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Article: Hedging against antiviral resistance during the next influenza pandemic using small stockpiles of an alternative chemotherapy

TitleHedging against antiviral resistance during the next influenza pandemic using small stockpiles of an alternative chemotherapy
Authors
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
Citation
Plos Medicine, 2009, v. 6 n. 5 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/60300
ISSN
2023 Impact Factor: 10.5
2023 SCImago Journal Rankings: 4.198
ISI Accession Number ID
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.

References

 

DC FieldValueLanguage
dc.contributor.authorWu, JTen_HK
dc.contributor.authorLeung, GMen_HK
dc.contributor.authorLipsitch, Men_HK
dc.contributor.authorCooper, BSen_HK
dc.contributor.authorRiley, Sen_HK
dc.date.accessioned2010-05-31T04:07:51Z-
dc.date.available2010-05-31T04:07:51Z-
dc.date.issued2009en_HK
dc.identifier.citationPlos Medicine, 2009, v. 6 n. 5en_HK
dc.identifier.issn1549-1277en_HK
dc.identifier.urihttp://hdl.handle.net/10722/60300-
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.en_HK
dc.languageengen_HK
dc.publisherPublic Library of Science. The Journal's web site is located at http://medicine.plosjournals.org/perlserv/?request=index-html&issn=1549-1676en_HK
dc.relation.ispartofPLoS Medicineen_HK
dc.titleHedging against antiviral resistance during the next influenza pandemic using small stockpiles of an alternative chemotherapyen_HK
dc.typeArticleen_HK
dc.identifier.emailWu, JT:joewu@hkucc.hku.hken_HK
dc.identifier.emailLeung, GM:gmleung@hku.hken_HK
dc.identifier.emailRiley, S:sriley@hkucc.hku.hk, steven.riley@hku.hken_HK
dc.identifier.authorityWu, JT=rp00517en_HK
dc.identifier.authorityLeung, GM=rp00460en_HK
dc.identifier.authorityRiley, S=rp00511en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1371/journal.pmed.1000085en_HK
dc.identifier.pmid19440354-
dc.identifier.scopuseid_2-s2.0-66349121943en_HK
dc.identifier.hkuros156035en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-66349121943&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume6en_HK
dc.identifier.issue5en_HK
dc.identifier.isiWOS:000267084100011-
dc.publisher.placeUnited Statesen_HK
dc.identifier.f10001159352-
dc.identifier.scopusauthoridWu, JT=7409256423en_HK
dc.identifier.scopusauthoridLeung, GM=7007159841en_HK
dc.identifier.scopusauthoridLipsitch, M=7006236353en_HK
dc.identifier.scopusauthoridCooper, BS=7401623515en_HK
dc.identifier.scopusauthoridRiley, S=7102619416en_HK
dc.identifier.citeulike9558359-
dc.identifier.issnl1549-1277-

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