Effects of Plasmodium falciparum Parasite Population Size and Patient Age on Early and Late Parasitological Outcomes of Antimalarial Treatment in Children

Abstract

The design and interpretation of trials assessing the chemotherapeutic effects of antimalarial drugs depend on our understanding of how different selection criteria affect treatment outcomes. In this study, we analyzed the effects of baseline parameters on the initial parasite elimination rate and the risk of subsequent recrudescence as a marker for incompletely eliminated asexual blood-stage parasites in pediatric patients with uncomplicated Plasmodium falciparum infection treated with amodiaquine in a high-transmission area. We found that (i) parasite population size and patient age independently determine early and late parasitological treatment outcome measurements; (ii) the rate of recrudescence is higher in patients 1 to 3 years of age than in patients aged <1 or >3 years; (iii) patients aged >5 years with parasite densities between 2,000 and 10,000/l have a lower recrudescence rate (13%; 95% confidence interval [CI], 8% to 21%) than patients aged <5 years with parasite densities of >10,000/l (40%; 95% CI, 30% to 50%); and (iv) the sensitivity of detecting recrudescences outside this high-risk group, i.e., in patients of >5 years of age or with parasite densities of <10,000/l, is as low as 27% or 22%, respectively. In conclusion, these findings highlight the need to use adequate selection criteria and to report parasitological outcome results adjusted for the readily available determinants of chemotherapeutic failure, i.e., patient age and baseline parasitemia. The thresholds may vary by transmission intensity and drug regimen. A better understanding of the limitations of antimalarial regimens in high-risk subgroups of patients has important implications for setting policy recommendations.Antimalarial treatment trials provide the empirical evidence base for antimalarial treatment policies in countries where malaria is endemic (44). These trials use variable endpoints to address a range of public health questions. For instance, trials conducted to monitor the emergence or the spread of in vivo resistance or to determine the chemotherapeutic efficacy of a new regimen are designed to measure the ability of the treatment to completely eliminate asexual blood-stage parasites and, thus, to prevent recrudescent infections. On the other hand, the delay of reinfection caused by the effects of slowly eliminated drugs on the erythrocytic and, in some cases, hepatic stages of Plasmodium falciparum infection (14) can be an important additional clinical benefit of antimalarial treatment. This has been investigated in studies that use a combined measurement of the chemotherapeutic and the "posttreatment prophylactic" effects ("recurrence rate") or that simply determine the requirement for retreatment (12). Regardless of the objectives in these trials, the characterization of the limitations of an antimalarial regimen in important subgroups of patients at high risk of failure, who may also be disproportionately susceptible to adverse clinical outcomes, will provide critical information for setting policy recommendations. ...

Inadequate Efficacy of a New Formulation of Fosmidomycin-Clindamycin Combination in Mozambican Children Less than Three Years Old with Uncomplicated Plasmodium falciparum Malaria

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Declining Responsiveness of Plasmodium falciparum Infections to Artemisinin-Based Combination Treatments on the Kenyan Coast

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In Vivo and In Vitro Efficacy of Amodiaquine againstPlasmodium falciparumin an Area of Continued Use of 4‐Aminoquinolines in East Africa

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