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

Abstract

BackgroundPrimaquine 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.MethodsFrom 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 %.ResultsWe 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.ConclusionsVivax-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 registrationThe trial was registered on 3/1/2013 and the registration number is ACTRN12613000003774.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-015-0441-1) contains supplementary material, which is available to authorized users.

An optimised age-based dosing regimen for single low-dose primaquine for blocking malaria transmission in Cambodia

“…In August 2015, Cambodia decided to deploy SLDPQ thanks, in part, to reassuring data on the use of 0.75 mg base/kg of weekly PQ (45 mg in a 60-kg adult) in vivax-infected G6PDd patients [15]. Moreover, a pilot study of SLDPQ is being conducted in acute uncomplicated falciparum malaria (ClinicalTrials.gov identifier, NCT02434952) and SLDPQ is being included in antimalarial drug resistance studies (NCT02453308).…”

“…Data in vivax-infected patients, with Hb concentrations ≥ 10 g/dL, showed that weekly-administered 0.75 mg base/kg of PQ resulted in a greater Hb level decline in G6PDd compared to G6PD normal patients. The greatest fractional fall in Hb occurred on D7 (median (range)): –16.3 % (–33.1 to 6.5) versus –3.7 % (–17.5 to 23.3) for corresponding absolute Hb concentration falls of –2.2 g/dL (–4.9 to 0.8) versus –0.5 g/dL (–2.2 to 2.8) [15]. …”

“…Methaemoglobinaemia (metHb, upper limit of normal approximately 2–3 %) is a dose-dependent side effect of PQ but is not considered a clinical worry because, in vivax infected patients, 0.75 mg base/kg of PQ resulted in a maximum metHb concentration of 4.9 %, a concentration that was well tolerated [15]; thus, 0.25 mg/kg of PQ is likely to result in very small increases in metHb. Abdominal pain, also dose-related, is reduced by food intake [43, 44] and was not an important symptom when 30 mg of PQ was given daily with a small snack for 1 year in Indonesian adults [45].…”

Single-Dose Primaquine in a Preclinical Model of Glucose-6-Phosphate Dehydrogenase Deficiency: Implications for Use in Malaria Transmission-Blocking Programs

“…A study published by Kheng et al in 2015 assessed the tolerability of PQ in Plasmodium vivax-infected G6PDd individuals primarily of the Viangchan variant, a class II G6PDd variant marked by a more severe G6PD deficiency similar to Med-G6PDd (29). PQ given at approximately 0.75 mpk weekly beginning on day 0 (once per week for 8 weeks) with dihydroartemisinin-piperaquine on days 0, 1, and 2 (once daily for 3 days) was generally well tolerated, with no severe anemia observed, but the authors acknowledged that a quarter of the G6PDd patients experienced a Ͼ25% drop in hemoglobin concentrations, with nearly one-third of patients exhibiting PQ toxicity by day 7 posttreatment and one patient even requiring a blood transfusion (29).…”

“…A study published by Kheng et al in 2015 assessed the tolerability of PQ in Plasmodium vivax-infected G6PDd individuals primarily of the Viangchan variant, a class II G6PDd variant marked by a more severe G6PD deficiency similar to Med-G6PDd (29). PQ given at approximately 0.75 mpk weekly beginning on day 0 (once per week for 8 weeks) with dihydroartemisinin-piperaquine on days 0, 1, and 2 (once daily for 3 days) was generally well tolerated, with no severe anemia observed, but the authors acknowledged that a quarter of the G6PDd patients experienced a Ͼ25% drop in hemoglobin concentrations, with nearly one-third of patients exhibiting PQ toxicity by day 7 posttreatment and one patient even requiring a blood transfusion (29). Therefore, they concluded that their data do not support unsupervised weekly PQ administration to prevent relapse in areas with severe G6PD deficiency and recommended G6PDd testing beforehand, though they speculated safety in mass administration of a lower (0.25 mpk) dose to block P. falciparum transmission in the context of circumventing the spread of artemisinin resistance that has emerged in the Greater Mekong Subregion, including the Cambodian-Thai and Thai-Myanmar borders in Southeast Asia (30).…”