Effectiveness and safety of artemether–lumefantrine versus artesunate–amodiaquine for unsupervised treatment of uncomplicated falciparum malaria in patients of all age groups in Nanoro, Burkina Faso: a randomized open label trial

Malaria remains the main cause of morbidity and mortality in Burkina Faso. Based on the recommendation of the World Health Organization, artemisinin-based combination therapy (ACT) was adopted by the national malaria control programme (NMCP) for the treatment of uncomplicated malaria since 2005. The two combinations adopted in the country as first-line regimen are artemether–lumefantrine (AL) and artesunate–amodiaquine (ASAQ) [1, 2]. Globally, several efficacy and effectiveness studies have demonstrated their high efficacy and safety for the treatment of uncomplicated Plasmodium falciparum malaria [3‐5].

However, in most of these studies, drug intake was supervised by a study team and treatment was strictly administered in accordance with manufacturer’s recommendations. Yet, in poor resource settings with high malaria morbidity, strict adherence to these conditions is often not observed in real life settings. A recent study conducted in this study area has already shown a lowering of the cure rate of ACT in real life comparative to the other efficacy studies [6]. In addition, most of those studies were limited to children under five and the older populations are typically not involved. Despite the upheld notion that adults are immune-protected, behaviour towards the treatment, such as not completing treatment regiments, could be higher in adults and this could negatively influence treatment outcomes. Therefore, an assessment of treatment outcomes that would fully reflects the reality in the field has to involve all age groups in the population. Moreover, the best indicator for safety could be obtained from adults since children are challenged to make recalls on safety information. It is based on these compelling reasons that this study was carried out in order to assess the effectiveness and safety of the two recommended forms of ACT in Burkina Faso as they are used routinely in treating uncomplicated malaria in all age groups in the country.

A total of 1480 patients was screened to be included in the study. Among them, 1010 (68.2 %) patients were positive for malaria. Out of them, 680 patients were randomized to receive one of the two treatments. A total of 340 patients received ASAQ as treatment and 340 patients received AL. Twenty (20) patients (2.9 %) were excluded from the analysis and the reasons for exclusion and sampling plan are shown in trial profile (Fig. 1). A total of 496 (75.1 %) patients were children under 5 years old versus 164 (24.8 %) over 5 years of age. The baseline characteristics of patients included in the study are shown in Table 1. At recruitment, the two treatment groups were comparable in all characteristics except for the haemoglobin level, which was higher in AL group than in ASAQ group (p = 0.019).

By day 28 the ACPR was significantly higher in ASAQ group than in AL group before and after adjustment by PCR (Table 2). Before PCR adjustment ACPR in AL group was 47.7 versus 67.0 % in ASAQ group [risk difference = −0.19, 95 % CI (−26.62; −11.81), p < 0.00001]. The adjusted ACPR was 77.8 % in AL group versus 84.1 % in ASAQ group [risk difference = −6.32, 95 % CI (−12.29; −0.34), p = 0.0389]. Two ETF were found in AL group versus three in ASAQ treated patients.

In both AL and ASAQ groups, treatment outcomes were better in patients over 5 years old than in children under five before adjustment by PCR. Before adjustment, ACPR in AL group was 43.3 and 61.7 % in children under 5 years and patients over 5 years old respectively (p = 0.004). In ASAQ group ACPR before adjustment was 63.1 % in children under 5 years old versus 78.3 % in patients over 5 years of age (p = 0.013). After PCR adjustment, ACPR was higher in older patients than in children less than 5 years old in both treatment groups but the difference was not statistically significant (Table 3).

The risk of recrudescence in both AL and ASAQ group is represented in Fig. 2. The risk of recrudescence was higher in AL treated patients than in those receiving ASAQ (p = 0.0059). In both groups the risk of recrudescence became more observable after day 14.

Figure 3 represents the risk of new infection in each of the two treatment arms. The new infections start after day 14 and it was significantly higher in AL group than in ASAQ group.

