Population-Wide Emergence of Antiviral Resistance during Pandemic Influenza 英文参考文献.docVIP

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Population-Wide Emergence of Antiviral Resistance during Pandemic Influenza 英文参考文献.doc

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Population-Wide Emergence of Antiviral Resistance during Pandemic Influenza 英文参考文献

Population-WideEmergenceofAntiviralResistance duringPandemicInfluenza SeyedM.Moghadas1,2*,ChristopherS.Bowman1,3,GergelyRo¨st4,5,JianhongWu5,6 1InstituteforBiodiagnostics,NationalResearchCouncilCanada,Winnipeg,Manitoba,Canada,2DepartmentofMathematicsandStatistics,TheUniversityofWinnipeg, Winnipeg,Manitoba,Canada,3DepartmentofElectricalandComputerEngineering,TheUniversityofManitoba,Winnipeg,Manitoba,Canada,4AnalysisandStochastics ResearchGroup,HungarianAcademyofSciences,BolyaiInstitute,UniversityofSzeged,Szeged,Hungary,5DepartmentofMathematicsandStatistics,YorkUniversity, Toronto,Ontario,Canada,6CentreforDiseaseModelling,YorkInstituteofHealthResearch,YorkUniversity,Toronto,Ontario,Canada Abstract Background:Theemergenceofneuraminidaseinhibitorresistancehasraisedconcernsabouttheprudentuseofantiviral 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 mutationsaffectthespreadofdiseaseinthepopulationcanhaveimportantimplicationsfordevelopingpandemicplans. Methodology/PrincipalFindings:Byemployingadeterministicmathematicalmodel,weinvestigatepossiblescenariosfor theemergenceofpopulation-wideresistanceinthepresenceofantiviraldrugs.Theresultsshowthatifthetreatmentlevel (thefractionofclinicalinfectionswhichreceivestreatment)ismaintainedconstantduringthecourseoftheoutbreak,there isanoptimallevelthatminimizesthefinalsizeofthepandemic.However,aggressivetreatmentabovetheoptimallevelcan substantiallypromotethespreadofhighlytransmissibleresistantmutantsandincreasethetotalnumberofinfections.We demonstrate that resistant outbreaks can occur more readily when the spread of disease is further delayed by applying othercurtailingmeasures,eveniftreatmentlevelsarekeptmodest.However,bychangingtreatmentlevelsoverthecourse of the pandemic, it is possible to reduce the final size of the pandemic below the min