In this large population of African infants and children with uncomplicated falciparum malaria, the high efficacy of AL was confirmed across all body weight groups. The 28-day PCR-corrected cure rate, the primary endpoint, exceeded 97% in each body weight group with no indication that outcome differed between groups. These findings confirm that a fixed-dose strategy according to certain body weight groups (i.e. use of discrete dosing for a continuous weight variable) does not result in under-dosing with reduced efficacy or, alternatively, overdosing and risk of toxicity, at the extremes of each body weight window. Thus, the current body-weight dosing recommendations for AL appear appropriate. Specifically, dosing advice for the lowest body weight group (5 to < 15 kg) and, indeed, for the smallest patients within this category (5 to < 10 kg) is adequate, as confirmed by the efficacy and safety findings. Additionally, analysis of age by body weight group in this population of children from sub-Saharan African countries showed there to be only a minor overlap of age ranges between body weight groups based on the 10-90th percentiles.
In endemic areas, effective anti-malarial treatment is particularly critical in young children, who are in the process of acquiring partial immunity and present with high parasite densities and acute clinical episodes that can progress rapidly into severe, life-threatening malaria . AL exposure was highest in the smallest children with body weight 5 to < 10 kg, but these results should be interpreted with caution due to the small sample size in this body weight group. Plasma levels of artemether, DHA and lumefantrine in all body weight groups (even in the smallest children, weighing 5 to < 10 kg) remained within the ranges reported in studies of adult patients [3, 5, 24, 25]. Lumefantrine exposure was apparently unchanged in the smallest (5 to < 10 kg) children. It is reassuring that there was no trend to any age group having reduced exposure to artemether, DHA or lumefantrine. These pharmacokinetic analyses did not, however, undergo formal statistical comparisons, so conclusions must be tentative. The tendency towards longer time to parasite and fever clearance in the lower body weight groups may be partly explained by the lower immunity of younger children. Moreover differences in time to parasite and fever clearance between body weight groups need to be interpreted with caution since the measurements were scheduled to take place at 8, 24, 36, 48, and 60 h after the start of treatment, i.e. there was no continuous monitoring. This may have magnified differences between values since, for example, fever clearance at 50 h will only have been recorded at 60 h. Regardless of these methodological issues, however, it is important to be aware that in malaria-endemic areas, infants may be particularly vulnerable to slower clearance rates for parasitaemia. This is because they may be starting to acquire protective immunity, and as a result the likelihood of detecting resistant parasites may be higher in this age group. Delayed clearance times have been phenotypically linked to artemisinin resistance in the Thai-Cambodian border . However, such cases may not necessarily represent a true emergence of parasite resistance to the drug because due to this lower immunity, infants can present with clinical evidence of malaria despite a relatively low parasite count i.e. fewer parasites may induce symptoms in infants than in older children. Nevertheless, the relevance of this finding needs to be reassessed to further clarify its potential impact. The current study excluded patients below 5 kg in weight, in accordance with WHO guidelines , since the safety and efficacy of ACT remains to be confirmed in this particular population. There were, however, 15 patients (1.7%) aged less than six months but weighing more than 5 kg included in the study.
Tolerability of AL was good, with no new safety concerns observed. The most frequently reported events were symptoms of malaria i.e. pyrexia, vomiting, cough and P. falciparum infection. The higher rate of vomiting and pyrexia in smaller children is expected, and in accordance with previous reports  it is possible that the increased incidence of headache in the higher body weight groups may have reflected the fact that smaller children are less likely to verbalize symptoms such as headache than the older patients. Cough tends to occur more frequently in young (< 5 years) patients with malaria  and the relatively high incidence reported here (24.2%) reflects the predominance of younger children in our population. P. falciparum infection reported as an adverse event most likely represents new infections, due to the long follow-up period, i.e. 42 days. The assessment of adverse events in cases of malaria, however, remains challenging because of the high background of malaria signs and symptoms . Here, clinical assessment prior to the first dose of AL was performed in an attempt to make the adverse event reporting as robust as possible, with only those events which worsened or first occurred after the start of treatment being considered treatment-emergent adverse events. Nevertheless, although ACTs are universally regarded as very safe and tolerable drugs, the possibility that serious and non-serious adverse events are more frequently detected with the widespread use of the drug should always be considered.
The study methodology was robust. The population was large and the age distribution, in which approximately 60% of patients fell into the 5 to < 15 kg body weight group, reflects the fact that young children are the most vulnerable to malaria morbidity and mortality . As specified in the protocol, artemether and lumefantrine plasma concentration was determined in separate subpopulations at different stages of the trial, but numbers were adequate for reliable estimations of pharmacokinetic parameters. The statistical methodology was sound, with the percentage of patients excluded from the mITT population (9.7%) being in the range of the pre-specified maximum of 10%.