Reply to Cavaco et al

TO THE EDITOR—The work by Cavaco et al [1] nicely addresses the issue of the possible interplay between host genetic variation and the risk of acquiring drugresistant Plasmodium falciparum strains. The involvement of the human genetic variation related to an impaired drug metabolism as a possible cofactor in the selection and spread of P. falciparum drug resistance was first addressed by Paganotti et al [2] for chloroquine (CQ) in Burkina Faso. The very important retrospective study performed by Cavaco et al [1] opens a new window of research related to artemisinin combination therapies (ACTs) and parasite resistance selection that is the ultimate tool in the research for drug resistance containment in malaria. However, some important points need to be clarified. First of all, the 2 studies were related to 2 very different epidemiological settings where different drugs were in use at different time points in the context of the spread of drug resistance. Both CQ and amodiaquine (AQ) are metabolized via the CYP2C8 enzyme, with the difference that CYP2C8 is one of at least 3 CYP450 enzymes contributing to the metabolism of CQ, whereas CYP2C8 is the main (or unique) actor of the metabolism of AQ. Moreover, the study of Paganotti et al [2] was focused on the defective allele CYP2C8*2, which is associated with drug metabolism that is impaired but not to a high level as high as that of CYP2C8*3. Unfortunately, the *3 allele is