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Article: Hedging against antiviral resistance during the next influenza pandemic using small stockpiles of an alternative chemotherapy
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TitleHedging against antiviral resistance during the next influenza pandemic using small stockpiles of an alternative chemotherapy
 
AuthorsWu, JT1
Leung, GM1
Lipsitch, M2
Cooper, BS3
Riley, S1
 
Issue Date2009
 
PublisherPublic Library of Science. The Journal's web site is located at http://medicine.plosjournals.org/perlserv/?request=index-html&issn=1549-1676
 
CitationPlos Medicine, 2009, v. 6 n. 5 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pmed.1000085
 
AbstractBackground: The effectiveness of single-drug antiviral interventions to reduce morbidity and mortality during the next influenza pandemic will be substantially weakened if transmissible strains emerge which are resistant to the stockpiled antiviral drugs. We developed a mathematical model to test the hypothesis that a small stockpile of a secondary antiviral drug could be used to mitigate the adverse consequences of the emergence of resistant strains. Methods and Findings: We used a multistrain stochastic transmission model of influenza to show that the spread of antiviral resistance can be significantly reduced by deploying a small stockpile (1% population coverage) of a secondary drug during the early phase of local epidemics. We considered two strategies for the use of the secondary stockpile: early combination chemotherapy (ECC; individuals are treated with both drugs in combination while both are available); and sequential multidrug chemotherapy (SMC; individuals are treated only with the secondary drug until it is exhausted, then treated with the primary drug). We investigated all potentially important regions of unknown parameter space and found that both ECC and SMC reduced the cumulative attack rate (AR) and the resistant attack rate (RAR) unless the probability of emergence of resistance to the primary drug pA was so low (less than 1 in 10,000) that resistance was unlikely to be a problem or so high (more than 1 in 20) that resistance emerged as soon as primary drug monotherapy began. For example, when the basic reproductive number was 1.8 and 40% of symptomatic individuals were treated with antivirals, AR and RAR were 67% and 38% under monotherapy if pA = 0.01. If the probability of resistance emergence for the secondary drug was also 0.01, then SMC reduced AR and RAR to 57% and 2%. The effectiveness of ECC was similar if combination chemotherapy reduced the probabilities of resistance emergence by at least ten times. We extended our model using travel data between 105 large cities to investigate the robustness of these resistance-limiting strategies at a global scale. We found that as long as populations that were the main source of resistant strains employed these strategies (SMC or ECC), then those same strategies were also effective for populations far from the source even when some intermediate populations failed to control resistance. In essence, through the existence of many wild-type epidemics, the interconnectedness of the global network dampened the international spread of resistant strains. Conclusions:Our results indicate that the augmentation of existing stockpiles of a single anti-influenza drug with smaller stockpiles of a second drug could be an effective and inexpensive epidemiological hedge against antiviral resistance if either SMC or ECC were used. Choosing between these strategies will require additional empirical studies. Specifically, the choice will depend on the safety of combination therapy and the synergistic effect of one antiviral in suppressing the emergence of resistance to the other antiviral when both are taken in combination. © 2009 Wu et al.
 
ISSN1549-1277
 
DOIhttp://dx.doi.org/10.1371/journal.pmed.1000085
 
ISI Accession Number IDWOS:000267084100011
Funding AgencyGrant Number
Hong Kong SAR Government
University of Hong Kong SARS Research Fund
EU Sixth Framework ProgrammeSP22-CT-2004-511066
Area of Excellence Scheme of the Hong Kong University Grants CommitteeAoE/M12/06
US National Institutes of Health MIDAS5U01GM076497
Fogarty International Center RAPIDD Program
Funding Information:

We thank the following for research funding: The Research Fund for the Control of Infectious Diseases of the Health, Welfare and Food Bureau of the Hong Kong SAR Government (JTW, GML, SR); The University of Hong Kong SARS Research Fund (GML, SR); the EU Sixth Framework Programme for research for policy support, contract SP22-CT-2004-511066 (JTW, GML, SR); the Area of Excellence Scheme of the Hong Kong University Grants Committee, grant no. AoE/M12/06 (JTW, GML, SR); and US National Institutes of Health MIDAS cooperative agreement 5U01GM076497 (JTW, GML, ML, SR). SR would like to acknowledge funding support from the Fogarty International Center RAPIDD Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorWu, JT
 
