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Review
. 2017 Jan;41(1):34-48.
doi: 10.1093/femsre/fuw037. Epub 2016 Sep 8.

The clinical impact of artemisinin resistance in Southeast Asia and the potential for future spread

Charles J Woodrow  1 , Nicholas J White  2
Affiliations
Review

The clinical impact of artemisinin resistance in Southeast Asia and the potential for future spread

Charles J Woodrow et al. FEMS Microbiol Rev. 2017 Jan.

Abstract

Artemisinins are the most rapidly acting of currently available antimalarial drugs. Artesunate has become the treatment of choice for severe malaria, and artemisinin-based combination therapies (ACTs) are the foundation of modern falciparum malaria treatment globally. Their safety and tolerability profile is excellent. Unfortunately, Plasmodium falciparum infections with mutations in the 'K13' gene, with reduced ring-stage susceptibility to artemisinins, and slow parasite clearance in patients treated with ACTs, are now widespread in Southeast Asia. We review clinical efficacy data from the region (2000-2015) that provides strong evidence that the loss of first-line ACTs in western Cambodia, first artesunate-mefloquine and then DHA-piperaquine, can be attributed primarily to K13 mutated parasites. The ring-stage activity of artemisinins is therefore critical for the sustained efficacy of ACTs; once it is lost, rapid selection of partner drug resistance and ACT failure are inevitable consequences. Consensus methods for monitoring artemisinin resistance are now available. Despite increased investment in regional control activities, ACTs are failing across an expanding area of the Greater Mekong subregion. Although multiple K13 mutations have arisen independently, successful multidrug-resistant parasite genotypes are taking over and threaten to spread to India and Africa. Stronger containment efforts and new approaches to sustaining long-term efficacy of antimalarial regimens are needed to prevent a global malaria emergency.

Keywords: ACT; artemisinin; kelch; malaria; resistance; southeast Asia.

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Figures

Graphical Abstract Figure.
Graphical Abstract Figure.
Artemisinin resistance in Plasmodium falciparum malaria is causing failure of artemisinin-based combination therapies across an expanding area of Southeast Asia, undermining control and elimination efforts. The potential global consequences can only be avoided by new approaches that ensure sustained efficacy for antimalarial regimens in malaria affected populations.
Figure 1.
Figure 1.
Longitudinal trends in cure rate (A), day 3 positivity (B) and K13 mutation prevalence (C), Cambodia, 2000–2015. In section A (cure rate), connecting lines are drawn for serial studies undertaken in Pursat (normal line), Pailin (dashed) and Oddar Meanchey (dotted) provinces. MAS = artesunate plus mefloquine, DP = DHA-piperaquine, Pyramax = artesunate-pyronaridine. Locations are stratified into western and eastern provinces according to their position with respect to the capital Phnom Penh, in line with previous work (Leang et al.2015). The midpoint of patient recruitment is used as the time point for each study, or half-way through the year if months were not stated. Only studies with n = 20 or more are included. For references see Additional File (Supporting Information).
Figure 2.
Figure 2.
Proposed mechanisms of artemisinin resistance. (A) Relevant biochemical pathways. In ring-stage parasites, artemisinin is primarily activated by haem produced in the process of haemoglobin digestion (1) although haem biosynthesis in mitochondria may also contribute (2). Activated artemisinins alkylate nearby proteins in an indiscriminate manner leading to cell death (3). In artemisinin-sensitive parasites, a transcriptional factor with potential to upregulate protein turnover and oxidative damage responses is bound via the K13 adaptor (4) leading to its ubiquitination and proteolysis (5). K13 mutation disrupts this binding (6) allowing the factor to enter the nucleus (7) with upregulation of a range of transcriptional responses that can mitigate the downstream consequences of artemisinins (8). (B) Proposed phenotypes associated with artemisinin resistance. The overall length and proportion of time spent in each stage appears relatively fixed in a given strain (A). By extending their ring-stage (B), parasites increase the period of reduced vulnerability to artemisinins. An alternative is to increase the proportion of parasites entering dormancy (C), a natural phenomenon observed in all parasite strains that allows escape from relatively short duration artemisinin exposures in patient treatments. Finally, increasing the proportion of parasites that differentiate into gametocytes (D) at a given timepoint could improve chances of transmission before treatment is administered.
Figure 3.
Figure 3.
The extent of ACT failure (in studies with at least 42 days of follow-up) and day 3 positivity across four time periods from 2000 to the present. If two studies were available in one location for the same time period, the higher failure rate is shown. MAS3: artesunate plus mefloquine; DP: DHA-piperaquine. For references, see Additional File (Supporting Information).
Figure 4.
Figure 4.
The relationship between the proportion of parasites with K13 propeller mutations and day 3 positivity in clinical studies in Southeast Asia. The oval ring indicates data from Yunnan Province, China in which the F446I K13 mutation was the most common. Only studies with n = 20 or more are included. For references see Additional File (Supporting Information).
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