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Throughout a phase IIIb/IV efficacy study of repeated treatment with four artemisinin-based combination therapies, significant heterogeneity was found in the number of clinical episodes experienced by individuals during the 2-year follow-up. Several factors, including host, parasite, and environmental factors, may contribute to the differential malaria incidence. We aimed to identify risk factors of malaria incidence in the context of a longitudinal study of the efficacy of different artemisinin-based combination therapy regimens in Bougoula-Hameau, a high-transmission setting in Mali. Risk factors including age, residence, and treatment regimen were compared among individuals experiencing eight or more clinical episodes of malaria (“high-incidence group”) and individuals experiencing up to three clinical episodes (“low-incidence group”). Consistent with the known association between age and malaria risk in high-transmission settings, individuals in the high incidence group were significantly younger than individuals in the low-risk group (mean age, 7.0 years versus 10.6 years, respectively; t-test, P < 0.0001). Compared with individuals receiving artemether-lumefantrine, those receiving artesunate-amodiaquine had greater odds of being in the high-incidence group (odds ratio [OR], 2.24; 95% CI, 1.03 – 4.83, P = 0.041), while individuals receiving dihydroartemisinin-piperaquine had a lower odds of being in high incidence group (OR: 0.30, 95% CI, 0.11–0.85; P = 0.024). Individuals residing in the forested areas of Sokourani and Karamogobougou had significantly greater odds of being in the high-incidence group compared with individuals residing in the semi-urban area of Bougoula-Hameau 1 (Karamogobougou: OR, 3.68; 95% CI, 1.46–9.31; P = 0.0059; Sokourani: OR, 11.46; 95% CI, 4.49–29.2; P < 0.0001). This study highlights the importance of fine-mapping malaria risks even at sub-district levels for targeted and customized interventions.

Artemisinin-resistant Plasmodium falciparum malaria has been documented in southeast Asia and may already be spreading in that region. Molecular markers are important tools for monitoring the spread of antimalarial drug resistance. Recently, single-nucleotide polymorphisms (SNPs) in the PF3D7_1343700 kelch propeller (K13-propeller) domain were shown to be associated with artemisinin resistance in vivo and in vitro. The prevalence and role of K13-propeller mutations are poorly known in sub-Saharan Africa. K13-propeller mutations were genotyped by direct sequencing of nested polymerase chain reaction (PCR) amplicons from dried blood spots of pre-treatment falciparum malaria infections collected before and after the use of artemisinin-based combination therapy (ACT) as first-line therapy in Mali. Although K13-propeller mutations previously associated with delayed parasite clearance in Cambodia were not identified, 26 K13-propeller mutations were identified in both recent samples and pre-ACT infections. Parasite clearance time was comparable between infections with non-synonymous K13-propeller mutations and infections with the reference allele. These findings suggest that K13-propeller mutations are present in artemisinin-sensitive parasites and that they preceded the wide use of ACTs in Mali.

Residents of malaria-endemic areas sometimes spontaneously clear Plasmodium falciparum infection without drug treatment, implying an important role for host factors such as immunity in this clearance. Host factors may also contribute to clearance of parasites resistant to a treatment drug. Chloroquine resistance is caused by point mutations in P. falciparum chloroquine resistance transporter (pfcrt) gene. We investigated the clearance of malaria parasites carrying the key chloroquine resistance-conferring PfCRT mutation K76T in patients treated with chloroquine. We found that the ability to clear these resistant parasites is strongly dependent on age (the best surrogate for protective immunity in endemic areas), suggesting that host immunity plays a critical role in the clearance of resistant P. falciparum infections. Age-adjusted comparison of subjects able to clear resistant parasites and those unable to do so provides a new phenotype for identifying host immune and genetic factors responsible for protective immunity against malaria.

Inappropriate use of antimalarial drugs undermines therapeutic efficacy and promotes the emergence and spread of drug-resistant malaria. Strategies for improving compliance require accurate information about current practices. Here we describe Knowledge-Attitude-Practice surveys conducted among health providers and consumers in two Malian villages, one rural and one periurban. All sanctioned providers limited their first choices of antimalarial drug to those recommended by the national malaria control program and reported using correct dosing regimens. However, the majority of consumers in the two villages chose non-recommended treatments for malaria and reported suboptimal treatment regimens when they did use recommended drugs. Antimalarial drugs were also widely available from unsanctioned sources, often accompanied by erroneous advice on dosing regimens. This study demonstrates that even when the most peripheral health providers are well-trained in correct use of antimalarial drugs, additional measures directly targeting consumers will be required to improve drug use practices.