Randomized trial of artesunate-amodiaquine, atovaquone-proguanil, and artesunate-atovaquone-proguanil for the treatment of uncomplicated falciparum malaria in children.

BACKGROUND: Artemisinin-based combination therapies (ACTs) are recommended for the treatment of acute uncomplicated falciparum malaria in many malaria-endemic countries. Despite the emergence of artemisinin resistance, few alternative non-ACTs, including atovaquone-proguanil, are currently available. METHODS: Plasmodium falciparum-infected Cameroonian children ≤5 years old (n = 338) were randomly assigned to artesunate-amodiaquine, atovaquone-proguanil, or artesunate-atovaquone-proguanil treatment groups and followed for 28 days, according to the standard World Health Organization protocol. In vitro response to atovaquone and cytochrome b sequence of clinical isolates were determined. RESULTS: Eight late failures and 16 failures (8 late and 8 early failures) were observed after artesunate-amodiaquine and atovaquone-proguanil therapies, respectively. Most late failures were due to reinfections. Artesunate-atovaquone-proguanil was not associated with any failure. After correction by genotyping, per-protocol analysis showed no difference in the efficacy of 3 drugs. However, the proportion of atovaquone-proguanil-treated patients with positive smears on day 3 was much higher (36.0%; P < .05) than that of the artesunate-amodiaquine (2.9%) and artesunate-atovaquone-proguanil (1.0%) groups. In vitro response and cytochrome b sequence did not indicate atovaquone resistance. CONCLUSIONS: Atovaquone-proguanil was characterized by a slow blood schizontocidal action and resulted in early treatment failure in a few patients. Artesunate-atovaquone-proguanil was a highly effective alternative treatment. CLINICAL TRIALS REGISTRATION: UMIN000003813.

Cytoadherence phenotype of Plasmodium falciparum-infected erythrocytes is associated with specific pfemp-1 expression in parasites from children with cerebral malaria.

BACKGROUND: Cytoadherence of Plasmodium falciparum-infected erythrocytes (IEs) in deep microvasculature endothelia plays a major role in the pathogenesis of cerebral malaria (CM). This biological process is thought to be mediated by P. falciparum erythrocyte membrane protein-1 (PfEMP-1) and human receptors such as CD36 and ICAM-1. The relationship between the expression of PfEMP-1 variants and cytoadherence phenotype in the pathology of malaria is not well established. METHODS: Cytoadherence phenotypes of IEs to CD36, ICAM-1, CSPG and the transcription patterns of A, B, var2csa, var3, var gene groups and domain cassettes DC8 and DC13 were assessed in parasites from children with CM and uncomplicated malaria (UM) to determine if cytoadherence is related to a specific transcription profile of pfemp-1 variants. RESULTS: Parasites from CM patients bind significantly more to CD36 than those from UM patients, but no difference was observed in their binding ability to ICAM-1 and CSPG. CM isolates highly transcribed groups A, B, var2csa, var3, DC8 and DC13 compared to UM parasites. The high transcription levels of var genes belonging to group B positively correlated with increased binding level to CD36. CONCLUSION: CM isolates bind significantly more to CD36 than to ICAM-1, which was correlated with high transcription level of group B var genes, supporting their implication in malaria pathogenesis.

Differences in gene transcriptomic pattern of Plasmodium falciparum in children with cerebral malaria and asymptomatic carriers.

The mechanisms underlying the heterogeneity of clinical malaria remain largely unknown. We hypothesized that differential gene expression contributes to phenotypic variation of parasites which results in a specific interaction with the host, leading to different clinical features of malaria. In this study, we analyzed the transcriptomes of isolates obtained from asymptomatic carriers and patients with uncomplicated or cerebral malaria. We also investigated the transcriptomes of 3D7 clone and 3D7-Lib that expresses severe malaria associated-variant surface antigen. Our findings revealed a specific up-regulation of genes involved in pathogenesis, adhesion to host cell, and erythrocyte aggregation in parasites from patients with cerebral malaria and 3D7-Lib, compared to parasites from asymptomatic carriers and 3D7, respectively. However, we did not find any significant difference between the transcriptomes of parasites from cerebral malaria and uncomplicated malaria, suggesting similar transcriptomic pattern in these two parasite populations. The difference between isolates from asymptomatic children and cerebral malaria concerned genes coding for exported proteins, Maurer's cleft proteins, transcriptional factor proteins, proteins implicated in protein transport, as well as Plasmodium conserved and hypothetical proteins. Interestingly, UPs A1, A2, A3 and UPs B1 of var genes were predominantly found in cerebral malaria-associated isolates and those containing architectural domains of DC4, DC5, DC13 and their neighboring rif genes in 3D7-lib. Therefore, more investigations are needed to analyze the effective role of these genes during malaria infection to provide with new knowledge on malaria pathology. In addition, concomitant regulation of genes within the chromosomal neighborhood suggests a common mechanism of gene regulation in P. falciparum.