dc.contributor.authorLeung, GM
 
dc.contributor.authorLipsitch, M
 
dc.contributor.authorCooper, BS
 
dc.contributor.authorRiley, S
 
dc.date.accessioned2010-05-31T04:07:51Z
 
dc.date.available2010-05-31T04:07:51Z
 
dc.date.issued2009
 
dc.description.abstractBackground: The effectiveness of single-drug antiviral interventions to reduce morbidity and mortality during the next influenza pandemic will be substantially weakened if transmissible strains emerge which are resistant to the stockpiled antiviral drugs. We developed a mathematical model to test the hypothesis that a small stockpile of a secondary antiviral drug could be used to mitigate the adverse consequences of the emergence of resistant strains. Methods and Findings: We used a multistrain stochastic transmission model of influenza to show that the spread of antiviral resistance can be significantly reduced by deploying a small stockpile (1% population coverage) of a secondary drug during the early phase of local epidemics. We considered two strategies for the use of the secondary stockpile: early combination chemotherapy (ECC; individuals are treated with both drugs in combination while both are available); and sequential multidrug chemotherapy (SMC; individuals are treated only with the secondary drug until it is exhausted, then treated with the primary drug). We investigated all potentially important regions of unknown parameter space and found that both ECC and SMC reduced the cumulative attack rate (AR) and the resistant attack rate (RAR) unless the probability of emergence of resistance to the primary drug pA was so low (less than 1 in 10,000) that resistance was unlikely to be a problem or so high (more than 1 in 20) that resistance emerged as soon as primary drug monotherapy began. For example, when the basic reproductive number was 1.8 and 40% of symptomatic individuals were treated with antivirals, AR and RAR were 67% and 38% under monotherapy if pA = 0.01. If the probability of resistance emergence for the secondary drug was also 0.01, then SMC reduced AR and RAR to 57% and 2%. The effectiveness of ECC was similar if combination chemotherapy reduced the probabilities of resistance emergence by at least ten times. We extended our model using travel data between 105 large cities to investigate the robustness of these resistance-limiting strategies at a global scale. We found that as long as populations that were the main source of resistant strains employed these strategies (SMC or ECC), then those same strategies were also effective for populations far from the source even when some intermediate populations failed to control resistance. In essence, through the existence of many wild-type epidemics, the interconnectedness of the global network dampened the international spread of resistant strains. Conclusions:Our results indicate that the augmentation of existing stockpiles of a single anti-influenza drug with smaller stockpiles of a second drug could be an effective and inexpensive epidemiological hedge against antiviral resistance if either SMC or ECC were used. Choosing between these strategies will require additional empirical studies. Specifically, the choice will depend on the safety of combination therapy and the synergistic effect of one antiviral in suppressing the emergence of resistance to the other antiviral when both are taken in combination. © 2009 Wu et al.
 
dc.description.naturelink_to_subscribed_fulltext
 
dc.identifier.citationPlos Medicine, 2009, v. 6 n. 5 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pmed.1000085
 
dc.identifier.citeulike9558359
 
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pmed.1000085
 
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dc.identifier.isiWOS:000267084100011
Funding AgencyGrant Number
Hong Kong SAR Government
University of Hong Kong SARS Research Fund
EU Sixth Framework ProgrammeSP22-CT-2004-511066
Area of Excellence Scheme of the Hong Kong University Grants CommitteeAoE/M12/06
US National Institutes of Health MIDAS5U01GM076497
Fogarty International Center RAPIDD Program
Funding Information:

We thank the following for research funding: The Research Fund for the Control of Infectious Diseases of the Health, Welfare and Food Bureau of the Hong Kong SAR Government (JTW, GML, SR); The University of Hong Kong SARS Research Fund (GML, SR); the EU Sixth Framework Programme for research for policy support, contract SP22-CT-2004-511066 (JTW, GML, SR); the Area of Excellence Scheme of the Hong Kong University Grants Committee, grant no. AoE/M12/06 (JTW, GML, SR); and US National Institutes of Health MIDAS cooperative agreement 5U01GM076497 (JTW, GML, ML, SR). SR would like to acknowledge funding support from the Fogarty International Center RAPIDD Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

 
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dc.identifier.urihttp://hdl.handle.net/10722/60300
 
dc.identifier.volume6
 
dc.languageeng
 
dc.publisherPublic Library of Science. The Journal's web site is located at http://medicine.plosjournals.org/perlserv/?request=index-html&issn=1549-1676
 
dc.publisher.placeUnited States
 
dc.relation.ispartofPLoS Medicine
 
dc.relation.referencesReferences in Scopus
 
dc.titleHedging against antiviral resistance during the next influenza pandemic using small stockpiles of an alternative chemotherapy
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine
  2. Harvard School of Public Health
  3. Health Protection Agency