All recommended treatments against malaria include a drug called artemisinin or some of its derivatives. However, there are concerns that Plasmodium falciparum, the parasite that causes most cases of malaria, will eventually develop widespread resistance to the drug. A strain of P. falciparum partially resistant to artemisinin was seen in Cambodia in 2008, and it has since spread across Southeast Asia. The resistance appears to be frequently linked to a mutation known as pfk13 C580Y.

Southeast Asia and Amazonia are considered to be hotspots for antimalarial drug resistance, and the pfk13 C580Y mutation was detected in the South American country of Guyana in 2010. To examine whether the mutation was still circulating in this part of the world, Mathieu et al. collected and analyzed 854 samples across Guyana between 2016 and 2017. Overall, 1.6% of the samples had the pfk13 C580Y mutation, but this number was as high as 8.8% in one region. Further analyses revealed that the mutation in Guyana had not spread from Southeast Asia, but that it had occurred in Amazonia independently.

To better understand the impact of the pfk13 C580Y mutation, Mathieu et al. introduced this genetic change into non-resistant parasites from a country neighbouring Guyana. As expected, the mutation made P. falciparum highly resistant to artemisinin, but it also slowed the growth rate of the parasite. This disadvantage may explain why the mutation has not spread more rapidly through Guyana in recent years.

Artemisinin and its derivatives are always associated with other antimalarial drugs to slow the development of resistance; there are concerns that reduced susceptibility to artemisinin leads to the parasites becoming resistant to the partner drugs. Further research is needed to evaluate how the pfk13 C580Y mutation affects the parasite’s response to the typical combination of drugs that are given to patients.

Malaria is an important parasitic disease that causes a high level of mortality worldwide. In 2018, malaria was estimated to have caused 405,000 deaths, most of them attributable to the virulent Plasmodium falciparum parasite species (World Health Organization, 2019). Most malaria cases occur in Sub-Saharan Africa, but Southeast Asia and South America are also affected. Since 2001, Artemisinin-based Combination Therapies (ACTs) have been the recommended first-line therapy for P. falciparum infection for almost all malaria-endemic areas (World Health Organization, 2001). ACTs combine an artemisinin derivative and one partner drug (most commonly lumefantrine, mefloquine, amodiaquine, piperaquine or pyronaridine). These treatments have contributed to a major reduction in malaria-related mortality and morbidity (Eastman and Fidock, 2009; Carrara et al., 2006; Bhatt et al., 2015). However, in 2008, the first instances of reduced artemisinin efficacy were described in western Cambodia (Dondorp et al., 2009; Ashley et al., 2014). Subsequent studies have documented the rapid spread of resistance throughout Southeast Asia (Dondorp et al., 2009; Ashley et al., 2014; World Health Organization, 2018). Resistance to artemisinin is partial and affects only rings (World Health Organization, 2018). Clinically, this partial resistance trait manifests as a parasite clearance half-life that exceeds 5.5 hr (WWARN K13 Genotype-Phenotype Study Group, 2019). This half-life represents the time required to achieve a two-fold reduction of the parasite biomass. Partial resistance also manifests as persistent parasitemia on day three with a complete clearance of parasites following full treatment with an artesunate monotherapy lasting seven days or with an ACT (World Health Organization, 2018). An analysis of P. falciparum parasites selected for artemisinin resistance in vitro as well as parasites from patients experiencing slow parasite clearance led to the identification of a genetic locus linked to resistance: a kelch domain-containing protein located on chromosome 13 (pfk13) (Ariey et al., 2014). To date, many missense mutations have been described in the BTP/POZ or kelch propeller domain-containing parts of this protein in clinical isolates, however only nine of them have been validated for artemisinin resistance (F446I, N458Y, M476I, Y493H, R539T, I543T, P553L, R561H and C580Y) (World Health Organization, 2018; Ariey et al., 2014; Straimer et al., 2015). A larger number have been associated with delayed parasite clearance (WWARN K13 Genotype-Phenotype Study Group, 2019). In most locations, the pfk13 C580Y mutation has overtaken other resistance-inducing variants, and it is now the most prevalent pfk13 variant in Southeast Asia (Ashley et al., 2014; Ariey et al., 2014).

