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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

Results of the fluorescent spot test as a function of the measured G6PD enzyme activity. One G6PD enzyme value was unavailable for a fluorescent spot test (FST)-diagnosed G6PD deficient male who was confirmed G6PD wild type by polymerase chain reaction
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Fig2: Results of the fluorescent spot test as a function of the measured G6PD enzyme activity. One G6PD enzyme value was unavailable for a fluorescent spot test (FST)-diagnosed G6PD deficient male who was confirmed G6PD wild type by polymerase chain reaction

Mentions: Baseline demographic, clinical and laboratory characteristics were similar between the two G6PD groups (Table 2), except for reported rates of abdominal pain, abnormal urine colour, mean body temperature and G6PD activity. Four PCR-determined G6PD wild-type patients had low G6PD enzyme activities that were probably due to delayed measurement; in three patients, the baseline values were inconsistent with later G6PD activity values and in one there were no other G6PD activity values. All such values have been excluded from Table 2. Two G6PDd patients had missing baseline enzyme activity values (also excluded from Table 2) but were classified using post D0 G6PD enzyme activity results. Of the 18 G6PDd patients, 13 were class II (1 to <10 % population median of 12 U/g Hb) and five were class III (≥10 to 60 %) G6PDd. Three patients had discordant FST results: two from Anlong Venh and Veal Veng were diagnosed as FST G6PDd but were subsequently confirmed as G6PD wild type and one FST-diagnosed G6PD normal patient was later confirmed PCR G6PDd (Fig. 2).Fig. 2


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)

Results of the fluorescent spot test as a function of the measured G6PD enzyme activity. One G6PD enzyme value was unavailable for a fluorescent spot test (FST)-diagnosed G6PD deficient male who was confirmed G6PD wild type by polymerase chain reaction
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Results of the fluorescent spot test as a function of the measured G6PD enzyme activity. One G6PD enzyme value was unavailable for a fluorescent spot test (FST)-diagnosed G6PD deficient male who was confirmed G6PD wild type by polymerase chain reaction
Mentions: Baseline demographic, clinical and laboratory characteristics were similar between the two G6PD groups (Table 2), except for reported rates of abdominal pain, abnormal urine colour, mean body temperature and G6PD activity. Four PCR-determined G6PD wild-type patients had low G6PD enzyme activities that were probably due to delayed measurement; in three patients, the baseline values were inconsistent with later G6PD activity values and in one there were no other G6PD activity values. All such values have been excluded from Table 2. Two G6PDd patients had missing baseline enzyme activity values (also excluded from Table 2) but were classified using post D0 G6PD enzyme activity results. Of the 18 G6PDd patients, 13 were class II (1 to <10 % population median of 12 U/g Hb) and five were class III (≥10 to 60 %) G6PDd. Three patients had discordant FST results: two from Anlong Venh and Veal Veng were diagnosed as FST G6PDd but were subsequently confirmed as G6PD wild type and one FST-diagnosed G6PD normal patient was later confirmed PCR G6PDd (Fig. 2).Fig. 2

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