistant strain.

Results: Under a basic reproduction number of R0 = 2.5, a NI resistant strain can only spread if its transmissibility (fitness) is at least 40% of the fitness of the drug-sensitive strain. Although NI drug resistance may emerge in treated patients in such a late state of their disease that passing on the newly developed resistant viruses is unlikely, resistant strains quickly become highly prevalent in the population if their fitness is high. Antiviral prophylaxis further increases the pressure on the drug-sensitive strain and favors the spread of resistant infections. The authors show scenarios where pre-exposure antiviral prophylaxis even increases the number of influenza cases and deaths.

Conclusion: If the fitness of a NI resistant pandemic strain is high, any use of prophylaxis may increase the number of hospitalizations and deaths in the population. The use of neuraminidase inhibitors should be restricted to the treatment of cases whereas prophylaxis should be reduced to an absolute minimum in that case.

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Comparison of de novo development of resistance and importation of resistance. Prevalence of infection with drug sensitive (solid curves) and drug resistant infection (dashed curves) during a pandemic wave in a population of 100,000 inhabitants. Scenario (a): a drug-sensitive infection is introduced on day 0; NI resistant infection develops de novo during antiviral treatment of cases throughout the simulation (treatment parameters see Figure 2; no prophylaxis; 100% fitness of the resistant virus; black curves). Scenario (b): the importation of a drug sensitive infection on day 0 is followed by an importation of a NI resistant infection on day 28. Treatment is given as in scenario (a), but no de novo development of resistance occurs within this scenario (grey curves). The resulting curves for Scenario (a) and (b) are nearly indistinguishable.
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Figure 4: Comparison of de novo development of resistance and importation of resistance. Prevalence of infection with drug sensitive (solid curves) and drug resistant infection (dashed curves) during a pandemic wave in a population of 100,000 inhabitants. Scenario (a): a drug-sensitive infection is introduced on day 0; NI resistant infection develops de novo during antiviral treatment of cases throughout the simulation (treatment parameters see Figure 2; no prophylaxis; 100% fitness of the resistant virus; black curves). Scenario (b): the importation of a drug sensitive infection on day 0 is followed by an importation of a NI resistant infection on day 28. Treatment is given as in scenario (a), but no de novo development of resistance occurs within this scenario (grey curves). The resulting curves for Scenario (a) and (b) are nearly indistinguishable.

Mentions: Even in the optimistic scenario where a drug sensitive infection is introduced into a population, de novo development of NI resistance in treated patients and the ensuing spread of resistant infections may lead to an early predominance of a resistant strain (Figs. 2a–c). De novo development of resistance in a person is a stochastic event and would demand for stochastic simulation in order to realistically describe the variability in the timing of such an event. Deterministic models like InfluSim only represent the average course the development of resistance in a population. For sake of simplicity, we have assumed that the development of resistance occurs in one step whereas other authors [18] assume that the first mutation leads to a resistant virus with impaired fitness and that the transmission fitness will gradually improve over time. Once a resistant virus with high fitness spreads in the population, the relatively rare de novo development of resistance in other people can be completely neglected because it is out-weighted by the multiplication of the virus in the population. This is because therapeutic and prophylactic NI use put pressure on the drug sensitive strain and favor the spread of circulating NI resistant infections. Figure 4 demonstrates this by comparing two scenarios: In scenario (a), NI resistance develops de novo by treatment of cases whereas in scenario (b) a NI resistant infection is introduced 4 weeks later, but no de novo development of NI resistance occurs. The resulting curves are nearly indistinguishable, indicating that once a resistant strain of high transmissibility spreads in a population where there is a lot of pressure on drug sensitive infection, any further de novo development of resistance can be neglected. Our calculations show that under widespread treatment, the NI resistant strain spreads faster than the non-resistant one if its fitness exceeds 81%. Prophylaxis will further increase the pressure, leading to a quicker replacement of the drug sensitive strain by the resistant one and increasing the number of unsuccessfully treated patients (Fig. 3a). If the fitness of the resistant virus is between 90 and 100%, prophylaxis even increases the total number of cases (Figs. 2a–c) and hospitalizations (Fig. 3b), and we obtain the counter-intuitive result that the work loss of those people who receive prophylaxis may become larger than without prophylaxis (Fig. 3c). Our simulations assume that a small fraction of the population receives prophylaxis during the whole course of the epidemic whereas individuals are only advised to take prophylaxis for a maximum of six weeks [19]. Another approach would be to split up the group of first responders into subgroups who alternatively receive prophylaxis, but the pressure on the drug sensitive virus exerted by prophylaxis mainly depends on the prophylaxis coverage and does not change much if different people receive the drug at different times. Especially for low prophylaxis coverage, our results should be relatively robust in spite of this over-simplification. Our simulation results confirm other authors' findings which indicate that the benefits of antiviral drug use to control pandemic influenza may be reduced by NI resistance in the virus [5,6]. Our model structure, assumptions and parameter values differ from those reports: we used higher values for R0 and for de novo development of NI resistance than [5], but lower values than [6], and we used a wide range of prophylaxis levels. In contrast to [5] and [6], we found clear detrimental effects of any level of prophylaxis if the relative fitness of the resistant strain is higher than 80% [20,21].


Antiviral prophylaxis during pandemic influenza may increase drug resistance.

