Dihydroartemisinin-piperaquine failure associated with a triple mutant including kelch13 C580Y in Cambodia: an observational cohort study

Spring, Michele; Lin, Jessica T.; Manning, Jessica E.; Vanachayangkul, Pattaraporn; Sok, Somethy; Bun, Rathvicheth; Se, Youry; Chann, Soklyda; Ittiverakul, Mali; Sia-ngam, Piyaporn; Kuntawunginn, Worachet; Arsanok, Montri; Buathong, Nillawan; Chaorattanakawee, Suwanna; Gosi, Panita; Ta-aksorn, Winita; Chanarat, Nitima; Sundrakes, Siratchana; Kong, Nareth; Heng, Thay Kheang; Nou, Samon; Teja‐Isavadharm, Paktiya; Pichyangkul, Sathit; Phann, Sut Thang; Balasubramanian, Sujata; Juliano, Jonathan J.; Meshnick, Steven R.; Chour, Char Meng; Prom, Satharath; Lanteri, Charlotte; Lon, Chanthap; Saunders, David

doi:10.1016/s1473-3099(15)70049-6

Cited by 219 publications

(254 citation statements)

References 28 publications

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“…followed by a probabilistic framework for detecting variants that incorporates multiple types of evidence (SI Materials and Methods, SI CNV in P. vivax and P. falciparum). A subset of P. falciparum md1 CNVs was confirmed using qPCR as described previously (1,94).…”

Section: Discussionmentioning

confidence: 99%

“…Plasmodium | malaria | vivax | transcription | genome D uring the last decade, western Cambodia has been the focus of numerous and multimodal interventions to control the spread of artemisinin-resistant Plasmodium falciparum (1,2). Such interventions, including increased vector control, increased surveillance, and improved access to quality artemisinin-combination therapy (ACT), would be expected to curtail coendemic Plasmodium vivax as well.…”

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Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

Parobek

Lin

Saunders

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cambodia, in which both Plasmodium vivax and Plasmodium falciparum are endemic, has been the focus of numerous malaria-control interventions, resulting in a marked decline in overall malaria incidence. Despite this decline, the number of P. vivax cases has actually increased. To understand better the factors underlying this resilience, we compared the genetic responses of the two species to recent selective pressures. We sequenced and studied the genomes of 70 P. vivax and 80 P. falciparum isolates collected between 2009 and 2013. We found that although P. falciparum has undergone population fracturing, the coendemic P. vivax population has grown undisrupted, resulting in a larger effective population size, no discernable population structure, and frequent multiclonal infections. Signatures of selection suggest recent, species-specific evolutionary differences. Particularly, in contrast to P. falciparum, P. vivax transcription factors, chromatin modifiers, and histone deacetylases have undergone strong directional selection, including a particularly strong selective sweep at an AP2 transcription factor. Together, our findings point to different population-level adaptive mechanisms used by P. vivax and P. falciparum parasites. Although population substructuring in P. falciparum has resulted in clonal outgrowths of resistant parasites, P. vivax may use a nuanced transcriptional regulatory approach to population maintenance, enabling it to preserve a larger, more diverse population better suited to facing selective threats. We conclude that transcriptional control may underlie P. vivax's resilience to malaria control measures. Novel strategies to target such processes are likely required to eradicate P. vivax and achieve malaria elimination.D uring the last decade, western Cambodia has been the focus of numerous and multimodal interventions to control the spread of artemisinin-resistant Plasmodium falciparum (1, 2). Such interventions, including increased vector control, increased surveillance, and improved access to quality artemisinin-combination therapy (ACT), would be expected to curtail coendemic Plasmodium vivax as well. However, even as P. falciparum infections in Cambodia decreased by 81% between 2009 and 2013, P. vivax cases have increased, making it the predominant species in the Mekong region (3-6). This scenario, repeated in Brazil and other areas of coendemicity, has led to growing awareness that P. vivax, although infecting the same populations and transmitted by the same mosquito vectors, will likely be the more challenging species to eradicate (6-9). In this study, we use population genomics to gain insight into the evolutionary factors underlying P. vivax's resilience to malaria control measures.Population genetic studies have previously hinted at the resilience of P. vivax populations in comparison with P. falciparum. Studies of microsatellites and highly variable antigens of sympatric P. vivax and P. falciparum populations in Southeast Asia and the Southwest Pacific have consistently shown P. viv...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

Parobek

Lin

Saunders

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Recent reports of falling efficacy rates of ACTs in Southeast Asia, as evidenced by increased treatment failures (3)(4)(5) and prolonged parasite clearance times following ACT treatment (6)(7)(8)(9)(10)(11), are of great concern. Molecular markers of artemisinin resistance, K13 propeller mutations, have been identified (12,13), and several recent reports suggest that resistance to the currently used ACTs is developing and spreading sooner than expected (14,15).…”

