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Modeling within-host effects of drugs on Plasmodium falciparum transmission and prospects for malaria elimination
Achieving a theoretical foundation for malaria elimination will require a detailed understanding of the quantitative relationships between patient treatment-seeking behavior, treatment coverage, and the effects of curative therapies that also block Plasmodium parasite transmission to mosquito vector...
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| Published in: | PLoS computational biology 2014-01, Vol.10 (1), p.e1003434-e1003434 |
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| creator | Johnston, Geoffrey L Gething, Peter W Hay, Simon I Smith, David L Fidock, David A |
| description | Achieving a theoretical foundation for malaria elimination will require a detailed understanding of the quantitative relationships between patient treatment-seeking behavior, treatment coverage, and the effects of curative therapies that also block Plasmodium parasite transmission to mosquito vectors. Here, we report a mechanistic, within-host mathematical model that uses pharmacokinetic (PK) and pharmacodynamic (PD) data to simulate the effects of artemisinin-based combination therapies (ACTs) on Plasmodium falciparum transmission. To contextualize this model, we created a set of global maps of the fold reductions that would be necessary to reduce the malaria R C (i.e. its basic reproductive number under control) to below 1 and thus interrupt transmission. This modeling was applied to low-transmission settings, defined as having a R 0 |
| doi_str_mv | 10.1371/journal.pcbi.1003434 |
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Here, we report a mechanistic, within-host mathematical model that uses pharmacokinetic (PK) and pharmacodynamic (PD) data to simulate the effects of artemisinin-based combination therapies (ACTs) on Plasmodium falciparum transmission. To contextualize this model, we created a set of global maps of the fold reductions that would be necessary to reduce the malaria R C (i.e. its basic reproductive number under control) to below 1 and thus interrupt transmission. This modeling was applied to low-transmission settings, defined as having a R 0<10 based on 2010 data. Our modeling predicts that treating 93-98% of symptomatic infections with an ACT within five days of fever onset would interrupt malaria transmission for ∼91% of the at-risk population of Southeast Asia and ∼74% of the global at-risk population, and lead these populations towards malaria elimination. This level of treatment coverage corresponds to an estimated 81-85% of all infected individuals in these settings. At this coverage level with ACTs, the addition of the gametocytocidal agent primaquine affords no major gains in transmission reduction. Indeed, we estimate that it would require switching ∼180 people from ACTs to ACTs plus primaquine to achieve the same transmission reduction as switching a single individual from untreated to treated with ACTs. Our model thus predicts that the addition of gametocytocidal drugs to treatment regimens provides very small population-wide benefits and that the focus of control efforts in Southeast Asia should be on increasing prompt ACT coverage. Prospects for elimination in much of Sub-Saharan Africa appear far less favorable currently, due to high rates of infection and less frequent and less rapid treatment.</description><identifier>ISSN: 1553-7358</identifier><identifier>ISSN: 1553-734X</identifier><identifier>EISSN: 1553-7358</identifier><identifier>DOI: 10.1371/journal.pcbi.1003434</identifier><identifier>PMID: 24465196</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Algorithms ; Animals ; Antimalarials ; Antimalarials - pharmacology ; Asia, Southeastern ; Biology ; Communicable Disease Control ; Computer Simulation ; Culicidae ; Disease transmission ; Dosage and administration ; Drug therapy ; Geography ; Health aspects ; Host-parasite relationships ; Humans ; Infections ; Malaria ; Malaria, Falciparum - drug therapy ; Malaria, Falciparum - parasitology ; Malaria, Falciparum - transmission ; Mathematical models ; Mathematics ; Medical research ; Medicine, Experimental ; Models, Theoretical ; Mortality ; Mosquitoes ; Plasmodium falciparum ; Plasmodium falciparum - drug effects ; Population ; Prevention ; Scholarships & fellowships ; Software</subject><ispartof>PLoS computational biology, 2014-01, Vol.10 (1), p.e1003434-e1003434</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Johnston et al</rights><rights>2014 Johnston et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Johnston GL, Gething PW, Hay SI, Smith DL, Fidock DA (2014) Modeling Within-Host Effects of Drugs on Plasmodium falciparum Transmission and Prospects for Malaria Elimination. 