South America has historically been a second hotspot outside Southeast Asia for the evolution of antimalarial drug resistance. For example, chloroquine and sulfadoxine-pyrimethamine resistance evolved simultaneously in both regions (Wootton et al., 2002; Roper et al., 2004). The Guiana Shield region of South America, which includes Guyana, Suriname, French Guiana and parts of Brazil, Venezuela and Colombia, is important as a potential source of emerging antimalarial drug resistance. In this region, the subsoil is rich in gold and other minerals, leading to extensive mining activities in forested areas. These mining activities favor malaria transmission, particularly P. falciparum (Douine et al., 2016; Heemskerk, 2011). Mining also generates human population movement and inappropriate use of ACTs, as people generally work deep in the forest, far from medical care (Pribluda et al., 2014; Douine et al., 2018). This erratic use of ACTs, as well as self-medication using ACTs of substandard quality or artemisinin monotherapies, may promote the emergence of resistance to artemisinin.

In Guyana in 2010, 5.1% (5 out of 98) of P. falciparum-infected clinical samples, sharing a common haplotype different from their Cambodian counterparts, exhibited the pfk13 C580Y mutation (Chenet et al., 2016). However, no clinical or in vitro resistance phenotypes were measured or associated with the genotype data. The most recent therapeutic efficacy study conducted in Guyana in 2014 with 50 patients failed to identify pfk13 mutations or delayed parasite clearance time after artemether/lumefantrine treatment (Rahman et al., 2016). The sample size, however, was too small to ensure detection of low-frequency resistance mutations. The objective of the present study was to evaluate whether pfk13 variants (C580Y or others) have persisted in Guyana since 2010, and if so, to evaluate their prevalence in 2016–2017. In the absence of available clinical phenotypes associated with the pfk13 C580Y variant from patients infected and treated in this region, we evaluated the impact of two pfk13 mutations, C580Y and R539T, on in vitro resistance and the rate of parasite growth in a South American parasite genetic background.

Results presented herein confirm the de novo emergence and long-term persistence of the pfk13 C580Y artemisinin resistance mutation in Guyana, South America. Six years after their first identification, pfk13 C580Y mutant parasites continue to circulate in Guyana at low prevalence (1.6%; 14/854). Parasites bearing this mutation belong to a single clonal lineage and are of autochthonous origin. Gene editing studies on French Guianan parasites, closely related to parasites from Guyana, showed that the pfk13 C580Y mutation is able to mediate artemisinin resistance in vitro at levels observed in Southeast Asian parasites harboring this mutation. An adverse impact of this pfk13 mutation on asexual blood stage growth rates of pfk13-edited French Guianan parasite lines in culture was also observed, providing evidence of a fitness cost similar to that previously described for Southeast Asian lines (Nair et al., 2018; Li et al., 2019).

