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

Kheng S, Muth S, Taylor WR, Tops N, Kosal K, Sothea K, Souy P, Kim S, Char CM, Vanna C, Ly P, Ringwald P, Khieu V, Kerleguer A, Tor P, Baird JK, Bjorge S, Menard D, Christophel E - BMC Med (2015)

Bottom Line: Reluctance to use primaquine is reinforced by a lack of quality safety data.By D7, five G6PDd patients (27.7 %) had a >25 % fall in Hb, compared to 0 G6PDn patients (P = 0.00049).Vivax-infected G6PDd Cambodian patients demonstrated significant, mostly transient, falls in Hb and one received a blood transfusion.

View Article: PubMed Central - PubMed

Affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia. khengsim@gmail.com.

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.

Trial registration: The trial was registered on 3/1/2013 and the registration number is ACTRN12613000003774.

No MeSH data available.


Related in: MedlinePlus

Trial profile. G6PD status was determined initially using the fluorescent spot test (FST). At Anlong Venh and Veal Veng, only FST-diagnosed G6PDd patients were recruited. Final G6PD status shown here is based on G6PD enzyme activity and G6PD genotype. DHAPP dihydroartemisinin/piperaquine, G6PD glucose-6-phosphate dehydrogenase
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Fig1: Trial profile. G6PD status was determined initially using the fluorescent spot test (FST). At Anlong Venh and Veal Veng, only FST-diagnosed G6PDd patients were recruited. Final G6PD status shown here is based on G6PD enzyme activity and G6PD genotype. DHAPP dihydroartemisinin/piperaquine, G6PD glucose-6-phosphate dehydrogenase

Mentions: From January 2013 to January 2014, 361 patients were screened and 75 with mono vivax infections were enrolled into the study; eight did not complete follow-up (Fig. 1). Because the sample size requirement for G6PDn was met in Pailin, we only recruited patients at the other two sites if the FST result showed they were G6PDd. Most patients were male (n = 63) of median age 24 years [range 5–63, interquartile range (IQR) 9–46]. Median female age was 29 years (range 9–56, IQR 15–45). Fifteen patients (20 %) were <18 years of age (Table 2). A total of 18 patients were G6PDd: 17 had the Viangchan variant (14 hemizygous males, 3 heterozygous females), and one male had the Canton variant.Fig. 1


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

Kheng S, Muth S, Taylor WR, Tops N, Kosal K, Sothea K, Souy P, Kim S, Char CM, Vanna C, Ly P, Ringwald P, Khieu V, Kerleguer A, Tor P, Baird JK, Bjorge S, Menard D, Christophel E - BMC Med (2015)

Trial profile. G6PD status was determined initially using the fluorescent spot test (FST). At Anlong Venh and Veal Veng, only FST-diagnosed G6PDd patients were recruited. Final G6PD status shown here is based on G6PD enzyme activity and G6PD genotype. DHAPP dihydroartemisinin/piperaquine, G6PD glucose-6-phosphate dehydrogenase
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4549079&req=5

Fig1: Trial profile. G6PD status was determined initially using the fluorescent spot test (FST). At Anlong Venh and Veal Veng, only FST-diagnosed G6PDd patients were recruited. Final G6PD status shown here is based on G6PD enzyme activity and G6PD genotype. DHAPP dihydroartemisinin/piperaquine, G6PD glucose-6-phosphate dehydrogenase
Mentions: From January 2013 to January 2014, 361 patients were screened and 75 with mono vivax infections were enrolled into the study; eight did not complete follow-up (Fig. 1). Because the sample size requirement for G6PDn was met in Pailin, we only recruited patients at the other two sites if the FST result showed they were G6PDd. Most patients were male (n = 63) of median age 24 years [range 5–63, interquartile range (IQR) 9–46]. Median female age was 29 years (range 9–56, IQR 15–45). Fifteen patients (20 %) were <18 years of age (Table 2). A total of 18 patients were G6PDd: 17 had the Viangchan variant (14 hemizygous males, 3 heterozygous females), and one male had the Canton variant.Fig. 1

Bottom Line: Reluctance to use primaquine is reinforced by a lack of quality safety data.By D7, five G6PDd patients (27.7 %) had a >25 % fall in Hb, compared to 0 G6PDn patients (P = 0.00049).Vivax-infected G6PDd Cambodian patients demonstrated significant, mostly transient, falls in Hb and one received a blood transfusion.

View Article: PubMed Central - PubMed

Affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia. khengsim@gmail.com.

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.

Trial registration: The trial was registered on 3/1/2013 and the registration number is ACTRN12613000003774.

No MeSH data available.


Related in: MedlinePlus