Eichner M, Schwehm M, Duerr HP, Witschi M, Koch D, Brockmann SO, Vidondo B - BMC Infect. Dis. (2009)

Comparison of de novo development of resistance and importation of resistance. Prevalence of infection with drug sensitive (solid curves) and drug resistant infection (dashed curves) during a pandemic wave in a population of 100,000 inhabitants. Scenario (a): a drug-sensitive infection is introduced on day 0; NI resistant infection develops de novo during antiviral treatment of cases throughout the simulation (treatment parameters see Figure 2; no prophylaxis; 100% fitness of the resistant virus; black curves). Scenario (b): the importation of a drug sensitive infection on day 0 is followed by an importation of a NI resistant infection on day 28. Treatment is given as in scenario (a), but no de novo development of resistance occurs within this scenario (grey curves). The resulting curves for Scenario (a) and (b) are nearly indistinguishable.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2654456&req=5

Figure 4: Comparison of de novo development of resistance and importation of resistance. Prevalence of infection with drug sensitive (solid curves) and drug resistant infection (dashed curves) during a pandemic wave in a population of 100,000 inhabitants. Scenario (a): a drug-sensitive infection is introduced on day 0; NI resistant infection develops de novo during antiviral treatment of cases throughout the simulation (treatment parameters see Figure 2; no prophylaxis; 100% fitness of the resistant virus; black curves). Scenario (b): the importation of a drug sensitive infection on day 0 is followed by an importation of a NI resistant infection on day 28. Treatment is given as in scenario (a), but no de novo development of resistance occurs within this scenario (grey curves). The resulting curves for Scenario (a) and (b) are nearly indistinguishable.
Mentions: Even in the optimistic scenario where a drug sensitive infection is introduced into a population, de novo development of NI resistance in treated patients and the ensuing spread of resistant infections may lead to an early predominance of a resistant strain (Figs. 2a–c). De novo development of resistance in a person is a stochastic event and would demand for stochastic simulation in order to realistically describe the variability in the timing of such an event. Deterministic models like InfluSim only represent the average course the development of resistance in a population. For sake of simplicity, we have assumed that the development of resistance occurs in one step whereas other authors [18] assume that the first mutation leads to a resistant virus with impaired fitness and that the transmission fitness will gradually improve over time. Once a resistant virus with high fitness spreads in the population, the relatively rare de novo development of resistance in other people can be completely neglected because it is out-weighted by the multiplication of the virus in the population. This is because therapeutic and prophylactic NI use put pressure on the drug sensitive strain and favor the spread of circulating NI resistant infections. Figure 4 demonstrates this by comparing two scenarios: In scenario (a), NI resistance develops de novo by treatment of cases whereas in scenario (b) a NI resistant infection is introduced 4 weeks later, but no de novo development of NI resistance occurs. The resulting curves are nearly indistinguishable, indicating that once a resistant strain of high transmissibility spreads in a population where there is a lot of pressure on drug sensitive infection, any further de novo development of resistance can be neglected. Our calculations show that under widespread treatment, the NI resistant strain spreads faster than the non-resistant one if its fitness exceeds 81%. Prophylaxis will further increase the pressure, leading to a quicker replacement of the drug sensitive strain by the resistant one and increasing the number of unsuccessfully treated patients (Fig. 3a). If the fitness of the resistant virus is between 90 and 100%, prophylaxis even increases the total number of cases (Figs. 2a–c) and hospitalizations (Fig. 3b), and we obtain the counter-intuitive result that the work loss of those people who receive prophylaxis may become larger than without prophylaxis (Fig. 3c). Our simulations assume that a small fraction of the population receives prophylaxis during the whole course of the epidemic whereas individuals are only advised to take prophylaxis for a maximum of six weeks [19]. Another approach would be to split up the group of first responders into subgroups who alternatively receive prophylaxis, but the pressure on the drug sensitive virus exerted by prophylaxis mainly depends on the prophylaxis coverage and does not change much if different people receive the drug at different times. Especially for low prophylaxis coverage, our results should be relatively robust in spite of this over-simplification. Our simulation results confirm other authors' findings which indicate that the benefits of antiviral drug use to control pandemic influenza may be reduced by NI resistance in the virus [5,6]. Our model structure, assumptions and parameter values differ from those reports: we used higher values for R0 and for de novo development of NI resistance than [5], but lower values than [6], and we used a wide range of prophylaxis levels. In contrast to [5] and [6], we found clear detrimental effects of any level of prophylaxis if the relative fitness of the resistant strain is higher than 80% [20,21].

Bottom Line: Neuraminidase inhibitors (NI) and social distancing play a major role in plans to mitigate future influenza pandemics.Although NI drug resistance may emerge in treated patients in such a late state of their disease that passing on the newly developed resistant viruses is unlikely, resistant strains quickly become highly prevalent in the population if their fitness is high.The authors show scenarios where pre-exposure antiviral prophylaxis even increases the number of influenza cases and deaths.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Biometry, University of Tübingen, Tübingen, Germany. martin.eichner@uni-tuebingen.de

ABSTRACT

Background: Neuraminidase inhibitors (NI) and social distancing play a major role in plans to mitigate future influenza pandemics.

Methods: Using the freely available program InfluSim, the authors examine to what extent NI-treatment and prophylaxis promote the occurrence and transmission of a NI resistant strain.

Results: Under a basic reproduction number of R0 = 2.5, a NI resistant strain can only spread if its transmissibility (fitness) is at least 40% of the fitness of the drug-sensitive strain. Although NI drug resistance may emerge in treated patients in such a late state of their disease that passing on the newly developed resistant viruses is unlikely, resistant strains quickly become highly prevalent in the population if their fitness is high. Antiviral prophylaxis further increases the pressure on the drug-sensitive strain and favors the spread of resistant infections. The authors show scenarios where pre-exposure antiviral prophylaxis even increases the number of influenza cases and deaths.

Conclusion: If the fitness of a NI resistant pandemic strain is high, any use of prophylaxis may increase the number of hospitalizations and deaths in the population. The use of neuraminidase inhibitors should be restricted to the treatment of cases whereas prophylaxis should be reduced to an absolute minimum in that case.

Show MeSH
Related in: MedlinePlus