Evidence of Plasmodium falciparum Malaria Multidrug Resistance to Artemisinin and Piperaquine in Western Cambodia: Dihydroartemisinin-Piperaquine Open-Label Multicenter Clinical Assessment

Leang, Rithea; Taylor, Walter; Bouth, Denis Mey; Song, Lijiang; Tärning, Joel; Char, Meng Chuor; Kim, Saorin; Witkowski, Benoît; Duru, Valentine; Domergue, Anais; Khim, Nimol; Ringwald, Pascal; Ménard, Didier

doi:10.1128/aac.00835-15

Cited by 262 publications

(250 citation statements)

References 31 publications

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“…In fact, miners on the Guiana Shield readily cross borders between Brazil, French Guiana, and Suriname and regularly automedicate with Artecom (33)(34)(35). This clue to the putative mechanism of resistance to PPQ is potentially of considerable importance, because PPQ treatment failure is a major and increasing concern in southeast Asia (36)(37)(38). Therefore, the association between PfCRT haplotypes and PPQ treatment failure should be further explored in southeast Asia, where polymorphisms in the pfcrt gene, notably in exon 10, were found to accompany mutations in the pfK13 gene associated with artemisinin resistance (39).…”

Section: Discussionmentioning

confidence: 99%

Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt

Moss

Dhingra

Volney

et al. 2015

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

110

105

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In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations can attain 100% prevalence, thereby precluding the return of WT parasites after the complete removal of drug pressure. In French Guiana, despite the fixation of the K76T allele, the prevalence of CQR isolates progressively dropped from >90% to <30% during 17 y after CQ withdrawal in 1995. Using a genome-wide association study with CQ-sensitive (CQS) and CQR isolates, we have identified a single mutation in pfcrt encoding a C350R substitution that is associated with the restoration of CQ susceptibility. Genome editing of the CQR reference strain 7G8 to incorporate PfCRT C350R caused a complete loss of CQR. A retrospective molecular survey on 580 isolates collected from 1997 to 2012 identified all C350R mutant parasites as being CQS. This mutation emerged in 2002 and rapidly spread throughout the P. falciparum population. The C350R allele is also associated with a significant decrease in piperaquine susceptibility in vitro, suggesting that piperaquine pressure in addition to potential fitness costs associated with the 7G8-type CQR pfcrt allele may have selected for this mutation. These findings have important implications for understanding the evolutionary dynamics of antimalarial drug resistance. malaria | drug resistance | evolution | Plasmodium falciparum | PfCRT

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Section: Discussionmentioning

confidence: 99%

Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt

Moss

Dhingra

Volney

et al. 2015

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

110

105

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“…In vitro and exvivo RSA Dondorp et al (2009, , Thriemer et al (2014), Ashley et al (2014), Leang et al (2015) and Tun et al (2016) In vitro and ex-vivo RSA 0-3h can measure slow-clearing and fast-clearing P.…”

Section: Reference Studies Strength and Weakness Of In Vitro/ex-vivo mentioning

confidence: 99%

“…The 28-day follow-up protocol (Chanda et al, 2006;Denis et al, 2002;Marquino et al, 2003) or 42-day follow-up protocol (Leang et al, 2015;Mårtensson et al, 2005;Mayxay et al, 2004;Valecha et al, 2010;Yeka et al, 2008) were usually used. Few studies used 63-day follow-up protocols for efficacy monitoring of ACTs containing a long half-life partner drug (Sodiomon et al, 2016;Valecha et al, 2010).…”

