No Clinical or Molecular Evidence of Plasmodium falciparum Resistance to Artesunate–Mefloquine in Northwestern Brazil

Ladeia‐Andrade, Simone; Melo, Gladson Naber P. de; Souza-Lima, Rita de Cássia de; Salla, Laís Camoese; Bastos, Melissa S.; Rodrigues, Priscila T.; Luz, F; Ferreira, Marcelo U.

doi:10.4269/ajtmh.16-0017

Cited by 21 publications

(23 citation statements)

References 22 publications

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“…Using our new sequencing protocol, which captures the entire K13 propeller region, we found no evidence for the presence of K13 propeller mutations. This finding is similar to that recently reported for 66 samples from Nariño, Guaviare, and Córdoba in 2012 to 2013 (20), and for 162 samples from Brazil in 2010 to 2013 (23), and contrasts sharply with the deep reservoir of K13 propeller polymorphism in Africa (24,25), where parasite diversity and transmission rates are much higher (26). However, we did identify 4/125 (3.2%) patients with D3 positivity, suggesting the possibility that a subset of parasites is becoming less susceptible to ART through mutation in other loci, that some individuals have relatively poor parasite-clearing immune responses, or that some patients were not self-administering their remaining doses of AL.…”

Section: Discussionsupporting

confidence: 92%

K13 Propeller Alleles, mdr1 Polymorphism, and Drug Effectiveness at Day 3 after Artemether-Lumefantrine Treatment for Plasmodium falciparum Malaria in Colombia, 2014-2015

Montenegro

Neal

Posada

et al. 2017

Antimicrob Agents Chemother

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High treatment failure rates for Plasmodium falciparum malaria have been reported in Colombia for chloroquine, amodiaquine, and sulfadoxine-pyrimethamine. Artemisinin combination therapies were introduced in 2006 in Colombia, where artemether-lumefantrine (AL) is currently used to treat uncomplicated P. falciparum malaria. Artemisinin (ART) resistance was initially observed in Southeast Asia as an increased parasite clearance time, manifesting as a positive thick-blood smear on day 3 after treatment (D3 positivity). Recently, mutations in the propeller domain of the P. falciparum kelch13 gene (K13 propeller) have been associated with ART resistance. In this study, we surveyed AL effectiveness at D3 and molecular markers of drug resistance among 187 uncomplicated P. falciparum cases in 4 regions of Colombia from June 2014 to July 2015. We found that 3.2% (4/125) of patients showed D3 positivity, 100% (163/163) of isolates carried wild-type K13 propeller alleles, 12.9% (23/178) of isolates had multiple copies of the multidrug resistance 1 gene (mdr1), and 75.8% (113/149) of isolates harbored the double mutant NFSDD mdr1 haplotype (the underlining indicates mutant alleles). These data suggest that ART resistance is not currently suspected in Colombia but that monitoring for lumefantrine resistance and AL failures should continue.

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Section: Discussionsupporting

confidence: 92%

K13 Propeller Alleles, mdr1 Polymorphism, and Drug Effectiveness at Day 3 after Artemether-Lumefantrine Treatment for Plasmodium falciparum Malaria in Colombia, 2014-2015

Montenegro

Neal

Posada

et al. 2017

Antimicrob Agents Chemother

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“…We used 200-l aliquots of venous blood samples collected at each home visit to isolate parasite DNA, using QIAamp DNA blood kits (Qiagen, Hilden, Germany), for confirmatory molecular diagnosis of malaria by quantitative real-time PCR targeting a species-specific 100-bp fragment of the Plasmodium falciparum and P. vivax 18S rRNA genes. We used a Step One Plus real-time PCR system (Applied Biosystems, Foster City, CA) for PCR amplification as described previously (38). The detection threshold of this diagnostic PCR is approximately 3 parasites/l of blood.…”

Section: Discussionmentioning

confidence: 99%

Monitoring the Efficacy of Chloroquine-Primaquine Therapy for Uncomplicated Plasmodium vivax Malaria in the Main Transmission Hot Spot of Brazil