Both AL and ASAQ treatment were well tolerated by the patients. An average of two AEs per patient was recorded in both AL and ASAQ treated patients. The most commonly observed AEs reported for each AL/ASAQ treatment were fever (n = 117/83) cough (n = 75/74), diarrhoea (n = 61/65), rhinitis (n = 19/20), anaemia (n = 17/17),vomiting (n = 11/20), abdominal pain (n = 15/11), anorexia (n = 9/12), conjunctivitis (n = 6/10), otitis (n = 9/5), headache (n = 7/7), and pruritus (n = 5/3). Six serious adverse events (SAE) were found in AL group versus four in ASAQ group and most of them were not linked to the treatment. The majority of AE was mild and was unlikely or definitely unrelated to the administrated treatment (Table 4).

Although numerous studies carried out in malaria endemic countries had shown good efficacy and safety of ACT for the treatment of uncomplicated malaria, the conditions of clinical trials do not fully reflect real field situation. Moreover, the assessment of the efficacy of the unsupervised therapy is of greatest interest in a context of home management of malaria by community medicines distributors. This study shows that the unsupervised cure rate after adjustment by day 28 is 77.8 and 84.1 %, respectively for AL and ASAQ, indicating a lowering of the cure rate when drug intake is not directly supervised. Similar findings have been observed in a study carried out on Gabonese children [12]. A recent study conducted in the same area has also shown a cure rate of 89.7 % for AL and 89.8 % for ASAQ after 42 days follow-up for the unsupervised malaria treatment [6]. However when drug administration is directly supervised a cure rate of about 90 % has always been observed [13, 14]. But as in this study drug intakes were not supervised and the assessment adherence was based on patient self-reporting on day 3, this lowering of the cure rate should be taken with caution. This constituted one of the limitations of our study because some studies have shown a difference in adherence rate obtained by the use of different methods and the assessment based on patients self-reporting seems not to be the most appropriate [15, 16]. Therefore, compliance to the treatment and above all, the preferable administration of AL with fatty food that could not be respected in real field conditions could explain the lowering of the cure rate. Thus the unsupervised therapy with AL results in lower plasma levels of lumefantrine with an increased risk for early infection [17]. Furthermore, vomiting was one of the commonest AEs observed in both AL and ASAQ treated patients. In the unsupervised condition it was difficult to obtain reliable information about time elapsed between drug intake and vomiting and this could affect the efficacy of the two drugs when it occurred a while after drugs intake. Moreover a recent ex vivo study conducted at the same area has shown a decrease in sensitivity of lumefantrine in the country and this could further explain this lowering of the cure rate [18]. In addition findings in a study carried out in Kenya indicated a decline in sensitivity of P. falciparum to ACT, in particular AL and dihydroartemisinin–piperaquine [19]. It is also known that some cases of artemisinin-resistance have been recorded in Asia, and a particular care for the wide spread use at community level should be taken for the preservation of the activity of these drugs [20]. Of particular interest in this study was the involvement of patients of all age groups and this shows that the parasitological cure rate in patients over 5 years is higher than for children under 5 years of age. This is not surprising and could be explained by the additive effect of the partially acquired immunity in aged patients living in endemic area due to frequent expositions to mosquito bites [21].

Both AL and ASAQ were well-tolerated, similar to many other studies with AEs mostly mild and not linked to the administrated treatment [5, 22]. A limitation to this study was the challenge of getting reliable safety recall information from young children who constituted an important part of the study population.

In a context where home management of malaria has been adopted as one of the main strategies for malaria control, the assessment of the effectiveness of unsupervised therapy is of fundamental importance. This study shows a lowering of the efficacy when drug intake is not directly supervised. The results reported here is worrying as both rates are lower than the critical threshold of 90 % required by the WHO to recommend the use of an anti-malarial drug in a treatment policy [23, 24]. Nevertheless, there is a need to conduct similar studies coupled with a collection of data on study participants’ adherence to treatment and diet habit to confirm these findings.