Glucose-6-phosphate dehydrogenase deficiency, chlorproguanil-dapsone with artesunate and post-treatment haemolysis in African children treated for uncomplicated malaria

Carine Van Malderen, Jean-Pierre Van Geertruyden, Sonia Machevo, Raquel González, Quique Bassat, Ambrose Talisuna, Adoke Yeka, Carolyn Nabasumba, Patrice Piola, Atwine Daniel, Eleanor Turyakira, Pascale Forret, Chantal Van Overmeir, Harry van Loen, Annie Robert, Umberto D' Alessandro, Carine Van Malderen, Jean-Pierre Van Geertruyden, Sonia Machevo, Raquel González, Quique Bassat, Ambrose Talisuna, Adoke Yeka, Carolyn Nabasumba, Patrice Piola, Atwine Daniel, Eleanor Turyakira, Pascale Forret, Chantal Van Overmeir, Harry van Loen, Annie Robert, Umberto D' Alessandro

Abstract

Background: Malaria is a leading cause of mortality, particularly in sub-Saharan African children. Prompt and efficacious treatment is important as patients may progress within a few hours to severe and possibly fatal disease. Chlorproguanil-dapsone-artesunate (CDA) was a promising artemisinin-based combination therapy (ACT), but its development was prematurely stopped because of safety concerns secondary to its associated risk of haemolytic anaemia in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. The objective of the study was to assess whether CDA treatment and G6PD deficiency are risk factors for a post-treatment haemoglobin drop in African children<5 years of age with uncomplicated malaria.

Methods: This case-control study was performed in the context of a larger multicentre randomized clinical trial comparing safety and efficacy of four different ACT in children with uncomplicated malaria. Children, who after treatment experienced a haemoglobin drop≥2 g/dl (cases) within the first four days (days 0, 1, 2, and 3), were compared with those without an Hb drop (controls). Cases and controls were matched for study site, sex, age and baseline haemoglobin measurements. Data were analysed using a conditional logistic regression model.

Results: G6PD deficiency prevalence, homo- or hemizygous, was 8.5% (10/117) in cases and 6.8% (16/234) in controls (p=0.56). The risk of a Hb drop≥2 g/dl was not associated with either G6PD deficiency (adjusted odds ratio (AOR): 0.81; p=0.76) or CDA treatment (AOR: 1.28; p=0.37) alone. However, patients having both risk factors tended to have higher odds (AOR: 11.13; p=0.25) of experiencing a Hb drop≥2 g/dl within the first four days after treatment, however this finding was not statistically significant, mainly because G6PD deficient patients treated with CDA were very few. In non-G6PD deficient individuals, the proportion of cases was similar between treatment groups while in G6PD-deficient individuals, haemolytic anaemia occurred more frequently in children treated with CDA (56%) than in those treated with other ACT (29%), though the difference was not significant (p=0.49).

Conclusion: The use of CDA for treating uncomplicated malaria may increase the risk of haemolytic anaemia in G6PD-deficient children.

Figures

Figure 1
Figure 1
Proportion of children with a Hb drop ≥2 g/dl (cases) across G6PD status and treatment groups. CDA = chlorproguanil-dapsone + artesunate. Other ACT = artemether-lumefantrine, dihydroartemisinin-piperaquine, amodiaquine-artesunate.

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