title: Safety, tolerability, and efficacy of repeated doses of dihydroartemisinin-piperaquine for prevention and treatment of malaria: a systematic review and meta-analysis.
abstract: BACKGROUND
  Intermittent preventive treatment (IPT) for malaria is used in infants, children, adults, and pregnant women. Dihydroartemisinin-piperaquine (DP) is an effective, well tolerated artemisinin-based combination therapy. The long half-life of piperaquine makes it attractive for IPT. We conducted a systematic review and meta-analysis to establish the efficacy and safety of repeated treatment with DP.
  
  
  METHODS
  Following PRISMA guidelines, we searched multiple databases on Sept 1, 2016, with the terms: "human" AND "dihydroartemisinin-piperaquine" OR "DHA-PPQ". Studies were eligible if they were randomised controlled trials (RCTs) or prospective cohort studies involving repeat exposures to standard 3-day courses of DP for either seasonal malaria chemoprevention, mass drug administration, or treatment of clinical malaria, conducted at any time and in any geographic location. Random-effects meta-analysis was used to generate pooled incidence rate ratios and relative risks, or risk differences.
  
  
  RESULTS
  11 studies were included: two repeat treatment studies (one in children younger than 5 years and one in pregnant women), and nine IPT trials (five in children younger than 5 years, one in schoolchildren, one in adults, two in pregnant women). Comparator interventions included placebo, artemether-lumefantrine, sulfadoxine-pyrimethamine (SP), SP+amodiaquine, SP+piperaquine, SP+chloroquine, and co-trimoxazole. Of 14 628 participants, 3935 received multiple DP courses (2-18). Monthly IPT-DP was associated with an 84% reduction in the incidence of malaria parasitaemia measured by microscopy compared with placebo. Monthly IPT-DP was associated with fewer serious adverse events than placebo, daily co-trimoxazole, or monthly SP. Among 56 IPT-DP recipients (26 children, 30 pregnant women) with cardiac parameters, all QTc intervals were within normal limits, with no significant increase in QTc prolongation with increasing courses of DP.
  
  
  CONCLUSIONS
  Monthly DP appears well tolerated and effective for IPT. Additional data are needed in pregnancy and to further explore the cardiac safety with monthly dosing.
  
  
  BACKGROUND
  Bill & Melinda Gates Foundation and NIH.
authors.affiliation: Malaria Branch, Division of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention, Atlanta, GA, USA. Electronic address: fff2@cdc.gov.
authors.forename: Julie
authors.initials: J
authors.lastname: Gutman
authors.affiliation: Department of Epidemiology, University of Washington, Seattle, WA, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kovacs
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, CA, USA.
authors.forename: Grant
authors.initials: G
authors.lastname: Dorsey
authors.affiliation: Department of Global Health, University of Washington, Seattle, WA, USA; Department of Pharmacy, University of Washington, Seattle, WA, USA.
authors.forename: Andy
authors.initials: A
authors.lastname: Stergachis
authors.affiliation: Liverpool School of Tropical Medicine, Liverpool, UK.
authors.forename: Feiko O
authors.initials: FO
authors.lastname: Ter Kuile
mesh_terms: D000962:Antimalarials / Q000627:therapeutic use*; D037621:Artemisinins / Q000627:therapeutic use*; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000517:prevention & control*; D011739:Pyrimethamine / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D013413:Sulfadoxine / Q000627:therapeutic use; D010879:Piperazines
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D011739:Pyrimethamine; D011804:Quinolines; D013413:Sulfadoxine; C001205:fanasil, pyrimethamine drug combination; C039060:artenimol; C034759:piperaquine; D010879:Piperazines