Antimalarial chemotherapy has been the primary option in the fight against malaria. However, the burden of this disease is still very heavy partly due to the development of multi-drug resistant Plasmodium falciparum strains 1234. The malaria community presently considers mono-therapy as an inappropriate approach for malaria treatment5. African countries have recently begun to scale up their antimalarial efforts, and are deploying strategies to combat the new face of malaria. One of these strategies is the use of artemisinin-based combination therapies (ACTs) which have proven to be very effective against malaria in Africa, and some African countries plagued with resistant forms of P.falciparum have started instituting the ACTs as first line malaria treatment 67.

Artesunate plus amodiaquine combination is one ACT recommended by the World Health Organization (WHO) for use in malaria control programmes and a first line treatment for African children with uncomplicated malaria 8. This recommendation is now a national policy in Gabon.

Artesunate and amodiaquine are generally safe and well tolerated when used as treatment for malaria 9101112131415161718. In a previous study the efficacy of artesunate-amodiaquine for uncomplicated P. falciparum malaria in Gabonese children was 94% 19, but the effectiveness of this combination under outpatient conditions in Gabon is not known.

There have been very few effectiveness studies on ACTs. Depoortere et al. 20 found that patients who received a combination of sulphadoxine/pyrimethamine and artesunate under supervision achieved a 28-day PCR corrected cure rate of 84% and effectiveness rate of 63%. The critical reader of the paper by Piola and colleagues 21 will find that despite final cure rates of 98% and 97% in both supervised and unsupervised subjects, there were substantial differences in lumefantrine blood concentrations in patients from the two groups, indicating that sometimes a difference between the efficacy and effectiveness of a highly efficacious drug like artemether-lumefantrine may not be demonstrable. It is important, therefore, that effectiveness of drugs is measured alongside clinical efficacy, considering that under everyday conditions many drug combinations do not reach the same cure rates that were measured in clinical trials under ideal conditions and supervised drug intake.

In the present study, we assessed the effectiveness of three-day artesunate plus amodiaquine combination administered unsupervised, compared with the efficacy when given under supervision to children with P. falciparum malaria was assessed.

Figure 1 depicts the trial profile. Baseline characteristics of study subjects are given in table 1. In the ATP analysis of this cohort of 61 patients, the proportion of children cured in the supervised group was 86% (25/29, 95% CI; 69% – 95%) and 63% (20/32, 95% CI; 45% – 77%) in the unsupervised group (p = 0.04) (Table 2). Intention-to-treat analysis yielded a similar decrease in proportion cured; 63% (30/48, 95 % CI; 48 – 75%) in the supervised group and 49% (20/41, 95 % CI; 34% – 63%) in the unsupervised group (p = 0.2).

The risk ratio in the ATP analysis indicates that supervised administration of artesunate plus amodiaquine combination to children aged below 30 months have a lower risk of failure to treatment compared to when unsupervised (risk ratio= 0.38, p = 0.04). Supervised administration of artesunate plus amodiaquine combination to children aged below 30 months is also positively associated with an increase in probability of achieving a cure from uncomplicated malaria (risk ratio of 1.4 and 1.2 respectively in the ATP and ITT analysis). This translates into an increase of 27% benefit if administration of this drug is supervised. Equivalently, one more cure with artesunate plus amodiaquine can be achieved for every 4 patients treated under supervision.

The median parasitaemia of our cohort was 7,500 parasites/μL. The mean haemoglobin concentration in the supervised and unsupervised groups on day 0 were 8.7 g/dL and 8.1 g/dL respectively (p = 0.16), and on day 28 were 9.5 g/dL and 8.9 g/dL respectively (p = 0.03). The mean changes were not different between the groups. However, on day 0, thirty-nine patients (64%) had anemia defined as haemoglobin between 5 and 9 g/dL. On day 28, eighteen patients (30%) fell under this definition of anemia. Overall the mean haemoglobin concentration increased from 8.4 g/dL on day 0 to 9.2 g/dL by day 28.

There were 36 adverse events reported during the course of this study, the most reported were cough (18%), diarrhoea (12%), vomiting (5.6%), and skin infections (4.5%). There was no serious adverse event or death recorded. In the supervised group, two subjects were treated with the five-day artesunate monotherapy 29, because they vomited after a repeated dose of artesunate plus amodiaquine. Three subjects missed the second dose, one missed the third dose and 1 missed the second and third dose, while in the unsupervised group, two subjects were hospitalized for weakness. These nine protocol violations were excluded from the ATP analysis.

This study shows that supervised administration of artesunate plus amodiaquine to Gabonese children aged less than 30 months with uncomplicated falciparum malaria substantially reduces the risk of treatment failure compared to unsupervised administration. The proportion of supervised children cured by day 28 was 86%, while that of unsupervised children was substantially lower (63%). In a previous randomized study carried out in Lambaréné, supervised administration of artesunate plus amodiaquine achieved a PCR corrected cure rate of 94% by day 28 19. The difference in proportion cured when supervised and when unsupervised does not only reflect the significant gap between the usual optimistic efficacy reports of studies and the real-life situation 20, but puts question on the effectiveness of this combination in the treatment of young children with falciparum malaria especially under the usual unsupervised outpatient condition.

Artesunate plus amodiaquine combination was well tolerated. There were no serious adverse events reported during the course of this study. The weakness of our study was that it was not randomized and the sample size was relatively small. Crushed tablets that are probably harder to administer than palatable syrup were used. There is a clear benefit of supervised compared to an unsupervised treatment shown in the ATP analysis which was less evident in the ITT analysis. Certainly the effectiveness of 63% under unsupervised conditions in this study is unacceptably low. This effectiveness might be higher with a fixed combination better tasting syrup given under supervised conditions.

The therapeutic life of this first line antimalarial recommended for the treatment of uncomplicated P.falciparum malaria 3031 can be maintained. The effectiveness of artesunate plus amodiaquine for treatment of falciparum malaria in Lambaréné will depend on how well adherence to this regimen can be ensured. The present plan of Drugs for Neglected Diseases Initiative (DNDi) 32 and partners to make this fixed-dose of artesunate-amodiaquine available in 2006, calls for more effectiveness data on this combination. This will guide policy implementation that will assist malaria control programmes and clinics to develop strategies that encourage adherence to this regimen, which in turn will prolong the effective life span of this combination for the treatment of falciparum malaria 2033.

SO designed the study, collected data and prepared the manuscript.

MP designed the study, collected data and prepared the manuscript.

NGS contributed in the preparation of the manuscript.

JD, ML and COS collected data and participated in the study design.

JFK contributed to the molecular genetic studies and contributed to draft the manuscript.

BL, PGK and MPG helped in designing the study and in data analysis and interpretation.