Treatment Failure of Dihydroartemisinin/Piperaquine for <i>Plasmodium falciparum</i> Malaria, Vietnam

Phuc, Bui Quang; Rasmussen, Charlotte; Duong, Tran Thanh; Dong, Le Than; Loi, Mai Anh; Ménard, Didier; Tärning, Joel; Bustos, Dorina; Ringwald, Pascal; Galappaththy, Gawrie Loku; Thieu, Nguyen Quang

doi:10.3201/eid2304.161872

Cited by 86 publications

(70 citation statements)

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“…[5][6][7] Loss of artemisinin efficacy in ACTs has facilitated the re-emergence of mefloquine resistance on the Thailand-Myanmar border and contributed to the emergence and spread of piperaquine resistance in P falciparum in Cambodia and southern Vietnam. [8][9][10][11] Several non-synonymous mutations in the propeller domain of the kelch13 gene have been associated with artemisinin resistance. 4,12 Amplification of the plasmepsin-2 and plasmepsin-3 genes on chromosome 14 has been strongly associated with reduced in vitro susceptibility to piperaquine, and with reduced treatment efficacy of dihydroartemisinin-piperaquine for uncomplicated P falciparum malaria.…”

Section: Introductionmentioning

confidence: 99%

Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study

Pluijm

Imwong

Chau

et al. 2019

The Lancet Infectious Diseases

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Background The emergence and spread of resistance in Plasmodium falciparum malaria to artemisinin combination therapies in the Greater Mekong subregion poses a major threat to malaria control and elimination. The current study is part of a multi-country, open-label, randomised clinical trial (TRACII, 2015-18) evaluating the efficacy, safety, and tolerability of triple artemisinin combination therapies. A very high rate of treatment failure after treatment with dihydroartemisinin-piperaquine was observed in Thailand, Cambodia, and Vietnam. The immediate public health importance of our findings prompted us to report the efficacy data on dihydroartemisinin-piperaquine and its determinants ahead of the results of the overall trial, which will be published later this year. Methods Patients aged between 2 and 65 years presenting with uncomplicated P falciparum or mixed species malaria at seven sites in Thailand, Cambodia, and Vietnam were randomly assigned to receive dihydroartemisinin-piperaquine with or without mefloquine, as part of the TRACII trial. The primary outcome was the PCR-corrected efficacy at day 42. Next-generation sequencing was used to assess the prevalence of molecular markers associated with artemisinin resistance (kelch13 mutations, in particular Cys580Tyr) and piperaquine resistance (plasmepsin-2 and plasmepsin-3 amplifications and crt mutations). This study is registered with ClinicalTrials.gov, number NCT02453308.

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Section: Introductionmentioning

confidence: 99%

Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study

Pluijm

Imwong

Chau

et al. 2019

The Lancet Infectious Diseases

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314

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“…However, artemisinin derivative-resistant P. falciparum strains emerged in western Cambodia, Myanmar, and Thailand, and eventually in all of Southeast Asia (3,4). As soon as the last marketed ACT, dihydroartemisinin-piperaquine, was used, resistance emerged in Cambodia and later in Vietnam (5)(6)(7)(8). In this context, it is essential to have markers of resistance to monitor the emergence and spread of resistance to dihydroartemisinin-piperaquine.…”

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Absence of a High Level of Duplication of the Plasmepsin II Gene in Africa

Robert

Tsombeng

Gendrot

et al. 2018

Antimicrob Agents Chemother

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Resistance to piperaquine has been associated with the amplification of the plasmepsin II gene in Cambodia. None of the 175 African isolates that we analyzed had plasmepsin II gene amplification (piperaquine 50% inhibitory concentration ranged from 0.94 to 137.5 nM), suggesting there is a low prevalence of piperaquine reduced susceptibility in Africa. Additionally, the few isolates with reduced susceptibility to piperaquine did not harbor amplification of the plasmepsin II gene.

