Abdoulaye Djimde

University of Bamako, Mali

Artemisinine-based combination therapies (ACTs) are the current best treatments available for malaria. However, beyond absolute drug efficacy, it is necessary to evaluate the overall public health impact of the different ACTs in Africa.  We are conducting a randomised controlled trial in Mali. Patients with uncomplicated malaria are randomised to receive AS/AQ (Arsucam® from Sanofi Synthelabo), AS/SP or AR-L (Coartem®, Novartis).  Once subjects have been assigned to a given group, subsequent malaria episodes are re-treated with that same treatment regimen.

Background
The spread of malaria parasites resistant to safe and affordable drugs is greatly hampering the control of malaria in Africa. As a consequence, sub-Saharan African countries including Mali are adopting artemisinine-based combinations (ACT) as first line anti-malarial therapy.

Reports suggest that efficacy measured at Day 14 or 28 may not adequately reflect the true public health impact of a treatment regimen. Therefore, it is important to assess the safety and overall public health impact of the repetitive administration of these new combinations in the African context.

Objectives
We will assess the public health benefit of the use of ACTs in sub-Saharan Africa. Specific objectives are:

1. To test the hypothesis that repeated administration of AS/AQ, AS/SP and AR-L for the treatment of consecutive episodes of uncomplicated malaria reduces the incidence of uncomplicated falciparum malaria and malaria attributable anemia
2. To measure the impact of the repeated administration of AS/AQ, AS/SP and AR-L on antimalarial immunity and malaria transmission.

Primary endpoint will be the incidence density of uncomplicated malaria over two years. Secondary end points will be incidence of anemia in each arm, impact on gametocyte carriage and transmissibility, clinical and biological tolerance. Patients are closely followed both clinically and biologically to record any adverse event. Training and capacity building activities are fostering the emergence of a  new research team of young Malian scientists.
 
Methods
Since June 2005 we are conducting a randomized controlled trial in Bougoula-Hameau, an area where malaria is hyper-endemic with seasonal transmission in Southern Mali. Patients with uncomplicated malaria are randomised to receive AS/AQ (Arsucam® from Sanofi Synthelabo), AS/SP or AR-L (Coartem®, Novartis). Once subjects have been assigned to a given group, subsequent malaria episodes are re-treated with that same treatment regimen. Patients are closely followed both clinically and biologically to record any adverse events. Training and capacity building activities are also underway.

Preliminary results
To date we have enrolled 973 episodes of uncomplicated malaria in the three arms. All treatments were highly efficacious. The majority of patients experienced one episode but in just the first year of follow-up some children have already experienced their fifth episode of malaria. There was no significant difference in the frequency of clinical episodes between the three arms. Direct feeding experiments suggest that ACT treatments do not decrease the infectivity of gametocytes to the vector.

Perspectives
We will extend the follow-up to a second year before final analyses.