Section: In Vivo Act Efficacy Evaluationmentioning

confidence: 99%

Methods for monitoring artemisinin-based combination therapies efficacy

Dama¹,

Djimdé²,

Doumbo³

2017

Clin. Rev. Opinions

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Plasmodium falciparum resistance to artemisinin and its derivatives is spreading in South-East Asia, and there is growing concern that this may reach other endemic countries. Methods used to assess P. falciparum resistance to artemisinin-based combination therapies (ACTs) are multiple and often divergent. This paper is a review of online accessible research publications from the past 20 years on ACTs, ranging from in vivo, in vitro/ex-vivo, molecular markers and pharmacokinetics studies. We highlight the procedures of the four main methods used for ACTs e f f i c a c y testing and provide a summary of published data. This review indicates that the most used method for ACT efficacy testing is the in vivo 28 days follow-up with molecular correction; the most widely used and reliable in vitro and ex-vivo method for artemisinin phenotyping is the ring stage survival assay from 0 to 3 h ring (RSA 0-3h ), and the main molecular marker of P. falciparum resistance to artemisinins are mutations on P. falciparum Kelch 13 propeller domain. Day 7 pharmacokinetics could help to predict resistance to artemether-lumefantrine and dihydroartemisinin-piperaquine. Findings from this review support that the combination of in vivo, in vitro/ex-vivo, molecular markers of drug resistance and day 7 PK levels of the partner drugs may be required for the optimal surveillance of artemisinin-based combination therapy efficacy in the field.

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“…This goal may be challenged by the emergence of multidrug-resistant, including artemisinin-resistant Plasmodium falciparum (ART-R) [5][6][7][8] and, now, the demise of dihydroartemisinin-piperaquine. 9 Accordingly, conducting accurate, large-scale assessments of malaria prevalence, including pools of asymptomatic individuals detected by the polymerase chain reaction (PCR), is crucial for planning malaria control and elimination efforts and in measuring the impact of pertinent interventions. In Cambodia, efforts are being focused on containing the spread and ultimately the elimination of ART-R; thus, identifying and quantifying reservoirs of falciparum infection are seen as essential because these pools represent areas where there is ongoing transmission of ART-R.…”

Section: Introductionmentioning

confidence: 99%

National Malaria Prevalence in Cambodia: Microscopy Versus Polymerase Chain Reaction Estimates

Lek¹,

Popovici²,

Ariey³

et al. 2016

The American Journal of Tropical Medicine and Hygiene

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Abstract. Accurate information regarding malaria prevalence at national level is required to design and assess malaria control/elimination efforts. Although many comparisons of microscopy and polymerase chain reaction (PCR)-based methods have been conducted, there is little published literature covering such comparisons in southeast Asia especially at the national level. Both microscopic examination and PCR detection were performed on blood films and dried blood spots samples collected from 8,067 individuals enrolled in a nationwide, stratified, multistage, cluster sampling malaria prevalence survey conducted in Cambodia in 2007. The overall malaria prevalence and prevalence rates of Plasmodium falciparum, Plasmodium vivax, and Plasmodium malariae infections estimated by microscopy (N ¼ 8,067) were 2.74% (95% confidence interval [CI]: 2.39-3.12%), 1.81% (95% CI: 1.53-2.13%), 1.14% (95% CI: 0.92-1.40%), and 0.01% (95% CI: 0.003-0.07%), respectively. The overall malaria prevalence based on PCR detection (N ¼ 7,718) was almost 2.5-fold higher (6.31%, 95% CI: 5.76-6.89%, P < 0.00001). This difference was significantly more pronounced for P. falciparum (4.40%, 95% CI: 3.95-4.90%, P < 0.00001) compared with P. vivax (1.89%, 95% CI: 1.60-2.22%, P < 0.001) and P. malariae infections (0.22%, 95% CI: 0.13-0.35%, P < 0.0001). The significant proportion of microscopy-negative but PCR-positive individuals (289/7,491, 3.85%) suggest microscopic examination frequently underestimated malaria infections and that active case detection based on microscopy may miss a significant reservoir of infection, especially in low-transmission settings. BACKGROUND

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Evidence of Plasmodium falciparum Malaria Multidrug Resistance to Artemisinin and Piperaquine in Western Cambodia: Dihydroartemisinin-Piperaquine Open-Label Multicenter Clinical Assessment

Cited by 262 publications

References 31 publications

Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt

Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt

Methods for monitoring artemisinin-based combination therapies efficacy

National Malaria Prevalence in Cambodia: Microscopy Versus Polymerase Chain Reaction Estimates

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