title: Artesunate plus pyronaridine for treating uncomplicated Plasmodium falciparum malaria.
abstract: BACKGROUND
  The World Health Organization (WHO) recommends that people with uncomplicated Plasmodium falciparum malaria are treated using Artemisinin-based Combination Therapy (ACT). ACT combines three-days of a short-acting artemisinin derivative with a longer-acting antimalarial which has a different mode of action. Pyronaridine has been reported as an effective antimalarial over two decades of use in parts of Asia, and is currently being evaluated as a partner drug for artesunate.
  
  
  OBJECTIVE
  To evaluate the efficacy and safety of artesunate-pyronaridine compared to alternative ACTs for treating people with uncomplicated P. falciparum malaria.
  
  
  METHODS
  We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; LILACS; ClinicalTrials.gov; the metaRegister of Controlled Trials (mRCT); and the WHO International Clinical Trials Search Portal up to 16 January 2014. We searched reference lists and conference abstracts, and contacted experts for information about ongoing and unpublished trials.
  
  
  METHODS
  Randomized controlled trials of artesunate-pyronaridine versus other ACTs in adults and children with uncomplicated P. falciparum malaria.For the safety analysis, we also included adverse events data from trials comparing any treatment regimen containing pyronaridine with regimens not containing pyronaridine.
  
  
  METHODS
  Two authors independently assessed trial eligibility and risk of bias, and extracted data. We combined dichotomous data using risk ratios (RR) and continuous data using mean differences (MD), and presented all results with a 95% confidence interval (CI). We used the GRADE approach to assess the quality of evidence.
  
  
  RESULTS
  We included six randomized controlled trials enrolling 3718 children and adults. Artesunate-pyronaridine versus artemether-lumefantrineIn two multicentre trials, enrolling mainly older children and adults from west and south-central Africa, both artesunate-pyronaridine and artemether-lumefantrine had fewer than 5% PCR adjusted treatment failures during 42 days of follow-up, with no differences between groups (two trials, 1472 participants, low quality evidence). There were fewer new infections during the first 28 days in those given artesunate-pyronaridine (PCR-unadjusted treatment failure: RR 0.60, 95% CI 0.40 to 0.90, two trials, 1720 participants, moderate quality evidence), but no difference was detected over the whole 42 day follow-up (two trials, 1691 participants, moderate quality evidence). Artesunate-pyronaridine versus artesunate plus mefloquineIn one multicentre trial, enrolling mainly older children and adults from South East Asia, both artesunate-pyronaridine and artesunate plus mefloquine had fewer than 5% PCR adjusted treatment failures during 28 days follow-up (one trial, 1187 participants, moderate quality evidence). PCR-adjusted treatment failures were 6% by day 42 for these treated with artesunate-pyronaridine, and 4% for those with artesunate-mefloquine (RR 1.64, 95% CI 0.89 to 3.00, one trial, 1116 participants, low quality evidence). Again, there were fewer new infections during the first 28 days in those given artesunate-pyronaridine (PCR-unadjusted treatment failure: RR 0.35, 95% CI 0.17 to 0.73, one trial, 1720 participants, moderate quality evidence), but no differences were detected over the whole 42 days (one trial, 1146 participants, low quality evidence). Adverse effectsSerious adverse events were uncommon in these trials, with no difference detected between artesunate-pyronaridine and comparator ACTs. The analysis of liver function tests showed biochemical elevation were four times more frequent with artesunate-pyronaridine than with the other antimalarials (RR 4.17, 95% CI 1.38 to 12.62, four trials, 3523 participants, moderate quality evidence).
  
  
  CONCLUSIONS
  Artesunate-pyronaridine performed well in these trials compared to artemether-lumefantrine and artesunate plus mefloquine, with PCR-adjusted treatment failure at day 28 below the 5% standard set by the WHO. Further efficacy and safety studies in African and Asian children are required to clarify whether this combination is an option for first-line treatment.
authors.affiliation: Makerere University Medical School, Mulago Hospital Complex, PO Box 24943, Kampala, Uganda.
authors.forename: Hasifa
authors.initials: H
authors.lastname: Bukirwa
authors.forename: B
authors.initials: B
authors.lastname: Unnikrishnan
authors.forename: Christine V
authors.initials: CV
authors.lastname: Kramer
authors.forename: David
authors.initials: D
authors.lastname: Sinclair
authors.forename: Suma
authors.initials: S
authors.lastname: Nair
authors.forename: Prathap
authors.initials: P
authors.lastname: Tharyan
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000009:adverse effects / Q000627:therapeutic use; D037621:Artemisinins / Q000009:adverse effects / Q000627:therapeutic use*; D000077332:Artesunate; D002648:Child; D004359:Drug Therapy, Combination / Q000379:methods; D004983:Ethanolamines / Q000009:adverse effects / Q000627:therapeutic use; D005449:Fluorenes / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000078102:Lumefantrine; D016778:Malaria, Falciparum / Q000188:drug therapy*; D015767:Mefloquine / Q000009:adverse effects / Q000627:therapeutic use; D009287:Naphthyridines / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004983:Ethanolamines; D005449:Fluorenes; D009287:Naphthyridines; D000077332:Artesunate; C031327:artemisinin; D000078102:Lumefantrine; C027871:pyronaridine; D015767:Mefloquine