Ladeia‐Andrade

et al. 2019

Antimicrob Agents Chemother

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Emerging Plasmodium vivax resistance to chloroquine (CQ) may undermine malaria elimination efforts in South America. CQ-resistant P. vivax has been found in the major port city of Manaus but not in the main malaria hot spots across the Amazon Basin of Brazil, where CQ is routinely coadministered with primaquine (PQ) for radical cure of vivax malaria. Here we randomly assigned 204 uncomplicated vivax malaria patients from Juruá Valley, northwestern Brazil, to receive either sequential (arm 1) or concomitant (arm 2) CQ-PQ treatment. Because PQ may synergize the blood schizontocidal effect of CQ and mask low-level CQ resistance, we monitored CQ-only efficacy in arm 1 subjects, who had PQ administered only at the end of the 28-day follow-up. We found adequate clinical and parasitological responses in all subjects assigned to arm 2. However, 2.2% of arm 1 patients had microscopy-detected parasite recrudescences at day 28. When PCR-detected parasitemias at day 28 were considered, response rates decreased to 92.1% and 98.8% in arms 1 and 2, respectively. Therapeutic CQ levels were documented in 6 of 8 recurrences, consistent with true CQ resistance in vivo. In contrast, ex vivo assays provided no evidence of CQ resistance in 49 local P. vivax isolates analyzed. CQ-PQ coadministration was not found to potentiate the antirelapse efficacy of PQ over 180 days of surveillance; however, we suggest that larger studies are needed to examine whether and how CQ-PQ interactions, e.g., CQ-mediated inhibition of PQ metabolism, modulate radical cure efficacy in different P. vivax-infected populations. (This study has been registered at ClinicalTrials.gov under identifier NCT02691910.)

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“…This decision was made based on a preoccupation of promoting artemisinin resistance due to mefloquine's longer half-life. However, a recent study in the southern amazon demonstrated that ASMQ use for a period of 6 years (between 2006 and 2012) has not led to clinical or molecular evidence of resistance,53 supports the decision taken by the Therapeutics Subcommittee of the NMCP of adopting ASMQ for the whole country. Neither chemoprophylaxis nor mass drug administration are common practice in Brazil.…”

Section: Malaria Control Interventionsmentioning

confidence: 86%

Plasmodium vivax Landscape in Brazil: Scenario and Challenges

Siqueira¹,

Mesones-Lapouble²,

Marchesini³

et al. 2016

Am J Trop Med Hyg

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Brazil is the largest country of Latin America, with a considerable portion of its territoritory within the malaria-endemic Amazon region in the North. Furthermore, a considerable portion of its territory is located within the Amazon region in the north. As a result, Brazil has reported half of the total malaria cases in the Americas in the last four decades. Recent progress in malaria control has been accompanied by an increasing proportion of Plasmodium vivax, underscoring a need for a better understanding of management and control of this species and associated challenges. Among these challenges, the contribution of vivax malaria relapses, earlier production of gametocytes (compared with Plasmodium falciparum), inexistent methods to diagnose hypnozoite carriers, and decreasing efficacy of available antimalarials need to be addressed. Innovative tools, strategies, and technologies are needed to achieve further progress toward sustainable malaria elimination. Further difficulties also arise from dealing with the inherent socioeconomic and environmental particularities of the Amazon region and its dynamic changes.

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No Clinical or Molecular Evidence of Plasmodium falciparum Resistance to Artesunate–Mefloquine in Northwestern Brazil

Abstract: Abstract. We evaluated the clinical efficacy of artesunate-mefloquine (ASMQ) fixed-dose combination to treat uncomplicated malaria in Juruá Valley, the main Plasmodium falciparum transmission hotspot in Brazil. Between

Cited by 21 publications

References 22 publications

K13 Propeller Alleles, mdr1 Polymorphism, and Drug Effectiveness at Day 3 after Artemether-Lumefantrine Treatment for Plasmodium falciparum Malaria in Colombia, 2014-2015

K13 Propeller Alleles, mdr1 Polymorphism, and Drug Effectiveness at Day 3 after Artemether-Lumefantrine Treatment for Plasmodium falciparum Malaria in Colombia, 2014-2015

Monitoring the Efficacy of Chloroquine-Primaquine Therapy for Uncomplicated Plasmodium vivax Malaria in the Main Transmission Hot Spot of Brazil

Plasmodium vivax Landscape in Brazil: Scenario and Challenges

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