Optimum population-level use of artemisinin combination therapies

A modelling study

Tran Dang Nguyen, Piero Olliaro, Arjen M. Dondorp, J. Kevin Baird, Ha Minh Lam, Jeremy Farrar, Guy E. Thwaites, Nicholas J. White, Maciej F. Boni

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Background: Artemisinin combination therapies (ACTs) are used worldwide as first-line treatment against confirmed or suspected Plasmodium falciparum malaria. Despite the success of ACTs at reducing the global burden of malaria, emerging resistance to artemisinin threatens these gains. Countering onset of resistance might need deliberate tactics aimed at slowing the reduction in ACT effectiveness. We assessed optimum use of ACTs at the population level, specifically focusing on a strategy of multiple first-line therapies (MFT), and comparing it with strategies of cycling or sequential use of single first-line ACTs. Methods: With an individual-based microsimulation of regional malaria transmission, we looked at how to apply a therapy as widely as possible without accelerating reduction of efficacy by drug resistance. We compared simultaneous distribution of artemether-lumefantrine, artesunate-amodiaquine, and dihydroartemisinin-piperaquine (ie, MFT) against strategies in which these ACTs would be cycled or used sequentially, either on a fixed schedule or when population-level efficacy reaches the WHO threshold of 10% treatment failure. The main assessment criterion was total number of treatment failures per 100 people per year. Additionally, we analysed the benefits of including a single non-ACT therapy in an MFT strategy, and did sensitivity analyses in which we varied transmission setting, treatment coverage, partner-drug half-life, fitness cost of drug resistance, and the relation between drug concentration and resistance evolution. Findings: Use of MFT was predicted to reduce the long-term number of treatment failures compared with strategies in which a single first-line ACT is recommended. This result was robust to various epidemiological, pharmacological, and evolutionary features of malaria transmission. Inclusion of a single non-ACT therapy in an MFT strategy would have substantial benefits in reduction of pressure on artemisinin resistance evolution, delaying its emergence and slowing its spread. Interpretation: Adjusting national antimalarial treatment guidelines to encourage simultaneous use of MFT is likely to extend the useful therapeutic life of available antimalarial drugs, resulting in long-term beneficial outcomes for patients. Funding: Wellcome Trust, UK Medical Research Council, Li Ka Shing Foundation.

Original languageEnglish (US)
Pages (from-to)e758-e766
JournalThe Lancet Global Health
Volume3
Issue number12
DOIs
StatePublished - Dec 1 2015

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Population Dynamics
Therapeutics
artemisinine
Treatment Failure
Drug Resistance
Malaria
dihydroartemisinin
Antimalarials
Falciparum Malaria

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Nguyen, Tran Dang ; Olliaro, Piero ; Dondorp, Arjen M. ; Baird, J. Kevin ; Lam, Ha Minh ; Farrar, Jeremy ; Thwaites, Guy E. ; White, Nicholas J. ; Boni, Maciej F. / Optimum population-level use of artemisinin combination therapies : A modelling study. In: The Lancet Global Health. 2015 ; Vol. 3, No. 12. pp. e758-e766.
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abstract = "Background: Artemisinin combination therapies (ACTs) are used worldwide as first-line treatment against confirmed or suspected Plasmodium falciparum malaria. Despite the success of ACTs at reducing the global burden of malaria, emerging resistance to artemisinin threatens these gains. Countering onset of resistance might need deliberate tactics aimed at slowing the reduction in ACT effectiveness. We assessed optimum use of ACTs at the population level, specifically focusing on a strategy of multiple first-line therapies (MFT), and comparing it with strategies of cycling or sequential use of single first-line ACTs. Methods: With an individual-based microsimulation of regional malaria transmission, we looked at how to apply a therapy as widely as possible without accelerating reduction of efficacy by drug resistance. We compared simultaneous distribution of artemether-lumefantrine, artesunate-amodiaquine, and dihydroartemisinin-piperaquine (ie, MFT) against strategies in which these ACTs would be cycled or used sequentially, either on a fixed schedule or when population-level efficacy reaches the WHO threshold of 10{\%} treatment failure. The main assessment criterion was total number of treatment failures per 100 people per year. Additionally, we analysed the benefits of including a single non-ACT therapy in an MFT strategy, and did sensitivity analyses in which we varied transmission setting, treatment coverage, partner-drug half-life, fitness cost of drug resistance, and the relation between drug concentration and resistance evolution. Findings: Use of MFT was predicted to reduce the long-term number of treatment failures compared with strategies in which a single first-line ACT is recommended. This result was robust to various epidemiological, pharmacological, and evolutionary features of malaria transmission. Inclusion of a single non-ACT therapy in an MFT strategy would have substantial benefits in reduction of pressure on artemisinin resistance evolution, delaying its emergence and slowing its spread. Interpretation: Adjusting national antimalarial treatment guidelines to encourage simultaneous use of MFT is likely to extend the useful therapeutic life of available antimalarial drugs, resulting in long-term beneficial outcomes for patients. Funding: Wellcome Trust, UK Medical Research Council, Li Ka Shing Foundation.",
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Nguyen, TD, Olliaro, P, Dondorp, AM, Baird, JK, Lam, HM, Farrar, J, Thwaites, GE, White, NJ & Boni, MF 2015, 'Optimum population-level use of artemisinin combination therapies: A modelling study', The Lancet Global Health, vol. 3, no. 12, pp. e758-e766. https://doi.org/10.1016/S2214-109X(15)00162-X

Optimum population-level use of artemisinin combination therapies : A modelling study. / Nguyen, Tran Dang; Olliaro, Piero; Dondorp, Arjen M.; Baird, J. Kevin; Lam, Ha Minh; Farrar, Jeremy; Thwaites, Guy E.; White, Nicholas J.; Boni, Maciej F.

