Antimalarial Drug Resistance: A Threat to Malaria Elimination

Abstract

Increasing antimalarial drug resistance once again threatens effective antimalarial drug treatment, malaria control, and elimination. Artemisinin combination therapies (ACTs) are first-line treatment for uncomplicated falciparum malaria in all endemic countries, yet partial resistance to artemisinins has emerged in the Greater Mekong Subregion. Concomitant emergence of partner drug resistance is now causing high ACT treatment failure rates in several areas. Genetic markers for artemisinin resistance and several of the partner drugs have been established, greatly facilitating surveillance. Single point mutations in the gene coding for the Kelch propeller domain of the K13 protein strongly correlate with artemisinin resistance. Novel regimens and strategies using existing antimalarial drugs will be needed until novel compounds can be deployed. Elimination of artemisinin resistance will imply elimination of all falciparum malaria from the same areas. In vivax malaria, chloroquine resistance is an increasing problem.

Figure 1.

Overview of the current situation of falciparum artemisinin resistance (A), and vivax chloroquine resistance (B). (A) Frequency distribution of the wild-type K13 allele worldwide (left panel) and in Asia (right panel). Malaria-endemic areas are from the maps from www.map.ox.ac.uk/browse-resources/endemicity/Pf_mean and shaded in gray. Areas in white are considered malaria free. The mean frequency of the wild-type allele is shown using the color code shown in the inset. Data were interpolated using two different approaches and the map censored for regions with very low to nil reported malaria prevalence. To generate the world map (left panel), we used an inverse distance-weighted interpolation method with the gstat package, where the inverse distance weighting power was arbitrarily set to 5. A 100-km radius surrounding the coordinate sampling site(s) was used. To generate the Asia map (right panel), we used the well-established spatial statistical interpolation of ordinary kriging using a 50-km radius for the area surrounding the coordinate sampling site(s). The individual sites of sample collection are indicated with a cross (reproduced, with permission). (B) Chloroquine resistance in Plasmodium vivax infections. The map summarizes evidence from published and unpublished data from 1980 to 2015 compiled by the WWARN, available at www.wwarn.org. Category 1: >10% recurrent infections by day 28 (with a lower 95% CI of >5%), irrespective of confirmation of adequacy of blood chloroquine concentrations at the moment of recurrence. The presence of >10% recurrent infections is highly suggestive of chloroquine resistance. Category 2: parasitological confirmed recurrent infection within 28 d, in the presence of adequate whole-blood chloroquine concentrations (>100 nm) at the moment of recurrence. This confirms chloroquine resistance. Category 3: >5% recurrent infections by day 28 (lower 95%, CI of <5%), irrespective of confirmation of adequacy of blood chloroquine concentrations at the moment of recurrence. In this category, the contribution of other factors than drug resistance, such as poor drug absorption or drug quality, cannot be ruled out. Category 4: chloroquine-sensitive P. vivax infections, concluded from studies reporting on ≥10 symptomatic patients with symptomatic malaria, treated with chloroquine monotherapy (without early primaquine treatment), showing fewer than 5% recurrent infections within 28 d. (Reproduced, with permission, from WWARN.)

Figure 2.

Current insights in artemisinin resistance from the molecular to the public health level.