During the 1990s, analyses of resistant parasites retrospectively suggested the simultaneous emergence of resistance to chloroquine and sulfadoxine/pyrimethamine in parasites from Southeast Asia and the Amazonian region of South America (Wootton et al., 2002; Roper et al., 2004; Vinayak et al., 2010). With artemisinin, the same scenario is occurring with evidence of an independent emergence of resistance mutation in South America. For artemisinin resistance, there is an opportunity to dissect the first steps of resistance selection in South America in ‘real time’, relying on genetic markers and phenotypic assays (genotypic surveys, therapeutic efficacy studies, and in vitro phenotyping through the Ring-stage Survival Assay (RSA_0-3h)) developed in Southeast Asia (Ariey et al., 2014; Witkowski et al., 2013). These genetic and phenotypic tools can help address the critical questions of why in vitro resistance to artemisinin has emerged in Region 1 in Guyana, a country with fewer than 20,000 malaria cases in 2018, and why this resistance is not increasing more quickly. In 2004, Guyana was one of the first South American malaria-endemic countries to adopt and implement artemether-lumefantrine (Coartem), the current first-line therapy against P. falciparum. Six years later, in 2010, pfk13 C580Y mutants were first identified. Until now, no further signals of artemisinin resistance or pfk13 mutations had been identified, despite studies incorporating pfk13 genotyping in Guyana (n = 50), Suriname (n = 40) and French Guiana (n = 198) (Rahman et al., 2016; Ménard et al., 2016; Chenet et al., 2017). Other than pfk13 C580Y, no other pfk13 propeller domain mutations have been observed in Guyana. In Southeast Asia, two molecular epidemiological profiles are currently observed. In Western Cambodia, one C580Y linage (KEL1) has displaced other mutations and has rapidly become the dominant pfk13 genotype in that population (>80%) (Amato et al., 2018; Takala-Harrison et al., 2015). This lineage has merged with a multicopy plasmepsin 2 and 3 lineage (PLA1) that is associated with piperaquine resistance (Amato et al., 2018). Nowadays, this co-lineage has colonized northeastern Thailand and southern Laos (Imwong et al., 2017). On the other side, in western Thailand, at the border with Myanmar, a six-year period was required for distinct mutant pfk13 parasite lineages to collectively reach a population prevalence of 20% (Amato et al., 2018; Anderson et al., 2017). At the present time, a patchwork of pfk13 genotypes co-circulates in that population and the prevalence of C580Y lineages fluctuates around 20–30% (Kobasa et al., 2018). In Myanmar, pfk13 mutants are more diverse and the F446I mutation presently dominates the pfk13 mutant parasite population in certain sites, with this mutation being associated with an intermediate resistance phenotype (Han et al., 2020; Bonnington et al., 2017).

Given this history of pfk13 propeller domain mutations in Southeast Asia, beginning with a soft sweep and transitioning to a hard sweep, we might have expected an increase in the prevalence of pfk13 C580Y mutant parasites during this 2010-2016/2017 period in Guyana. However, the situation in this part of the world differs from Southeast Asia. First, efforts to monitor pfk13 mutations in Guyana were not systematically conducted between 2010 and 2017. Sample size could therefore explain why the C580Y mutation was only sporadically observed. Nonetheless, the present study indicates that the mutation has not drastically increased in the parasite population. Differences in the resistance profile to artemisinin partner drugs could also account for the heterogeneity in pfk13 mutational trajectories in Southeast Asia vs. Guyana, a region where markers of resistance have historically reached fixation (Pelleau et al., 2015; Legrand et al., 2012). In Southeast Asia, the rapid spread of artemisinin-resistant genomic lineages can be explained in part by a multidrug-resistant profile, which includes pfk13 variants as well as mutations conferring resistance to the partner drug piperaquine (Amato et al., 2018; Ross et al., 2018; Kim et al., 2019). Our genomic analysis of a panel of Guyanese isolates identified the common South American profile for known drug resistance markers (pfcrt, pfdhps, pfdhfr and pfmdr1) in both mutant and wild-type pfk13 samples (Wootton et al., 2002; Roper et al., 2004; Vinayak et al., 2010; Legrand et al., 2012). In the Guiana Shield, lumefantrine remains a highly effective partner drug for artemisinin, and no mutations or phenotypes associated with lumefantrine resistance have been observed (Legrand et al., 2012). High efficacy of the partner drug could therefore be an important factor limiting the spread of pfk13 C580Y in Guyana. Finally, both the low synonymous pairwise genetic diversity (π_syn = 3.4 x 10⁻⁴) and the low complexity of infection (COI, 2.2% of samples with a COI > 1) in Guyana are in keeping with the expectation that the P. falciparum population in South America is smaller and more recently established than in Southeast Asia (Yalcindag et al., 2012).

