In areas where malaria is highly endemic (much of Africa) patients, especially children, are often treated repeatedly over a relatively short period of time. Typically, studies of antimalarial drug efficacy have focused on individual episodes of disease, and limited follow-up to 2, 4 or at most 8 weeks. There is an assumption that using more effective treatments will lead to significantly fewer episodes of malaria and thus lower morbidity (e.g. anaemia), and that drugs that are safe when used once are safe with repeated use. Both assumptions may well be true but have not been demonstrated directly in high-transmission settings. This has significant implications for the public health impact and cost-effectiveness of using more effective drugs. Broadly, the greater the effect of ACTs on reducing the incidence of symptomatic malaria and frequency of treatment the more cost-effective they are likely to be both for the family unit and the healthcare system. The cost-effectiveness is likely to depend on the efficacy of the drug, the incidence of malaria, and the pharmacokinetic characteristics of the drug combination. In high-transmission settings, slowly eliminated companion drugs such as lumefantrine or piperaquine might be expected to provide post-treatment prophylaxis and prevent new malaria infections. This may have a substantial impact on the effectiveness and cost-effectiveness of new regimens, especially in highly endemic areas. It remains unclear whether more expensive drugs should be deployed as first-line therapy in high-transmission settings or reserved for second-line treatment of probable treatment failures. Both models have been advocated; currently there are no data on which to decide between these two strategies. Cost-effectiveness models based on a singe episode treated or not treated fail to capture the effect of repeated treatment episodes except indirectly; the studies proposed will provide the data to do this directly.
Additionally, although the safety of ACTs has been assessed in single-dose trials, with reassuring results, the safety of repeated dosing has not been determined, especially in infants and young children, and data from animal studies suggest that the possibility of cumulative toxicity cannot be excluded. If this is a problem it is likely to be most apparent in infants and young children with developing brains exposed to repeated dosing. The average adult in the parts of Asia where artemisinins are widely deployed is unlikely to be treated more than once every few years. The average child in many parts of Africa has true clinical malaria three or more times a year and may be treated for malaria more frequently, so if there is any risk it is likely to be substantially higher.
Treatment trials using repeated dosing with the same drug are not a substitute for conventional drug efficacy and safety trials, but are a necessary follow-on and are particularly important for accurate assessment of cost-effectiveness.