Background: Malaria causes a reduction in haemoglobin that is compounded by primaquine, particularly in\npatients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The aim of this study was to determine the\nrelative contributions to red cell loss of malaria and primaquine in patients with uncomplicated Plasmodium vivax.\nMethods: A systematic review identified P. vivax efficacy studies of chloroquine with or without primaquine\npublished between January 2000 and March 2017. Individual patient data were pooled using standardised\nmethodology, and the haematological response versus time was quantified using a multivariable linear mixed\neffects model with non-linear terms for time. Mean differences in haemoglobin between treatment groups at day\nof nadir and day 42 were estimated from this model.\nResults: In total, 3421 patients from 29 studies were included: 1692 (49.5%) with normal G6PD status, 1701 (49.7%)\nwith unknown status and 28 (0.8%) deficient or borderline individuals. Of 1975 patients treated with chloroquine\nalone, the mean haemoglobin fell from 12.22 g/dL [95% CI 11.93, 12.50] on day 0 to a nadir of 11.64 g/dL [11.36,\n11.93] on day 2, before rising to 12.88 g/dL [12.60, 13.17] on day 42. In comparison to chloroquine alone, the mean\nhaemoglobin in 1446 patients treated with chloroquine plus primaquine was - 0.13 g/dL [- 0.27, 0.01] lower at day\nof nadir (p = 0.072), but 0.49 g/dL [0.28, 0.69] higher by day 42 (p < 0.001). On day 42, patients with recurrent\nparasitaemia had a mean haemoglobin concentration - 0.72 g/dL [- 0.90, - 0.54] lower than patients without\nrecurrence (p < 0.001). Seven days after starting primaquine, G6PD normal patients had a 0.3% (1/389) risk\nof clinically significant haemolysis (fall in haemoglobin > 25% to < 7 g/dL) and a 1% (4/389) risk of a fall in\nhaemoglobin > 5 g/dL.\nConclusions: Primaquine has the potential to reduce malaria-related anaemia at day 42 and beyond by\npreventing recurrent parasitaemia. Its widespread implementation will require accurate diagnosis of G6PD\ndeficiency to reduce the risk of drug-induced haemolysis in vulnerable individuals.
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