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“…We have presented a novel mathematical model to investigate the efficacy of different regimens for triple artemisinin combination therapies (TACTs). Our analysis focused on DHA-PQ-MQ, since DHA-PQ is a widely used ACT in South-East Asia with declining efficacy in several locations (9, 10, 11). The addition of MQ to DHA-PQ has potential to improve treatment, since the ACT of artesunate-MQ retains high efficacy, following its reintroduction as a first-line treatment in Cambodia (7).…”

Section: Discussionmentioning

confidence: 99%

“…In this work, we developed a within-host mathematical model (8) to explore the efficacy of TACTs, with a particular focus on DHA-PQ-MQ, since DHA-PQ is widely administered in South-East Asia, and is currently associated with very high failure rates in some regions (9, 10, 11). The model accommodates a high level of biological details, such as drug-drug interaction (12, 13), stage-specificity of parasite killing (14, 15, 16, 17) and between-patient and between-isolate variability (17).…”

Section: Introductionmentioning

confidence: 99%

Investigating the efficacy of triple artemisinin-based combination therapies (TACTs) for treatingPlasmodium falciparummalaria patients using mathematical modelling

Simpson

McCaw

Cao³

et al. 2018

Preprint

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22The first line treatment for uncomplicated falciparum malaria is artemisinin-based com-23 bination therapy (ACT), which consists of an artemisinin derivative co-administered with 24 a longer acting partner drug. However, the spread of Plasmodium falciparum resistant 25 to both artemisinin and its partner drugs poses a major global threat to malaria control 26 activities. Novel strategies are needed to retard and reverse the spread of these resistant 27 parasites. One such strategy is triple artemisinin-based combination therapy (TACT). 28 We developed a mechanistic within-host mathematical model to investigate the e cacy of 29 a TACT (dihydroartemisinin-piperaquine-mefloquine -DHA-PQ-MQ), for use in South- 30 East Asia, where DHA and PQ resistance are now increasingly prevalent. Comprehensive 31 model simulations were used to explore the degree to which the underlying resistance in-32 fluences the parasitological outcomes. The e↵ect of MQ dosing on the e cacy of TACT 33 was quantified at varying degrees of DHA and PQ resistance. To incorporate interactions 34 between drugs, a novel model is presented for the combined e↵ect of DHA-PQ-MQ, which 35 illustrates how the interactions can influence treatment e cacy. When combined with a 36 standard regimen of DHA and PQ, the administration of three 8.3 mg/kg doses of MQ 37 was su cient to achieve parasitological e cacy greater than that currently recommended 38 by WHO guidelines. 39 Introduction 40Over the last decade, significant gains have been made towards the control and elimina-41 tion of malaria. Despite this progress, almost half a billion people still die from malaria 42 2 each year. Disturbingly, in 2016 there were five million more cases of malaria than the 43 previous year (2017 WHO report (1)), emphasising the fragile nature of malaria control. 44Early diagnosis and treatment with highly e↵ective antimalarial drug regimens remains 45 central to all national malaria control activities. Artemisinin-based combination thera-46 pies (ACTs) are the first line therapy in almost all malaria endemic countries, due to 47 their high e cacy, tolerability and ability to reduce ongoing transmission of the para-48 site. ACTs are comprised of two components: an artemisinin derivative and a partner 49 drug. The artemisinin derivative has a high antimalarial potency, killing a large propor-50 tion of parasites, however, these compounds are rapidly eliminated, leaving a residual 51 parasite population that, if left untreated, will likely recrudesce. A slowly eliminated, 52 partner drug, is required to provide a sustained antimalarial activity, capable of killing 53 the remaining parasites (2). 54ACTs have remained highly e cacious for almost two decades, but are now under 55 threat from the emergence of drug resistant parasites (2, 3). In 2009, a high proportion 56 of patients with markedly delayed parasite clearance were reported from the western re-57 gion of Cambodia, and this was confirmed as being attributable to artemisinin resistance 58 (3). These parasite...

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Treatment Failure of Dihydroartemisinin/Piperaquine for Plasmodium falciparum Malaria, Vietnam

Cited by 86 publications

References 6 publications

Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study

Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study

Absence of a High Level of Duplication of the Plasmepsin II Gene in Africa

Investigating the efficacy of triple artemisinin-based combination therapies (TACTs) for treatingPlasmodium falciparummalaria patients using mathematical modelling

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