1. Tolerability and safety of weekly primaquine against relapse of Plasmodium vivax in Cambodians with glucose-6-phosphate dehydrogenase deficiency
- Author
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Phum Souy, Narann Tops, Saorin Kim, Khem Kosal, Eva Christophel, Chan Vanna, Sinoun Muth, Khon Sothea, Didier Menard, Pascal Ringwald, Sim Kheng, Chuor Meng Char, Po Ly, Alexandra Kerleguer, Walter R. J. Taylor, Pety Tor, Virak Khieu, John Kevin Baird, Steven Bjorge, National Center for Parasitology, Entomology and Malaria Control [Phnom Penh, Cambodia] (CNM), Service de Médecine Tropicale et Humanitaire [Geneva, Suisse], Hôpitaux Universitaires de Genève (HUG), Mahidol Oxford Tropical Medicine Research Unit, University of Oxford [Oxford]-Mahidol University [Bangkok], World Health Organization [Phnom Penh] (WHO), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Pailin Referral Hospital [Pailin, Cambodge], Anlong Veng Referral Hospital [Anlong Venh, Cambodge]., Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Pramoy Health Centre [Cambodia], Eijkman Oxford Clinical Research Unit [Jakarta, Indonesie], Eijkman Institute of Molecular Biology [Jakarta, Indonesie], Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford [Oxford]-University of Oxford [Oxford], Regional Office of the Western Pacific (WHO), Funding for this study was obtained by PR of WHO Geneva via a grant from UKAid without which this study would not have taken place. We record our profound gratitude to the taxpayers of the United Kingdom. WRJT was part supported by France Expertise International through the 5 % initiative as a consultant to CNM in operational research and he expresses 'ses remerciements profonds au peuple français.' JKB is supported by Wellcome Trust grant B9RJIXO. DM is supported the French Ministry of Foreign Affairs and SKim was part funded by a grant from the Asia Pacific Malaria Elimination Network. None of the funders had any role in study design, data collection, analysis, and interpretation, or writing of the manuscript or in the decision to submit the manuscript for publication., and We wish to express our sincere and profound thanks to the patients who took part in this study and to the nurses and laboratory staff who contributed to its successful and safe execution. We thank our DSMB who reviewed the G6PDd data in real time and provided very valuable and timely responses and advice: Drs Toby Leslie (Chairperson), Chanthap Lon, Isabella Ribeiro and Professor Lucio Luzzatto.
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Male ,Primaquine ,Blood transfusion ,medicine.medical_treatment ,Plasmodium vivax ,MESH: Comorbidity ,Comorbidity ,Pharmacology ,Gastroenterology ,0302 clinical medicine ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,MESH: Child ,Outcome Assessment, Health Care ,Secondary Prevention ,030212 general & internal medicine ,Child ,Village Malaria Worker ,Medicine(all) ,MESH: Middle Aged ,MESH: Secondary Prevention ,biology ,General Medicine ,MESH: Primaquine ,Middle Aged ,MESH: Plasmodium vivax ,3. Good health ,MESH: Glucosephosphate Dehydrogenase Deficiency ,Tolerability ,Female ,Cambodia ,G6PD Activity ,medicine.drug ,Research Article ,Adult ,medicine.medical_specialty ,Anemia, Hemolytic ,Adolescent ,Anemia ,030231 tropical medicine ,Dihydroartemisinin ,MESH: Blood Transfusion ,MESH: Drug Administration Schedule ,Drug Administration Schedule ,03 medical and health sciences ,Antimalarials ,Internal medicine ,parasitic diseases ,medicine ,Malaria, Vivax ,Humans ,Blood Transfusion ,MESH: Outcome Assessment, Health Care ,MESH: Anemia, Hemolytic ,MESH: Adolescent ,MESH: Humans ,business.industry ,MESH: Cambodia ,MESH: Malaria, Vivax ,MESH: Adult ,Thick Blood Film ,medicine.disease ,biology.organism_classification ,MESH: Antimalarials ,MESH: Male ,Hemizygous Male ,Regimen ,Glucosephosphate Dehydrogenase Deficiency ,business ,MESH: Female ,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] 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. Trial registration The trial was registered on 3/1/2013 and the registration number is ACTRN12613000003774. Electronic supplementary material The online version of this article (doi:10.1186/s12916-015-0441-1) contains supplementary material, which is available to authorized users.
- Published
- 2015
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