Tolerability and safety of weekly primaquine against relapse of Plasmodium vivax in Cambodians with glucose-6-phosphate dehydrogenase deficiency

Authors

Sim Kheng, National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia
Sinoun Muth, National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia
Walter R.J. Taylor, National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia
Narann Tops, WHO Cambodia Country Office, Pasteur Street, Phnom Penh, Cambodia
Khem Kosal, Pailin Referral Hospital, Pailin, Cambodia
Khon Sothea, Pailin Referral Hospital, Pailin, Cambodia
Phum Souy, Anlong Veng Referral Hospital, Anlong Venh, Oddar Meanchey, Cambodia
Saorin Kim, Institut Pasteur in Cambodia, Phnom Penh, Cambodia
Chuor Meng Char, National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia
Chan Vanna, Pramoy Health Centre, Veal Veng, Pursat, Cambodia
Po Ly, National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia
Pascal Ringwald, WHO Headquarters, Geneva, Switzerland
Virak Khieu, National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia
Alexandra Kerleguer, Institut Pasteur in Cambodia, Phnom Penh, Cambodia
Pety Tor, Institut Pasteur in Cambodia, Phnom Penh, Cambodia
J. Kevin Baird, US Navy ResearchFollow
Steven Bjorge, WHO Cambodia Country Office, Pasteur Street, Phnom Penh, Cambodia
Didier Menard, Institut Pasteur in Cambodia, Phnom Penh, Cambodia
Eva Christophel, WHO Western Pacific Regional Office, Manila, Philippines

Date of this Version

2015

Citation

Kheng et al. BMC Medicine (2015) 13:203

Comments

U.S. Government Work

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]/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.