title: Optimum population-level use of artemisinin combination therapies: a modelling study.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Wellcome Trust, UK Medical Research Council, Li Ka Shing Foundation.
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam.
authors.forename: Tran Dang
authors.initials: TD
authors.lastname: Nguyen
authors.affiliation: University of Oxford, Oxford, UK.
authors.forename: Piero
authors.initials: P
authors.lastname: Olliaro
authors.affiliation: University of Oxford, Oxford, UK; Mahidol-Oxford Research Unit, Wellcome Trust Major Overseas Programme, Bangkok, Thailand.
authors.forename: Arjen M
authors.initials: AM
authors.lastname: Dondorp
authors.affiliation: University of Oxford, Oxford, UK; Eikman-Oxford Clinical Research Unit, Jakarta, Indonesia.
authors.forename: J Kevin
authors.initials: JK
authors.lastname: Baird
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam.
authors.forename: Ha Minh
authors.initials: HM
authors.lastname: Lam
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam; Wellcome Trust, London, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Farrar
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam; University of Oxford, Oxford, UK.
authors.forename: Guy E
authors.initials: GE
authors.lastname: Thwaites
authors.affiliation: University of Oxford, Oxford, UK; Mahidol-Oxford Research Unit, Wellcome Trust Major Overseas Programme, Bangkok, Thailand.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.affiliation: University of Oxford, Oxford, UK. Electronic address: mboni@oucru.org.
authors.forename: Maciej F
authors.initials: MF
authors.lastname: Boni
mesh_terms: D000655:Amodiaquine / Q000008:administration & dosage* / Q000627:therapeutic use; D000962:Antimalarials / Q000008:administration & dosage* / Q000627:therapeutic use; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000008:administration & dosage* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004351:Drug Resistance; D004983:Ethanolamines / Q000008:administration & dosage* / Q000627:therapeutic use; D005449:Fluorenes / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008954:Models, Biological; D010963:Plasmodium falciparum; D011804:Quinolines / Q000008:administration & dosage* / Q000627:therapeutic use; D017211:Treatment Failure; D010879:Piperazines
chemical_list: D000655:Amodiaquine; D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D011804:Quinolines; C515299:amodiaquine, artesunate drug combination; C039060:artenimol; C031327:artemisinin; C034759:piperaquine; D010879:Piperazines