title: Tolerability and safety of weekly primaquine against relapse of Plasmodium vivax in Cambodians with glucose-6-phosphate dehydrogenase deficiency.
abstract: BACKGROUND
  Primaquine is used to prevent Plasmodium vivax relapse; however, it is not implemented in many malaria-endemic countries, including Cambodia, for fear of precipitating primaquine-induced acute haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency (G6PDd). Reluctance to use primaquine is reinforced by a lack of quality safety data. This study was conducted to assess the tolerability of a primaquine regimen in Cambodian severely deficient G6PD variants to ascertain whether a weekly primaquine could be given without testing for G6PDd.
  
  
  METHODS
  From January 2013 to January 2014, Cambodians with acute vivax malaria were treated with dihydroartemisinin/piperaquine on days (D) 0, 1 and 2 with weekly doses of primaquine 0.75 mg/kg for 8 weeks (starting on D0, last dose on D49), and followed until D56. Participants' G6PD status was confirmed by G6PD genotype and measured G6PD activity. The primary outcome was treatment completion without primaquine toxicity defined as any one of: (1) severe anaemia (haemoglobin [Hb] <7 g/dL), (2) a >25 % fractional fall in Hb from D0, (3) the need for a blood transfusion, (4) haemoglobinuria, (5) acute kidney injury (an increase in baseline serum creatinine >50 %) or (6) methaemoglobinaemia >20 %.
  
  
  RESULTS
  We enrolled 75 patients with a median age of 24 years (range 5-63); 63 patients (84 %) were male. Eighteen patients were G6PDd (17/18 had the Viangchan variant) and had D0 G6PD activity ranging from 0.1 to 1.5 U/g Hb (median 0.85 U/g Hb). In the 57 patients with normal G6PD (G6PDn), D0 G6PD activity ranged from 6.9 to 18.5 U/g Hb (median 12 U/g Hb). Median D0 Hb concentrations were similar (P = 0.46) between G6PDd (13 g/dL, range 9.6-16) and G6PDn (13.5 g/dL, range 9-16.3) and reached a nadir on D2 in both groups: 10.8 g/dL (8.2-15.3) versus 12.4 g/dL (8.8-15.2) (P = 0.006), respectively. By D7, five G6PDd patients (27.7 %) had a >25 % fall in Hb, compared to 0 G6PDn patients (P = 0.00049). One of these G6PDd patients required a blood transfusion (D0-D5 Hb, 10.0-7.2 g/dL). No patients developed severe anaemia, haemoglobinuria, a methaemoglobin concentration >4.9 %, or acute kidney injury.
  
  
  CONCLUSIONS
  Vivax-infected G6PDd Cambodian patients demonstrated significant, mostly transient, falls in Hb and one received a blood transfusion. Weekly primaquine in G6PDd patients mandates medical supervision and pre-treatment screening for G6PD status. The feasibility of implementing a package of G6PDd testing and supervised primaquine should be explored.
  
  
  BACKGROUND
  The trial was registered on 3/1/2013 and the registration number is ACTRN12613000003774.
authors: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia. khengsim@gmail.com.
authors: Sim
authors: S
authors: Kheng
authors: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia. sinuonm@gmail.com.
authors: Sinoun
authors: S
authors: Muth
authors: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia. bob@tropmedres.ac.|Service de Médecine Tropicale et Humanitaire, Hôpitaux Universitaires de Genève, Geneva, Switzerland. bob@tropmedres.ac.|Mahidol Oxford Tropical Medicine Research Unit, 420/60 Rajvithi Road, Bangkok, 10400, Thailand. bob@tropmedres.ac.
authors: Walter R J
authors: WR
authors: Taylor
authors: WHO Cambodia Country Office, Pasteur Street, Phnom Penh, Cambodia. tops@wpro.who.int.
authors: Narann
authors: N
authors: Tops
authors: Pailin Referral Hospital, Pailin, Cambodia. khem_monykosal@yahoo.com.
authors: Khem
authors: K
authors: Kosal
authors: Pailin Referral Hospital, Pailin, Cambodia. khonsothea44@gmail.com.
authors: Khon
authors: K
authors: Sothea
authors: Anlong Veng Referral Hospital, Anlong Venh, Oddar Meanchey, Cambodia. Phumsouy@gmail.com.
authors: Phum
authors: P
authors: Souy
authors: Institut Pasteur in Cambodia, Phnom Penh, Cambodia. ksaorin@pasteur-kh.org.
authors: Saorin
authors: S
authors: Kim
authors: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia. mengchuor@gmail.com.
authors: Chuor Meng
authors: CM
authors: Char
authors: Pramoy Health Centre, Veal Veng, Pursat, Cambodia. chanvanna@hotmail.com.
authors: Chan
authors: C
authors: Vanna
authors: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia. polyteng168@gmail.com.
authors: Po
authors: P
authors: Ly
authors: WHO Headquarters, Geneva, Switzerland. ringwaldp@who.int.
authors: Pascal
authors: P
authors: Ringwald
authors: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia. virak.khieu@gmail.com.
authors: Virak
authors: V
authors: Khieu
authors: Institut Pasteur in Cambodia, Phnom Penh, Cambodia. akerleguer@pasteur-kh.org.
authors: Alexandra
authors: A
authors: Kerleguer
authors: Institut Pasteur in Cambodia, Phnom Penh, Cambodia. tpety@pasteur-kh.org.
authors: Pety
authors: P
authors: Tor
authors: Eijkman Oxford Clinical Research Unit, Jakarta, Indonesia. jkevinbaird@yahoo.com.|Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK. jkevinbaird@yahoo.com.
authors: John K
authors: JK
authors: Baird
authors: WHO Cambodia Country Office, Pasteur Street, Phnom Penh, Cambodia. steven_bjorge@hotmail.com.
authors: Steven
authors: S
authors: Bjorge
authors: Institut Pasteur in Cambodia, Phnom Penh, Cambodia. dmenard@pasteur-kh.org.
authors: Didier
authors: D
authors: Menard
authors: WHO Western Pacific Regional Office, Manila, Philippines. ChristophelE@wpro.who.int.
authors: Eva
authors: E
authors: Christophel
mesh_terms: D000293:Adolescent; D000328:Adult; D000743:Anemia, Hemolytic / Q000139:chemically induced / Q000175:diagnosis / Q000628:therapy; D000962:Antimalarials / Q000008:administration & dosage / Q000009:adverse effects; D001803:Blood Transfusion / Q000706:statistics & numerical data; D002160:Cambodia / Q000453:epidemiology; D002648:Child; D015897:Comorbidity; D004334:Drug Administration Schedule; D005260:Female; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000175:diagnosis / Q000453:epidemiology / Q000503:physiopathology; D006801:Humans; D016780:Malaria, Vivax / Q000453:epidemiology / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D010966:Plasmodium vivax / Q000187:drug effects*; D011319:Primaquine / Q000008:administration & dosage / Q000009:adverse effects; D055502:Secondary Prevention / Q000379:methods*
chemical_list: D000962:Antimalarials; D011319:Primaquine