Malaria remains a major cause of illness and death in developing countries. As resistance of malaria parasites to conventional antimalarial drugs is emerging, it is important to support development of new drugs and combination regimens. Since 2003, EDCTP has supported 19 projects on malaria treatment, which include studies of artemisinin-based combination therapies (ACTs) and non-ACTs. The studies aimed to establish therapies that are safe and highly effective in actual health care situations. Moreover, current studies aim to address the needs of patient groups that need special attention such as infants, malnourished children, HIV/AIDS co-infected individuals and pregnant women.

The Four Artemisinin-Based Combinations (4ABC) study was coordinated by Professor Umberto D’Alessandro, then at the Institute for Tropical Medicine, Antwerp, Belgium, currently at the Medical Research Council, The Gambia research unit. It compared 4ABC treatments of malaria in children between 6 and 59 months old.

A large multicentre randomised trial was set up to test four different treatments: amodiaquineartesunate (ASAQ), dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine (AL) and chlorproguanil/dapsoneartesunate (CD+A). Each site tested three of these treatments. Children with uncomplicated malaria were randomised to one of the study treatments, followed up actively until day 28 post-treatment and then passively for the next six months. The group also evaluated the safety and efficacy of repeated treatments.

The 4ABC study was successfully conducted in 7 sub-Saharan African countries (Burkina Faso, Gabon, Mozambique, Rwanda, Tanzania, Uganda and Zambia) at 12 trial centres. The study screened more than 10,000 children between 6 and 59 months old; a total of 4,116 children were included in the study and treated. The three novel artemisinin-based combination drugs were found to be safe and efficacious in treating children with uncomplicated malaria. AL, ASAQ, and DHAPQ had excellent efficacy up to day 63 post-treatment. However, the risk of recurrent infections was significantly lower, even in areas of high transmission, for DHAPQ, followed by ASAQ, and then AL. CDA treatment was withdrawn early in the course of the study for safety reasons (high risk of developing severe anaemia in glucose-6 phosphate dehydrogenase-deficient individuals).

This study contributed to the evidence on safety and efficacy of dihydroartemsinin plus piperaquine (DHAPQ) for its addition to the list of ACTs options recommended for the treatment of uncomplicated Plasmodium falciparum malaria by WHO. The policy will assist national malaria control programmes in sub-Saharan Africa in choosing the most appropriate ACTs for their specific setting. AL and ASAQ are already included in the antimalarial drug policies of many sub-Saharan African countries. Importantly, the data also showed that DHAPQ is a new option for the treatment of uncomplicated malaria with the added value of its long lasting prophylaxis in comparison to the other two ACTs. These results have contributed to the recent registration of DHAPQ by the European Medicines Agency (EMA).

Relevant publications:

1. D’Alessandro, U on behalf of The Four Artemisinin-Based Combinations (4ABC) Study Group. (2011) ‘A head-to-head comparison of four artemisinin-based combinations for treating uncomplicated malaria in African children: a randomised trial. PLOS Medicine. 8(11):e1001119
2. D’Alessandro, U. (2010) ‘Artemisinin combination therapies (ACTs) for uncomplicated malaria in African children: the 4ABC trial, preliminary results’. Tropical Medicine and International Health. 15(8):S13
3. Yeka, A; Tibenderana, J; Achan, J; D’Alessandro, U; Talisuna, AO. (2013) ‘Efficacy of quinine, artemetherlumefantrine and dihydroartemisinin-piperaquine as rescue treatment for uncomplicated malaria in Ugandan children’. PLOS ONE. 8(1):e53772.