title: Declining responsiveness of Plasmodium falciparum infections to artemisinin-based combination treatments on the Kenyan coast.
abstract: BACKGROUND
  The emergence of artemisinin-resistant P. falciparum malaria in South-East Asia highlights the need for continued global surveillance of the efficacy of artemisinin-based combination therapies.
  
  
  METHODS
  On the Kenyan coast we studied the treatment responses in 474 children 6-59 months old with uncomplicated P. falciparum malaria in a randomized controlled trial of dihydroartemisinin-piperaquine vs. artemether-lumefantrine from 2005 to 2008. (ISRCTN88705995).
  
  
  RESULTS
  The proportion of patients with residual parasitemia on day 1 rose from 55% in 2005-2006 to 87% in 2007-2008 (odds ratio, 5.4, 95%CI, 2.7-11.1; P<0.001) and from 81% to 95% (OR, 4.1, 95%CI, 1.7-9.9; P = 0.002) in the DHA-PPQ and AM-LM groups, respectively. In parallel, Kaplan-Meier estimated risks of apparent recrudescent infection by day 84 increased from 7% to 14% (P = 0.1) and from 6% to 15% (P = 0.05) with DHA-PPQ and AM-LM, respectively. Coinciding with decreasing transmission in the study area, clinical tolerance to parasitemia (defined as absence of fever) declined between 2005-2006 and 2007-2008 (OR body temperature >37.5°C, 2.8, 1.9-4.1; P<0.001). Neither in vitro sensitivity of parasites to DHA nor levels of antibodies against parasite extract accounted for parasite clearance rates or changes thereof.
  
  
  CONCLUSIONS
  The significant, albeit small, decline through time of parasitological response rates to treatment with ACTs may be due to the emergence of parasites with reduced drug sensitivity, to the coincident reduction in population-level clinical immunity, or both. Maintaining the efficacy of artemisinin-based therapy in Africa would benefit from a better understanding of the mechanisms underlying reduced parasite clearance rates.
  
  
  BACKGROUND
  Controlled-Trials.com ISRCTN88705995.
authors.affiliation: Kenya Medical Research Institute/Wellcome Trust Research Programme, Kilifi, Kenya. sborrmann@kilifi.kemri-wellcome.org
authors.forename: Steffen
authors.initials: S
authors.lastname: Borrmann
authors.forename: Philip
authors.initials: P
authors.lastname: Sasi
authors.forename: Leah
authors.initials: L
authors.lastname: Mwai
authors.forename: Mahfudh
authors.initials: M
authors.lastname: Bashraheil
authors.forename: Ahmed
authors.initials: A
authors.lastname: Abdallah
authors.forename: Steven
authors.initials: S
authors.lastname: Muriithi
authors.forename: Henrike
authors.initials: H
authors.lastname: Frühauf
authors.forename: Barbara
authors.initials: B
authors.lastname: Schaub
authors.forename: Johannes
authors.initials: J
authors.lastname: Pfeil
authors.forename: Judy
authors.initials: J
authors.lastname: Peshu
authors.forename: Warunee
authors.initials: W
authors.lastname: Hanpithakpong
authors.forename: Anja
authors.initials: A
authors.lastname: Rippert
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Juma
authors.forename: Benjamin
authors.initials: B
authors.lastname: Tsofa
authors.forename: Moses
authors.initials: M
authors.lastname: Mosobo
authors.forename: Brett
authors.initials: B
authors.lastname: Lowe
authors.forename: Faith
authors.initials: F
authors.lastname: Osier
authors.forename: Greg
authors.initials: G
authors.lastname: Fegan
authors.forename: Niklas
authors.initials: N
authors.lastname: Lindegårdh
authors.forename: Alexis
authors.initials: A
authors.lastname: Nzila
authors.forename: Norbert
authors.initials: N
authors.lastname: Peshu
authors.forename: Margaret
authors.initials: M
authors.lastname: Mackinnon
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
mesh_terms: D000962:Antimalarials / Q000627:therapeutic use*; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000627:therapeutic use*; D002675:Child, Preschool; D004338:Drug Combinations; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D004983:Ethanolamines / Q000627:therapeutic use*; D005260:Female; D005449:Fluorenes / Q000627:therapeutic use*; D006801:Humans; D007223:Infant; D007630:Kenya; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000401:mortality / Q000469:parasitology*; D008297:Male; D010963:Plasmodium falciparum / Q000187:drug effects*; D011804:Quinolines / Q000627:therapeutic use*; D015996:Survival Rate; D010879:Piperazines
chemical_list: D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D011804:Quinolines; C039060:artenimol; C034759:piperaquine; D010879:Piperazines
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