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Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) provides hydroxyurea at maximum tolerated dose (MTD) for children with sickle cell anemia (SCA) in sub-Saharan Africa. Beyond reducing sickle-related clinical events, documented treatment benefits include ~50% malaria incidence. To identify associations and propose mechanisms by which hydroxyurea could be associated with lower malaria rates, infections were recorded across all clinical sites (Angola, Democratic Republic of Congo, Kenya, and Uganda). Hazard ratios (HR) with 95% Confidence Intervals (CI) for baseline demographic, and time-varying laboratory and clinical parameters were estimated in a modified Cox gap-time model for repeated events. A total of 717 clinical malaria episodes occurred in 336 of 606 study participants over 3,387 patient-years of hydroxyurea treatment; over half were confirmed by blood smear and/or rapid diagnostic testing with 97.8% Plasmodium falciparum. In univariate analysis limited to 4 confirmed infections per child, malaria risk was significantly associated with absolute neutrophil count (ANC), splenomegaly, hemoglobin, and achieving MTD; age, malaria season, MTD dose, fetal hemoglobin, a-thalassemia, and G6PD deficiency had no effect. In multivariable regression of confirmed infections, ANC was significant (HR=1.37 per doubled value, CI=1.10-1.70, p=0.0052) and ANC values <3.0 x 109/L were associated with lower malaria incidence. Compared to non-palpable, 1-4cm splenomegaly also was associated with higher malaria risk (HR=2.01, CI=1.41-2.85, p=0.0001). Hydroxyurea at MTD is associated with lower malaria incidence in SCA through incompletely defined mechanisms, but treatment-associated mild myelosuppression with ANC <3.0 x 109/L is salutary. Splenomegaly represents an unexplained risk factor for malaria infections among children with SCA in Africa.

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Mbale Clinical Research Institute, Mbale, Uganda.