The genomic structure of the Guyana parasite population could also help explain why the mutation arose there, rather than other settings in South America. The present findings indicate high outcrossing rates and few clonal lineages in Guyana (0.54% pairs with IBD >0.75). This clonal diversity is relatively high, especially within a South American context. Previous studies have found much higher proportions of non-unique haplotype backgrounds (>30% of samples) within parasite populations from Colombia (Echeverry et al., 2013), Peru (Dharia et al., 2010), and Ecuador (Sáenz et al., 2015; Sáenz et al., 2017). These prior analyses used fewer genomic markers, but the results still suggest that clonal diversity may be greater in the Guiana Shield relative to the rest of the continent, possibly driven by the high P. falciparum transmission level observed in mining areas (Douine et al., 2016; Ministry of Public Health, 2018). As genomic background likely plays a key role in the persistence of resistance mutations like C580Y, this haplotype richness may increase the likelihood that resistance mutations can successfully establish themselves in a permissive background. Subsequently, a low recombination rate may allow these beneficial combinations to then persist within the population. A more definitive exploration of this hypothesis, and of whether Guyana’s current clonal structure represents recent demographic change or historic population subdivision, will be possible as more whole-genome sequence data become available for the continent. The slower trajectory of pfk13 C580Y may also be due to an impaired asexual blood-stage growth rate, and the absence of compensatory mutations that have been hypothesized to aid the spread of the C580Y mutation in Southeast Asia (Amato et al., 2018; Li et al., 2019).

We chose to introduce two pfk13 mutations by gene editing: C580Y mutation because of its presence in Guyana and its dominance in Southeast Asia, and R539T as a positive control for in vitro resistance, as it exhibits the highest RSA observed in Southeast Asian strains along with I543T (Ariey et al., 2014; Straimer et al., 2015). Introducing these mutations conferred high levels of in vitro artemisinin resistance and both mutations negatively impacted growth rates in vitro in our parasite isolates from French Guiana, a neighboring country of Guyana. These growth rate differences provide a surrogate marker of fitness and do not necessarily predict in vivo success of the mutations, as multiple other parameters are also important including gametocyte production, impacts on transmission, and immunity. Our data show that the C580Y mutation was associated with a more severe growth defect compared to the R539T mutation in these asexual blood stage parasites. A similar finding was also recently reported in C580Y-edited isolates from the Thailand-Myanmar border (Nair et al., 2018), although disparate results were obtained for C580Y-edited isolates from Cambodia (Straimer et al., 2017). These contrasting data underline the influence of the parasite’s genomic background, which potentially involves compensatory mutations that impact the overall growth. Further studies will be needed to screen for potential secondary mutations that may be offsetting these fitness costs. It will also be important to examine factors that could drive the persistence of mutant pfk13 in Guyana despite the apparent fitness cost, including a consideration of local antimalarial drug usage and quality, transmission levels, and population movement.

The World Health Organization (WHO) has categorized countries regarding artemisinin resistance based on pfk13 mutant prevalence and the clinical response to artemisinin derivatives (World Health Organization, 2017). The threshold of 5% of pfk13 mutants has been met on several occasions in Guyana, first in 2010 (Chenet et al., 2016), then punctually in 2016–2017 in Region 1. The situation is evolving and a marker could disappear for reasons that are currently unclear. Nonetheless, in light of these findings, Guyana has the status of suspected resistance to artemisinin derivatives (World Health Organization, 2017). The clinical and public health significance of the presence of these mutations on the therapeutic efficacy of artemisinin-based combination therapies in Guyana, and more precisely artemether/lumefantrine - first line in the country, should be directly evaluated. We note that our study had limitations including the small number of analyzed samples and the in vitro phenotypic impact evaluated in parasites from nearby French Guiana and not Guyana itself. Nonetheless, we observed that pfk13 mutants still circulated in 2016–2017. Given their decreased susceptibility to DHA in vitro, these mutants are likely to expose the partner drug to the risk of emerging resistance. This situation could defeat P. falciparum elimination strategies in this region. Therefore, national health authorities should continue to work together in order to overcome difficulties coming from their multiplicity of regulations, malaria control strategies and transmission levels in the context of major human migrations across borders. The Guiana Shield initiative launched by the Pan American Health Organization (PAHO) and the WHO in 2016 will have a crucial role to reinforce and to coordinate the different malaria control measures.

The authors declare that the data supporting the findings of this study are available within the paper and its supplementary information. Whole genome sequencing data from this study are available from the NCBI Sequence Read Archive under BioProject ID PRJNA543530. Genome data from the Pf3K project are available at https://www.malariagen.net/projects/pf3k.