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Here, we report a mechanistic, within-host mathematical model that uses pharmacokinetic (PK) and pharmacodynamic (PD) data to simulate the effects of artemisinin-based combination therapies (ACTs) on Plasmodium falciparum transmission. To contextualize this model, we created a set of global maps of the fold reductions that would be necessary to reduce the malaria R C (i.e. its basic reproductive number under control) to below 1 and thus interrupt transmission. This modeling was applied to low-transmission settings, defined as having a R 0<10 based on 2010 data. Our modeling predicts that treating 93-98% of symptomatic infections with an ACT within five days of fever onset would interrupt malaria transmission for ∼91% of the at-risk population of Southeast Asia and ∼74% of the global at-risk population, and lead these populations towards malaria elimination. This level of treatment coverage corresponds to an estimated 81-85% of all infected individuals in these settings. At this coverage level with ACTs, the addition of the gametocytocidal agent primaquine affords no major gains in transmission reduction. Indeed, we estimate that it would require switching ∼180 people from ACTs to ACTs plus primaquine to achieve the same transmission reduction as switching a single individual from untreated to treated with ACTs. Our model thus predicts that the addition of gametocytocidal drugs to treatment regimens provides very small population-wide benefits and that the focus of control efforts in Southeast Asia should be on increasing prompt ACT coverage. Prospects for elimination in much of Sub-Saharan Africa appear far less favorable currently, due to high rates of infection and less frequent and less rapid treatment.</description><subject>Algorithms</subject><subject>Animals</subject><subject>Antimalarials</subject><subject>Antimalarials - pharmacology</subject><subject>Asia, Southeastern</subject><subject>Biology</subject><subject>Communicable Disease Control</subject><subject>Computer Simulation</subject><subject>Culicidae</subject><subject>Disease transmission</subject><subject>Dosage and administration</subject><subject>Drug therapy</subject><subject>Geography</subject><subject>Health aspects</subject><subject>Host-parasite relationships</subject><subject>Humans</subject><subject>Infections</subject><subject>Malaria</subject><subject>Malaria, Falciparum - drug therapy</subject><subject>Malaria, Falciparum - parasitology</subject><subject>Malaria, Falciparum - transmission</subject><subject>Mathematical models</subject><subject>Mathematics</subject><subject>Medical research</subject><subject>Medicine, Experimental</subject><subject>Models, Theoretical</subject><subject>Mortality</subject><subject>Mosquitoes</subject><subject>Plasmodium falciparum</subject><subject>Plasmodium falciparum - drug effects</subject><subject>Population</subject><subject>Prevention</subject><subject>Scholarships & fellowships</subject><subject>Software</subject><issn>1553-7358</issn><issn>1553-734X</issn><issn>1553-7358</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>DOA</sourceid><recordid>eNqVkktv1DAUhSMEoqXwDxBEYgOLGezY8WODVFU8RioP8Vhbju1kXCV2aic8_j03M9OqI7FBWeTK_s7x1b2nKJ5itMaE49dXcU5B9-vRNH6NESKU0HvFKa5rsuKkFvfv1CfFo5yvgKmFZA-Lk4pSVmPJTovrj9G63oeu_OWnrQ-rbcxT6drWmSmXsS1tmjsoQvml13mI1s9D2ere-FEnKKekQx58zh4QHWw5ppjHnbiNqRx0r5PXJTwx-KAnoB4XD0Cf3ZPD_6z48e7t94sPq8vP7zcX55crwwiZVoRp3iBsBW04ldjxxmGOhRQa6VpSZBGlVavr2vC6Qs5WFAsHN5JTLSxy5Kx4vvcd-5jVYVpZYSoFkZQQDMRmT9ior9SY_KDTHxW1V7uDmDql0-RN7xTHjDcEM1S1jCIhJJGyEdRw0vCamsXrzeG1uRmcNS7AZPoj0-Ob4Leqiz8VkbAWLsHg5cEgxevZ5UnBVI3rex1cnHd9V0xwwhb0xR7tNLTmQxvB0Sy4OicMlg6bXTpa_4OCz7rBmxhc6-H8SPDqSADM5H5PnZ5zVptvX_-D_XTM0j1rIBo5ufZ2KhipJco3y1FLlNUhyiB7dneit6Kb7JK_sH3v3g</recordid><startdate>20140101</startdate><enddate>20140101</enddate><creator>Johnston, Geoffrey L</creator><creator>Gething, Peter W</creator><creator>Hay, Simon I</creator><creator>Smith, David L</creator><creator>Fidock, David A</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>ISN</scope><scope>ISR</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20140101</creationdate><title>Modeling within-host effects of drugs on Plasmodium falciparum transmission and prospects for malaria elimination</title><author>Johnston, Geoffrey L ; Gething, Peter W ; Hay, Simon I ; Smith, David L ; Fidock, David A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c633t-36a7b01d84b7491e7be171898a0a5940d0442fa55c7520ed2418ea59974a8d0e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Algorithms</topic><topic>Animals</topic><topic>Antimalarials</topic><topic>Antimalarials - pharmacology</topic><topic>Asia, Southeastern</topic><topic>Biology</topic><topic>Communicable Disease Control</topic><topic>Computer Simulation</topic><topic>Culicidae</topic><topic>Disease