Intensity of malaria transmission and the evolution of drug resistance.

The intensity of malaria transmission varies both naturally and as a consequence of human public health intervention. The relationship between transmission intensity and the rate at which antimalarial drug resistance evolves affects the design of surveillance programmes, and the likely impact of malaria control programmes. Several theoretical studies have investigated this relationship and their key results are summarised and interpreted. The most important result is that transmission intensity does not directly affect the evolution of resistance. It exerts its influence through three clinical/epidemiological "mediators" (clonal multiplicity, the threat of infection, level of human immunity) which ultimately determine the dynamics of resistance via five "effector" variables: sexual recombination, intrahost dynamics, community drug use, proportion of malaria infections treated, and the number of parasites per host. We argue that the evolution of resistance is likely to be a two-stage process: mutations encoding drug tolerance preceding those encoding resistance. The evolution of drug tolerance is determined solely by the level of drug use in the community which is likely to have an extremely weak relationship with transmission intensity. The evolution of resistance is more complex and affected by all five effectors. The most likely scenarios are that resistance evolves faster in areas of high transmission if encoded by a single gene but if encoded by two or more genes it evolves fastest in areas of high or low transmission, with a minimum at intermediate levels of transmission.