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-endemie 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 artesunateamodiaquine and atovaquone-proguanil therapies, respectively. Most late failures were due to reinfections. Artesunateatovaquone-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