Efficacy of artesunate plus amodiaquine versus that of artemether-lumefantrine for the treatment of uncomplicated childhood Plasmodium falciparum malaria in Zanzibar, Tanzania

Background. This is the first clinical trial comparing the efficacy of artesunate plus amodiaquine (ASAQ) and artemether-lumefantrine (AL)-the major artemisinin-based combination therapy (ACT) candidates for treatment of malaria in Africa - that involved an extended, 42-day follow-up period, polymerase chain reaction - adjusted parasitological cure rates (PCR APCRs), and systematic analyses of genetic markers related to quinoline resistance. Methods. A total of 408 children with uncomplicated Plasmodium falciparum malaria in Zanzibar, Tanzania, were enrolled. Children who were 6 - 8 months of age and/or who weighed 6 - 8 kg were assigned to receive ASAQ for 3 days. Children who were 9 - 59 months of age and who weighted >= 9 kg were randomly assigned to receive either ASAQ or AL for 3 days in standard doses. Intention-to-treat analyses were performed. Results. Age- and weight-adjusted PCR-APCRs by follow-up day 42 were 91% ( 188 of 206 patients) in the ASAQ group and 94% (185 of 197 patients) in the AL group (odds ratio [OR] for the likelihood of cure, 2.07; 95% confidence interval [CI], 0.84 - 5.10;). A total of 5 and 7 recrudescences occurred after day 28 in Pp. 115 the ASAQ and AL groups, respectively. On the assumption that 10 malaria episodes with uncertain PCR results were recrudescences, PCR-APCRs decreased to 88% in the ASAQ group and to 92% in the AL group. Unadjusted cure rates by day 42 were 56% (116 of 206 patients) in the ASAQ group versus 77% (151 of 197 patients) in the AL group (OR, 2.55; 95% CI, 1.66 - 3.91;). Rates of reinfection by day 42 were 36% (65 of 181 patients) P < .001 in the ASAQ arm versus 17% (31 of 182 patients) in the AL arm (OR, 0.37; 95% CI, 0.22 - 0.60;). A P < .001 significant selection of P. falciparum multidrug resistance gene 1 allele 86N was found in isolates associated with reinfection after AL treatment, compared with isolates at baseline (2.2-fold increase;). P < .001 Conclusions. Both treatments were highly efficacious, but AL provided stronger prevention against reinfection. The high proportion of recrudescences found after day 28 and the genetic selection by the long-acting partner drug underlines the importance of long follow-up periods in clinical trials. A long follow-up duration and performance of PCR genotyping should be implemented in programmatic surveillance of antimalarial drugs.