Comparative Impacts Over 5 Years of Artemisinin-Based Combination Therapies on Plasmodium falciparum Polymorphisms That Modulate Drug Sensitivity in Ugandan Children

Conrad, Melissa D.; LeClair, Norbert P.; Arinaitwe, Emmanuel; Wanzira, Humphrey; Kakuru, Abel; Bigira, Victor; Muhindo, Mary; Kamya, Moses R.; Tappero, Jordan W.; Greenhouse, Bryan; Dorsey, Grant; Rosenthal, Philip J.

doi:10.1093/infdis/jiu141

Cited by 92 publications

(150 citation statements)

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“…However, earlier studies from Burkina Faso showed that prior treatment with DP did not select for pfcrt and pfmdr1 polymorphisms associated with resistance to CQ and AQ (28). These results differ from those in a recent study in Uganda, in which therapy with DP selected in recurrent infections for pfmdr1 polymorphisms (86Y and 1246Y) also selected by AQ-containing regimens (29). The reasons for different results between Uganda and Burkina Faso and for differential effects of the different aminoquinolines in Burkina Faso are not known.…”

Section: Discussioncontrasting

confidence: 84%

“…Specifically, in infections occurring within 28 to 42 days of prior therapy in Burkina Faso, AQ/SP selected for mutations in pfdhfr, pfdhps, pfcrt, and pfmdr1 associated with drug resistance, but DP did not select for any of these polymorphisms (20,26,28). However, in a recent study in East Africa, prior use of DP selected in recurrent infections for polymorphisms in pfmdr1 that were also selected for by AQ/SP (29); the reasons for differences in selection between East and West Africa are unknown. To evaluate the relative selective pressures of AQ/SP and DP administered as SMC, we evaluated the prevalences of key resistance-mediating P. falciparum polymorphisms in parasites collected from children before the initiation of the intervention, from children a month after the completion of three monthly treatments, and from a control group of children not subject to the intervention.…”

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confidence: 99%

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Selection of Drug Resistance-Mediating Plasmodium falciparum Genetic Polymorphisms by Seasonal Malaria Chemoprevention in Burkina Faso

Somé

Zongo

Compaoré

et al. 2014

Antimicrob Agents Chemother

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e Seasonal malaria chemoprevention (SMC), with regular use of amodiaquine plus sulfadoxine-pyrimethamine (AQ/SP) during the transmission season, is now a standard malaria control measure in the Sahel subregion of Africa. Another strategy under study is SMC with dihydroartemisinin plus piperaquine (DP). Plasmodium falciparum single nucleotide polymorphisms (SNPs) in P. falciparum crt (pfcrt), pfmdr1, pfdhfr, and pfdhps are associated with decreased response to aminoquinoline and antifolate antimalarials and are selected by use of these drugs. To characterize selection by SMC of key polymorphisms, we assessed 13 SNPs in P. falciparum isolated from children aged 3 to 59 months living in southwestern Burkina Faso and randomized to receive monthly DP or AQ/SP for 3 months in 2009. We compared SNP prevalence before the onset of SMC and 1 month after the third treatment in P. falciparum PCR-positive samples from 120 randomly selected children from each treatment arm and an additional 120 randomly selected children from a control group that did not receive SMC. The prevalence of relevant mutations was increased after SMC with AQ/SP. Significant selection was seen for pfcrt 76T (68.5% to 83.0%, P ‫؍‬ 0.04), pfdhfr 59R (54.8% to 83.3%, P ‫؍‬ 0.0002), and pfdhfr 108N (55.0% to 87.2%, P ‫؍‬ 0.0001), with trends toward selection of pfmdr1 86Y, pfdhfr 51I, and pfdhps 437G. After SMC with DP, only borderline selection of wild-type pfmdr1 D1246 (mutant; 7.7% to 0%, P ‫؍‬ 0.05) was seen. In contrast to AQ/SP, SMC with DP did not clearly select for known resistance-mediating polymorphisms. SMC with AQ/ SP, but not DP, may hasten the development of resistance to components of this regimen. (This study has been registered at ClinicalTrials.gov under registration no. NCT00941785.)