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confidence: 99%

The Spiroindolone KAE609 Does Not Induce Dormant Ring Stages in Plasmodium falciparum Parasites

Chavchich¹,

Breda²,

Rowcliffe³

et al. 2016

Antimicrob Agents Chemother

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In vitro drug treatment with artemisinin derivatives, such as dihydroartemisinin (DHA), results in a temporary growth arrest (i.e., dormancy) at an early ring stage in Plasmodium falciparum. This response has been proposed to play a role in the recrudescence of P. falciparum infections following monotherapy with artesunate and may contribute to the development of artemisinin resistance in P. falciparum malaria. We demonstrate here that artemether does induce dormant rings, a finding which further supports the class effect of artemisinin derivatives in inducing the temporary growth arrest of P. falciparum parasites. In contrast and similarly to lumefantrine, the novel and fast-acting spiroindolone compound KAE609 does not induce growth arrest at the early ring stage of P. falciparum and prevents the recrudescence of DHA-arrested rings at a low concentration (50 nM). Our findings, together with previous clinical data showing that KAE609 is active against artemisinin-resistant K13 mutant parasites, suggest that KAE609 could be an effective partner drug with a broad range of antimalarials, including artemisinin derivatives, in the treatment of multidrug-resistant P. falciparum malaria. Over the last 2 decades, artemisinin-based combination therapies (ACTs) have been the most efficacious treatments against malaria and have contributed greatly to the decline in malaria mortality and morbidity (1, 2). Recent reports of falling efficacy rates of ACTs in Southeast Asia, as evidenced by increased treatment failures (3-5) and prolonged parasite clearance times following ACT treatment (6-11), are of great concern. Molecular markers of artemisinin resistance, K13 propeller mutations, have been identified (12, 13), and several recent reports suggest that resistance to the currently used ACTs is developing and spreading sooner than expected (14, 15). It remains unclear whether this resistance is a result of changes in the parasite molecular machinery required for the mode of action of artemisinin derivatives (16) or due to a recently described phenomenon of dormancy (growth retardation), where Plasmodium falciparum rings are able to survive dihydroartemisinin (DHA) treatment by undergoing a temporary growth arrest (17)(18)(19). Despite many unanswered questions about the role of dormancy, the importance of this phenomenon in the context of antimalarial chemotherapy and artemisinin resistance has become increasingly evident (17-23). Furthermore, the growth arrest of ring-stage parasites and their recovery rates observed in the in vitro ring survival assay (RSA) correlate strongly with parasite clearance half-lives after treatment of P. falciparum malaria with ACTs (22, 23), providing further support for the link between dormancy and treatment failures and possible resistance.Despite the concerns over emerging artemisinin resistance, ACTs still remain the treatment of choice for uncomplicated P. falciparum malaria (1). Therefore, to enhance or prolong the activity of ACTs against the emergence of resistance, it is important to d...

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“…The dihydroartemisinin-piperaquine combination was then recommended as a second-line treatment for uncomplicated P. falciparum malaria in Senegal. But it seems that the combination dihydroartemisinin-piperaquine is not yet widely used in Da- (12,13). In 2012 to 2014, 57% of the patients were still parasitemic at 72 h (13).…”

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confidence: 99%

“…But it seems that the combination dihydroartemisinin-piperaquine is not yet widely used in Da- (12,13). In 2012 to 2014, 57% of the patients were still parasitemic at 72 h (13). Based on data from 40 P. falciparum isolates, there was no association between the D113N mutation and ex vivo susceptibility to 10 conventional antimalarial drugs, although more data may show a different outcome.…”

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confidence: 99%

Absence of Association between Polymorphisms in the RING E3 Ubiquitin Protein Ligase Gene and Ex Vivo Susceptibility to Conventional Antimalarial Drugs in Plasmodium falciparum Isolates from Dakar, Senegal

Gendrot

Fall

Madamet

et al. 2016

Antimicrob Agents Chemother

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The RING E3 ubiquitin protein ligase is crucial for facilitating the transfer of ubiquitin. The only polymorphism identified in the E3 ubiquitin protein ligase gene was the D113N mutation (62.5%) but was not significantly associated with the 50% inhibitory concentration (IC 50 ) of conventional antimalarial drugs. However, some mutated isolates (D113N) present a trend of reduced susceptibility to piperaquine (P ‫؍‬ 0.0938). To evaluate the association of D113N polymorphism with susceptibility to antimalarials, more isolates are necessary.

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Dihydroartemisinin-piperaquine failure associated with a triple mutant including kelch13 C580Y in Cambodia: an observational cohort study

Cited by 219 publications

References 28 publications

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

The Spiroindolone KAE609 Does Not Induce Dormant Ring Stages in Plasmodium falciparum Parasites

Absence of Association between Polymorphisms in the RING E3 Ubiquitin Protein Ligase Gene and Ex Vivo Susceptibility to Conventional Antimalarial Drugs in Plasmodium falciparum Isolates from Dakar, Senegal

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