RESPONSIVENESS OF CHILDHOLD Plasmodium falciparum INFECTION AND THE ASSOCIATED ANAEMIA TO ARTEMISININ -BASED COMBINATION TREATMENTS

Abstract

Artemisinin-based combination treatments (ACTs) rapidly clear asexual parasitaemia but may cause an Early Rising, Asexual Parasitaemia (ERAP) and a Late Appearing Anaemia (LAA) post-treatment initiation. However, there are few studies on effects of ACTs on malaria-associated anaemia and parasite population changes in children with ERAP. The study was designed to evaluate changes in parasite populations in children with ERAP and evaluate the changes in haematocrit following ACTs. Children aged <16 years (n=1,405), who had symptoms and signs of uncomplicated malaria, Plasmoddium falciparum parasitaemia ≥2.0000uL⁻ᶦ and were enrolled from 2005 to 2015 after informed consent was taken from parents, were drawn from six geographical areas of Nigeria: Ibadan, Ijede, Makarfi, Barkin Ladi, Damboa and Agbani. They were randomly allotted to oral artesunate-amodiaquine (n=829), artemether-lumefantrine (n=517) or dihydroartemisinin-piperaquine (n=59) treatments. Physical examination and Giemsa-stained blood slides obtained from a finger prick for parasitaemia quantification were done pre- (day 0) and post-treatment for 28-42 days. Haematocrit values were estimated using microhaematocrit centrifuge and changes were characterised based on haematocrit <30% or ≥30%. A non-compartment model was used to characterise the kinetics of disposition of haematocrit deficit from 30%; one-compartment constant rate intravascular infusion model for increases in haematocrit and the method of residuals for mobilisation of asexual parasitaemias. Parasite genotyping used for correction of efficacy 4-6 weeks, and characterisation of parasite DNA clones pre and post-treatment was done using polymerase chain reaction (PCR). Data were analysed using Chi-square, Student's t-lest, analysts of variance and Kruskal-Wallis test at α0.05≤. In ≤ 2 year -old (n=250), PCR-corrected efficacy was 97.2% and similar to all treatments. A late monophasic fall in haematocrit to <30%, with monoexponential decline in haematocrit deficit from 30% [mean halftime 1.3±0.4 days (range 0.2-2.0 days)] occurred in 3% of children 3-5 weeks post-treatment initiation and it corresponded clinically with LAA. Asymptomatic LAA occurred in 84 of 609 children (13.8%). In a constant rate intravascular infusion model (n=112), mean and time to plateau haematocrit were 6.7±4.1% (range 0.5-20.5%) and 28 days, respectively. Overall, declines from plateau haematocrit were monoexponential- [mean half-time 2.5±1.6 days (range 0.2±8.1 days)] but half-times were significantly lower in anaemic compared to non-anaemic children. An ERAP occurred in 205 of 416 children (49.3%). Lag time, half-time and rate constant of asexual parasite release were: 0.2±0.1 hour (range 0.2-1 hour), 1.0±0.7 hour (range 0.1±5 hour) and 0.9±0.6 hour¹ (range 0.1-5.6 hour¹), respectively. Parasite DNA clearance time and DNA clone area under curve were significantly higher in children with compared to those without ERAP; suggesting peripheral asexual parasites mobilisation and retention in children with ERAP. Declines in DNA clones were monoexponential. In uncomplicated childhood faIciparum malaria, artemisinin-based combination treatments are efficacious but may cause late-appearing anaemia. Following treatment, the kinetics of increases in haematocrit, rapid asexual parasite mobilization into peripheral blood after first dose, and parasite DNA crone elimination are first order processes.