Intramuscular Artesunate for Severe Malaria in African Children: A Multicenter Randomized Controlled Trial

Abstract

BackgroundCurrent artesunate (ARS) regimens for severe malaria are complex. Once daily intramuscular (i.m.) injection for 3 d would be simpler and more appropriate for remote health facilities than the current WHO-recommended regimen of five intravenous (i.v.) or i.m. injections over 4 d. We compared both a three-dose i.m. and a three-dose i.v. parenteral ARS regimen with the standard five-dose regimen using a non-inferiority design (with non-inferiority margins of 10%).Methods and FindingsThis randomized controlled trial included children (0.5–10 y) with severe malaria at seven sites in five African countries to assess whether the efficacy of simplified three-dose regimens is non-inferior to a five-dose regimen. We randomly allocated 1,047 children to receive a total dose of 12 mg/kg ARS as either a control regimen of five i.m. injections of 2.4 mg/kg (at 0, 12, 24, 48, and 72 h) (n = 348) or three injections of 4 mg/kg (at 0, 24, and 48 h) either i.m. (n = 348) or i.v. (n = 351), both of which were the intervention arms. The primary endpoint was the proportion of children with ≥99% reduction in parasitemia at 24 h from admission values, measured by microscopists who were blinded to the group allocations. Primary analysis was performed on the per-protocol population, which was 96% of the intention-to-treat population. Secondary analyses included an analysis of host and parasite genotypes as risks for prolongation of parasite clearance kinetics, measured every 6 h, and a Kaplan–Meier analysis to compare parasite clearance kinetics between treatment groups. A post hoc analysis was performed for delayed anemia, defined as hemoglobin ≤ 7g/dl 7 d or more after admission.The per-protocol population was 1,002 children (five-dose i.m.: n = 331; three-dose i.m.: n = 338; three-dose i.v.: n = 333); 139 participants were lost to follow-up. In the three-dose i.m. arm, 265/338 (78%) children had a ≥99% reduction in parasitemia at 24 h compared to 263/331 (79%) receiving the five-dose i.m. regimen, showing non-inferiority of the simplified three-dose regimen to the conventional five-dose regimen (95% CI −7, 5; p = 0.02). In the three-dose i.v. arm, 246/333 (74%) children had ≥99% reduction in parasitemia at 24 h; hence, non-inferiority of this regimen to the five-dose control regimen was not shown (95% CI −12, 1; p = 0.24). Delayed parasite clearance was associated with the N86YPfmdr1 genotype. In a post hoc analysis, 192/885 (22%) children developed delayed anemia, an adverse event associated with increased leukocyte counts. There was no observed difference in delayed anemia between treatment arms.A potential limitation of the study is its open-label design, although the primary outcome measures were assessed in a blinded manner.ConclusionsA simplified three-dose i.m. regimen for severe malaria in African children is non-inferior to the more complex WHO-recommended regimen. Parenteral ARS is associated with a risk of delayed anemia in African children.Trial registrationPan African Clinical Trials Registry PACTR201102000277177

New developments in anti-malarial target candidate and product profiles

“…Any new medicine would therefore have to free up the microvasculature, either by disengaging or killing the parasites; the drug’s speed of onset of activity is therefore of paramount concern. The AQUAMAT and SEAQUAMAT studies that compared intravenous artesunate and intravenous quinine [74, 75] and other studies that compared intravenous or intramuscular artesunate [76, 77] showed that injected artesunate reduces the overall severe malaria patient mortality by between a third and a quarter. From a safety viewpoint, quinine use has been associated with injection-site pathologies, cinchonism [78, 79] and also risks of hypoglycemia.…”

Plasmodium falciparum Clearance Is Pitting-Dependent With Artemisinin-Based Drugs but Pitting-Independent With Atovaquone-Proguanil or Mefloquine

“…We suggest that drug-induced pitting should be evaluated early in the development of new generations of antimalarial molecules such as spiroindolones [11], which have an effect on ring circulating forms. This would help better grasp their mode of action in vivo, which helps predict the risk of posttreatment hemolysis observed in severe [4,[12][13][14] and more recently in uncomplicated malaria [9,15]. In the context of artemisinin resistance in Southeast Asia characterized by slow parasite clearance, a specific study on the role of pitting may explain how parasites initially escape clearance mechanisms.…”

Prevalence of malaria, typhoid and co-infection in District DIR (lower), Pakistan

“…Malaria is transferred to human through a female Anopheles' mosquito (WANG; JACOBS-LORENA, 2017). During malaria hematological and biochemical changes take place due to which the infection become more severe (KREMSNER et al, 2016). White blood cell (WBC) count remains constant while lactate dehydrogenase increases in malarial patients.…”