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confidence: 84%

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confidence: 99%

Selection of Drug Resistance-Mediating Plasmodium falciparum Genetic Polymorphisms by Seasonal Malaria Chemoprevention in Burkina Faso

Somé

Zongo

Compaoré

et al. 2014

Antimicrob Agents Chemother

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“…This effect of C350R on QN and MQ, however, was not replicated in field isolates, underscoring a complex genetic basis of susceptibility in the field. Another primary determinant of susceptibility to these drugs in P. falciparum is the pfmdr1 gene, which in French Guiana harbors the 86N and 184F residues that are associated with increased LUM susceptibility (31,32). Of note, all isolates remained highly susceptible to LUM, a finding that argues for maintaining the artemether + LUM combination as first-line therapy in the region.…”

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.

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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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“…In contrast, the A578S polymorphism is present in Africa (8,(24)(25)(26)(27)(28) and Bangladesh (29). Conflicting findings have been reported regarding the role of A578S in artemisinin resistance (8,26,30). Previous computational modeling using the betapropeller domain of the btbkelch protein krp1 (PDB ID 2WOZ) suggested that a structural change induced by the A578S mutation potentially disrupts the normal function of the Pfkelch13 protein (29).…”

Section: Discussionmentioning

confidence: 99%

Little Polymorphism at the K13 Propeller Locus in Worldwide Plasmodium falciparum Populations Prior to the Introduction of Artemisinin Combination Therapies

Mita

Culleton

Takahashi

et al. 2016

Antimicrob Agents Chemother

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The emergence and spread of artemisinin-resistant Plasmodium falciparum is of huge concern for the global effort toward malaria control and elimination. Artemisinin resistance, defined as a delayed time to parasite clearance following administration of artemisinin, is associated with mutations in the Pfkelch13 gene of resistant parasites. To date, as many as 60 nonsynonymous mutations have been identified in this gene, but whether these mutations have been selected by artemisinin usage or merely reflect natural polymorphism independent of selection is currently unknown. To clarify this, we sequenced the Pfkelch13 propeller domain in 581 isolates collected before (420 isolates) and after (161 isolates) the implementation of artemisinin combination therapies (ACTs), from various regions of endemicity worldwide. Nonsynonymous mutations were observed in 1% of parasites isolated prior to the introduction of ACTs. Frequencies of mutant isolates, nucleotide diversity, and haplotype diversity were significantly higher in the parasites isolated from populations exposed to artemisinin than in those from populations that had not been exposed to the drug. In the artemisinin-exposed population, a significant excess of dN compared to dS was observed, suggesting the presence of positive selection. In contrast, pairwise comparison of dN and dS and the McDonald and Kreitman test indicate that purifying selection acts on the Pfkelch13 propeller domain in populations not exposed to ACTs. These population genetic analyses reveal a low baseline of Pfkelch13 polymorphism, probably due to purifying selection in the absence of artemisinin selection. In contrast, various Pfkelch13 mutations have been selected under artemisinin pressure.

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Comparative Impacts Over 5 Years of Artemisinin-Based Combination Therapies on Plasmodium falciparum Polymorphisms That Modulate Drug Sensitivity in Ugandan Children

Abstract: NCT00527800.

Cited by 92 publications

References 46 publications

Selection of Drug Resistance-Mediating Plasmodium falciparum Genetic Polymorphisms by Seasonal Malaria Chemoprevention in Burkina Faso

Selection of Drug Resistance-Mediating Plasmodium falciparum Genetic Polymorphisms by Seasonal Malaria Chemoprevention in Burkina Faso

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

Little Polymorphism at the K13 Propeller Locus in Worldwide Plasmodium falciparum Populations Prior to the Introduction of Artemisinin Combination Therapies

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