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Author details

1. Luana C Mathieu

   1. Laboratoire de parasitologie, Centre Nationale de Référence du Paludisme, World Health Organization Collaborating Center for surveillance of antimalarial drug resistance, Institut Pasteur de la Guyane, Cayenne, French Guiana
   2. Ecole Doctorale n°587, Diversités, Santé, et Développement en Amazonie, Université de Guyane, Cayenne, French Guiana

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Methodology, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6021-468X

2. Horace Cox

   Ministry of Public Health, Georgetown, Guyana

   Contribution

   Conceptualization, Resources, Methodology, Project administration, Writing - review and editing, Coordinate sample collection

   Competing interests

   No competing interests declared

3. Angela M Early

   1. Broad Institute of MIT and Harvard, Cambridge, United States
   2. Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, United States

   Contribution

   Conceptualization, Software, Formal analysis, Validation, Investigation, Methodology, Writing - original draft, Writing - review and editing

   Contributed equally with

   Sachel Mok

   Competing interests

   No competing interests declared

4. Sachel Mok

   Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Methodology, Writing - original draft, Writing - review and editing

   Contributed equally with

   Angela M Early

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9605-0154

5. Yassamine Lazrek

   Laboratoire de parasitologie, Centre Nationale de Référence du Paludisme, World Health Organization Collaborating Center for surveillance of antimalarial drug resistance, Institut Pasteur de la Guyane, Cayenne, French Guiana

   Contribution

   Supervision, Investigation, Project administration

   Competing interests

   No competing interests declared

6. Jeanne-Celeste Paquet

   Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, United States

   Contribution

   Data curation, Investigation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-6046-0154

7. Maria-Paz Ade

   Department of Communicable Diseases and Environmental Determinants of Health, Pan American Health Organization/World Health Organization, Washington, United States

   Contribution

   Conceptualization, Supervision, Funding acquisition, Methodology, Project administration, Writing - review and editing, Coordinate sample collection

   Competing interests

   MPA, JSFA, and PR are staff members of the World Health Organization. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy or views of the World Health Organization.

8. Naomi W Lucchi

   Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, United States

   Contribution

   Data curation, Investigation, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

9. Quacy Grant

   Ministry of Public Health, Georgetown, Guyana

   Contribution

   Conceptualization, Supervision, Project administration

   Competing interests

   No competing interests declared

10. Venkatachalam Udhayakumar

    Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, United States

    Contribution

    Formal analysis, Supervision, Validation, Investigation, Methodology

    Competing interests

    No competing interests declared

11. Jean SF Alexandre

    Pan American Health Organization, Georgetown, Guyana

    Contribution

    Resources, Supervision, Funding acquisition, Project administration, Coordinate sample collection

    Competing interests

    MPA, JSFA, and PR are staff members of the World Health Organization. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy or views of the World Health Organization.

12. Magalie Demar

    1. Service de Maladies Infectieuses et Tropicales, Centre Hospitalier Andrée Rosemon, Cayenne, French Guiana
    2. Ecosystèmes Amazoniens et Pathologie Tropicale (EPAT), EA3593, Université de Guyane, Cayenne, French Guiana

    Contribution

    Supervision, Project administration

    Competing interests

    No competing interests declared

13. Pascal Ringwald

    Global Malaria Program, World Health Organization, Geneva, Switzerland

    Contribution

    Conceptualization, Resources, Formal analysis, Supervision, Validation, Project administration, Writing - review and editing

    Competing interests

    MPA, JSFA, and PR are staff members of the World Health Organization. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy or views of the World Health Organization.

14. Daniel E Neafsey

    1. Broad Institute of MIT and Harvard, Cambridge, United States
    2. Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, United States

    Contribution

    Conceptualization, Resources, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Writing - review and editing

    Contributed equally with

    David A Fidock

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-1665-9323

15. David A Fidock

    1. Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, United States
    2. Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, United States

    Contribution

    Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Methodology, Writing - review and editing

    Contributed equally with

    Daniel E Neafsey

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-6753-8938

16. Lise Musset

    Laboratoire de parasitologie, Centre Nationale de Référence du Paludisme, World Health Organization Collaborating Center for surveillance of antimalarial drug resistance, Institut Pasteur de la Guyane, Cayenne, French Guiana

    Contribution

    Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Methodology, Writing - original draft, Project administration, Writing - review and editing

    For correspondence

    lisemusset@gmail.com

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-0215-4110

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