title: Adding a single low-dose of primaquine (0.25 mg/kg) to artemether-lumefantrine did not compromise treatment outcome of uncomplicated Plasmodium falciparum malaria in Tanzania: a randomized, single-blinded clinical trial.
abstract: BACKGROUND
  The World Health Organization (WHO) recently recommended the addition of a single low-dose of the gametocytocidal drug primaquine (PQ) to artemisinin-based combination therapy (ACT) in low transmission settings as a component of pre-elimination or elimination programmes. However, it is unclear whether that influences the ACT cure rate. The study assessed treatment outcome of artemether-lumefantrine (AL) plus a single PQ dose (0.25 mg/kg) versus standard AL regimen for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania.
  
  
  METHODS
  A randomized, single-blinded, clinical trial was conducted in Yombo, Bagamoyo district, Tanzania. Acute uncomplicated P. falciparum malaria patients aged ≥1 year, with the exception of pregnant and lactating women, were enrolled and treated with AL plus a single PQ dose (0.25 mg/kg) or AL alone under supervision. PQ was administered together with the first AL dose. Clinical and laboratory assessments were performed at 0, 8, 24, 36, 48, 60, and 72 h and on days 7, 14, 21, and 28. The primary end-point was a polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) on day 28. Secondary outcomes included: fever and asexual parasitaemia clearance, proportion of patients with PCR-determined parasitaemia on day 3, and proportion of patients with Pfmdr1 N86Y and Pfcrt K76T on days 0, 3 and day of recurrent infection.
  
  
  RESULTS
  Overall 220 patients were enrolled, 110 were allocated AL + PQ and AL, respectively. Parasite clearance by microscopy was fast, but PCR detectable parasitaemia on day 3 was 31/109 (28.4 %) and 29/108 (26.9 %) in patients treated with AL + PQ and AL, respectively (p = 0.79). Day 28 PCR-adjusted ACPR and re-infection rate was 105/105 (100 %) and 101/102 (99 %) (p = 0.31), and 5/107 (4.7 %) and 5/8 (4.8 %) (p = 0.95), in AL + PQ and AL arm, respectively. There was neither any statistically significant difference in the proportion of Pfmdr1 N86Y or Pfcrt K76T between treatment arms on days 0, 3 and day of recurrent infection, nor within treatment arms between days 0 and 3 or day 0 and day of recurrent infection.
  
  
  CONCLUSIONS
  The new WHO recommendation of adding a single low-dose of PQ to AL did not compromise treatment outcome of uncomplicated P. falciparum malaria in Tanzania. Trial registration number NCT02090036.
authors: Department of Parasitology and Medical Entomology, Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania.
authors: Richard
authors: R
authors: Mwaiswelo
authors: Department of Parasitology and Medical Entomology, Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania. bngasala@muhas.ac.tz.
authors: Billy
authors: B
authors: Ngasala
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors: Irina
authors: I
authors: Jovel
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors: Berit
authors: B
authors: Aydin-Schmidt
authors: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.|Global Health Group, University of California San Francisco, San Francisco, CA, USA.
authors: Roland
authors: R
authors: Gosling
authors: Aga Khan University Hospital, Nairobi, Kenya.
authors: Zul
authors: Z
authors: Premji
authors: Tanga Centre, National Institute for Medical Research, Tanga, Tanzania.
authors: Bruno
authors: B
authors: Mmbando
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors: Anders
authors: A
authors: Björkman
authors: Department of Women's and Children's Health, International Maternal and Child Health (IMCH), Uppsala University, Uppsala, Sweden.
authors: Andreas
authors: A
authors: Mårtensson
mesh_terms: D000293:Adolescent; D000962:Antimalarials / Q000008:administration & dosage*; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000008:administration & dosage*; D002648:Child; D002675:Child, Preschool; D016054:DNA, Protozoan / Q000032:analysis / Q000235:genetics; D004338:Drug Combinations; D004983:Ethanolamines / Q000008:administration & dosage*; D005260:Female; D005449:Fluorenes / Q000008:administration & dosage*; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D018512:Parasitemia / Q000188:drug therapy / Q000469:parasitology; D010963:Plasmodium falciparum / Q000235:genetics / Q000302:isolation & purification; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011319:Primaquine / Q000008:administration & dosage*; D016037:Single-Blind Method; D013636:Tanzania; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D016054:DNA, Protozoan; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D011319:Primaquine
keywords: Artemether-lumefantrine; Cure rate; Plasmodium falciparum malaria; Primaquine