How to combat emerging artemisinin resistance: Lessons from “The Three Little Pigs”

Abstract

It is rare to come across an Aesop’s fable in respectable journals. It might catch scientists outside the malaria field by surprise to learn that the famous story of “The Boy Who Cried Wolf” has been repeatedly compared to the threat from artemisinin-resistant malaria parasites, including the two latest reports on the rise of a specific haplotype in Cambodia and Thailand, sensationally dubbed “Super Malaria” by the media [1, 2]. The comparison to a children’s tale should not negate the fact that malaria drug resistance is one of the most pressing threats to the global public health community. Here, the findings leading to this contentious discourse will be delineated in order to provide a perspective. Possible solutions will be presented to stimulate further research and discussion to solve one of the greatest public health challenges of our lifetime.

Clinical impact of the two ART resistance markers, K13 gene mutations and DPC3 in Vietnam

“…On the other hand, the increasing rates of ART resistance markers, the appearance of piperaquine resistance at the Cambodian border [23,38], the threat of multidrug resistant parasites and a moderate increase of malaria cases observed in 2017 in Vietnam, are raising concern. On the other hand, the actual relevance of the ART resistance markers in predicting the risk of treatment failure is still debated [15], the significance of artemisinin resistance is constantly updated [12,39–46] and the available literature is sometime incomplete or contradictory[8,11,16,20–25]. To establish the impact of ART resistance on clinical treatment failure we followed a comprehensive, in dept, approach: we measured the rates of suspected endemic artemisinin resistance and confirmed endemic artemisinin resistance according to the current WHO guidelines[12,45] to identify areas with markedly different prevalence of confirmed ART resistance (from 1.7% to 75.8%).…”

“…Anyway, the definition and the clinical impact of ART resistance are still controversial [15]. As a matter of facts, WHO updates from 2011 to 2018 reveal that the definition of ART resistance is undergoing a constant evolution.…”

The resistome and genomic reconnaissance in the age of malaria elimination

“…The delayed clearance following artemisinin treatment was first observed in few cases at the border between Cambodia and Thailand, but these parasites have now spread to many Greater Mekong Subregion countries in Southeast Asia (Amato et al, 2018;Dondorp et al, 2009;Imwong et al, 2017). It is obvious that the problem is growing, but the current artemisinin regimen and dosage can still treat malaria patients (Chookajorn, 2018). However, the spread of full-blown resistance to Africa could cost millions of lives.…”

“…Genome-wide association studies identified candidates and narrowed the linkage sites to certain chromosomes (Cheeseman et al, 2012). An important consideration for this discussion is that emerging artemisinin resistance does not fit a conventional drug resistance phenotype (Chookajorn, 2018), which is defined as treatment failure at the recommended dosage and treatment regimen. Artemisinin and its derivatives can still kill parasites at the recommended dose, but the clearance time is delayed by hours (Ashley et al, 2014).…”

“…kelch13 mutations alone are not likely to be the sole driver of artemisinin resistance, but the implementation of kelch13 mutations as a molecular marker played a pivotal role in tracking the spread of the parasites with reduced artemisinin sensitivity (Amato et al, 2018;Imwong et al, 2017;Sa et al, 2018;Wilairat et al, 2016). It is not yet possible to ignore the foreseeable threat of full-blown artemisinin resistance (Chookajorn, 2018). Nevertheless, the studies on kelch13 and its role in emerging artemisinin resistance have undoubtedly established a new paradigm for a combination of genomic surveillance in the field, with long-term drug selection and genome-editing experiments to prevent and mitigate the spread of drug-resistant pathogens.…”