Reconsidering the clinical assessment of resistance to slowly eliminated antimalarial drugs in high-transmission settings.

Therapeutic efficacy surveillance (TES) is the current WHO recommended method of assessing antimalarial treatment efficacy in vivo. TES has considerable limitations: it is logistically demanding, expensive, can only be conducted in a few sites, and is underpowered, and therefore, has low sensitivity for detecting emerging resistance. In high transmission settings, TES tends to overcall treatment failure and misses earlier recurrence caused by reinfection, which is the key identifiable feature of emerging resistance to slowly eliminated antimalarial drugs. We suggest an alternative approach to TES. At sentinel sites, the proportion of patients with symptomatic malaria who received a full artemisinin-based combination therapy course within the previous 3 weeks should be recorded. If this proportion exceeds a threshold (provisionally set at 5%), capillary blood spots dried on filter paper are taken for measurement of drug levels and PCR for malaria parasite identification and quantitation on all such patients. Resistance is defined by PCR-confirmed parasitaemia in the presence of therapeutic drug levels. This approach also facilitates conduct of genome-wide association studies with parasite density as the phenotype, adjusted for drug level. Compared with TES, our suggested approach should be a simpler, more readily deployable, less expensive, more sensitive, more generalisable, and more accurate method of identifying and characterising emerging resistance to slowly eliminated antimalarial drugs.