In: The Lancet Global Health, Vol. 3, No. 12, 01.12.2015, p. e758-e766.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Optimum population-level use of artemisinin combination therapies

T2 - A modelling study

AU - Nguyen, Tran Dang

AU - Olliaro, Piero

AU - Dondorp, Arjen M.

AU - Baird, J. Kevin

AU - Lam, Ha Minh

AU - Farrar, Jeremy

AU - Thwaites, Guy E.

AU - White, Nicholas J.

AU - Boni, Maciej F.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - Background: Artemisinin combination therapies (ACTs) are used worldwide as first-line treatment against confirmed or suspected Plasmodium falciparum malaria. Despite the success of ACTs at reducing the global burden of malaria, emerging resistance to artemisinin threatens these gains. Countering onset of resistance might need deliberate tactics aimed at slowing the reduction in ACT effectiveness. We assessed optimum use of ACTs at the population level, specifically focusing on a strategy of multiple first-line therapies (MFT), and comparing it with strategies of cycling or sequential use of single first-line ACTs. Methods: With an individual-based microsimulation of regional malaria transmission, we looked at how to apply a therapy as widely as possible without accelerating reduction of efficacy by drug resistance. We compared simultaneous distribution of artemether-lumefantrine, artesunate-amodiaquine, and dihydroartemisinin-piperaquine (ie, MFT) against strategies in which these ACTs would be cycled or used sequentially, either on a fixed schedule or when population-level efficacy reaches the WHO threshold of 10% treatment failure. The main assessment criterion was total number of treatment failures per 100 people per year. Additionally, we analysed the benefits of including a single non-ACT therapy in an MFT strategy, and did sensitivity analyses in which we varied transmission setting, treatment coverage, partner-drug half-life, fitness cost of drug resistance, and the relation between drug concentration and resistance evolution. Findings: Use of MFT was predicted to reduce the long-term number of treatment failures compared with strategies in which a single first-line ACT is recommended. This result was robust to various epidemiological, pharmacological, and evolutionary features of malaria transmission. Inclusion of a single non-ACT therapy in an MFT strategy would have substantial benefits in reduction of pressure on artemisinin resistance evolution, delaying its emergence and slowing its spread. Interpretation: Adjusting national antimalarial treatment guidelines to encourage simultaneous use of MFT is likely to extend the useful therapeutic life of available antimalarial drugs, resulting in long-term beneficial outcomes for patients. Funding: Wellcome Trust, UK Medical Research Council, Li Ka Shing Foundation.

AB - Background: Artemisinin combination therapies (ACTs) are used worldwide as first-line treatment against confirmed or suspected Plasmodium falciparum malaria. Despite the success of ACTs at reducing the global burden of malaria, emerging resistance to artemisinin threatens these gains. Countering onset of resistance might need deliberate tactics aimed at slowing the reduction in ACT effectiveness. We assessed optimum use of ACTs at the population level, specifically focusing on a strategy of multiple first-line therapies (MFT), and comparing it with strategies of cycling or sequential use of single first-line ACTs. Methods: With an individual-based microsimulation of regional malaria transmission, we looked at how to apply a therapy as widely as possible without accelerating reduction of efficacy by drug resistance. We compared simultaneous distribution of artemether-lumefantrine, artesunate-amodiaquine, and dihydroartemisinin-piperaquine (ie, MFT) against strategies in which these ACTs would be cycled or used sequentially, either on a fixed schedule or when population-level efficacy reaches the WHO threshold of 10% treatment failure. The main assessment criterion was total number of treatment failures per 100 people per year. Additionally, we analysed the benefits of including a single non-ACT therapy in an MFT strategy, and did sensitivity analyses in which we varied transmission setting, treatment coverage, partner-drug half-life, fitness cost of drug resistance, and the relation between drug concentration and resistance evolution. Findings: Use of MFT was predicted to reduce the long-term number of treatment failures compared with strategies in which a single first-line ACT is recommended. This result was robust to various epidemiological, pharmacological, and evolutionary features of malaria transmission. Inclusion of a single non-ACT therapy in an MFT strategy would have substantial benefits in reduction of pressure on artemisinin resistance evolution, delaying its emergence and slowing its spread. Interpretation: Adjusting national antimalarial treatment guidelines to encourage simultaneous use of MFT is likely to extend the useful therapeutic life of available antimalarial drugs, resulting in long-term beneficial outcomes for patients. Funding: Wellcome Trust, UK Medical Research Council, Li Ka Shing Foundation.

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