transmission</topic><topic>Dosage and administration</topic><topic>Drug therapy</topic><topic>Geography</topic><topic>Health aspects</topic><topic>Host-parasite relationships</topic><topic>Humans</topic><topic>Infections</topic><topic>Malaria</topic><topic>Malaria, Falciparum - drug therapy</topic><topic>Malaria, Falciparum - parasitology</topic><topic>Malaria, Falciparum - transmission</topic><topic>Mathematical models</topic><topic>Mathematics</topic><topic>Medical research</topic><topic>Medicine, Experimental</topic><topic>Models, Theoretical</topic><topic>Mortality</topic><topic>Mosquitoes</topic><topic>Plasmodium falciparum</topic><topic>Plasmodium falciparum - drug effects</topic><topic>Population</topic><topic>Prevention</topic><topic>Scholarships & fellowships</topic><topic>Software</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Johnston, Geoffrey L</creatorcontrib><creatorcontrib>Gething, Peter W</creatorcontrib><creatorcontrib>Hay, Simon I</creatorcontrib><creatorcontrib>Smith, David L</creatorcontrib><creatorcontrib>Fidock, David A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS computational biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Johnston, Geoffrey L</au><au>Gething, Peter W</au><au>Hay, Simon I</au><au>Smith, David L</au><au>Fidock, David A</au><au>Ferguson, Neil M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Modeling within-host effects of drugs on Plasmodium falciparum transmission and prospects for malaria elimination</atitle><jtitle>PLoS computational biology</jtitle><addtitle>PLoS Comput Biol</addtitle><date>2014-01-01</date><risdate>2014</risdate><volume>10</volume><issue>1</issue><spage>e1003434</spage><epage>e1003434</epage><pages>e1003434-e1003434</pages><issn>1553-7358</issn><issn>1553-734X</issn><eissn>1553-7358</eissn><abstract>Achieving a theoretical foundation for malaria elimination will require a detailed understanding of the quantitative relationships between patient treatment-seeking behavior, treatment coverage, and the effects of curative therapies that also block Plasmodium parasite transmission to mosquito vectors. Here, we report a mechanistic, within-host mathematical model that uses pharmacokinetic (PK) and pharmacodynamic (PD) data to simulate the effects of artemisinin-based combination therapies (ACTs) on Plasmodium falciparum transmission. To contextualize this model, we created a set of global maps of the fold reductions that would be necessary to reduce the malaria R C (i.e. its basic reproductive number under control) to below 1 and thus interrupt transmission. This modeling was applied to low-transmission settings, defined as having a R 0<10 based on 2010 data. Our modeling predicts that treating 93-98% of symptomatic infections with an ACT within five days of fever onset would interrupt malaria transmission for ∼91% of the at-risk population of Southeast Asia and ∼74% of the global at-risk population, and lead these populations towards malaria elimination. This level of treatment coverage corresponds to an estimated 81-85% of all infected individuals in these settings. At this coverage level with ACTs, the addition of the gametocytocidal agent primaquine affords no major gains in transmission reduction. Indeed, we estimate that it would require switching ∼180 people from ACTs to ACTs plus primaquine to achieve the same transmission reduction as switching a single individual from untreated to treated with ACTs. Our model thus predicts that the addition of gametocytocidal drugs to treatment regimens provides very small population-wide benefits and that the focus of control efforts in Southeast Asia should be on increasing prompt ACT coverage. Prospects for elimination in much of Sub-Saharan Africa appear far less favorable currently, due to high rates of infection and less frequent and less rapid treatment.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24465196</pmid><doi>10.1371/journal.pcbi.1003434</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Algorithms Animals Antimalarials Antimalarials - pharmacology Asia, Southeastern Biology Communicable Disease Control Computer Simulation Culicidae Disease transmission Dosage and administration Drug therapy Geography Health aspects Host-parasite relationships Humans Infections Malaria Malaria, Falciparum - drug therapy Malaria, Falciparum - parasitology Malaria, Falciparum - transmission Mathematical models Mathematics Medical research Medicine, Experimental Models, Theoretical Mortality Mosquitoes Plasmodium falciparum Plasmodium falciparum - drug effects Population Prevention Scholarships & fellowships Software |
| title | Modeling within-host effects of drugs on Plasmodium falciparum transmission and prospects for malaria elimination |
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