scholarly journals Analysis of Major Genome Loci Underlying Artemisinin Resistance and pfmdr1 Copy Number in pre- and post-ACTs in Western Kenya

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Bidii S. Ngalah ◽  
Luiser A. Ingasia ◽  
Agnes C. Cheruiyot ◽  
Lorna J. Chebon ◽  
Dennis W. Juma ◽  
...  
Keyword(s):  
Copy Number ◽  
Artemisinin Resistance ◽  
Western Kenya ◽  
Major Genome ◽  
Pfmdr1 Copy Number

scholarly journals Erratum to: K13 mutations and pfmdr1 copy number variation in Plasmodium falciparum malaria in Myanmar

2016 ◽  
Vol 15 (1) ◽  
Author(s):  
Aye A. Win ◽  
Mallika Imwong ◽  
Myat P. Kyaw ◽  
Charles J. Woodrow ◽  
Kesinee Chotivanich ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Copy Number Variation ◽  
Falciparum Malaria ◽  
Copy Number ◽  
Plasmodium Falciparum Malaria ◽  
Number Variation ◽  
Pfmdr1 Copy Number

scholarly journals Plasmodium falciparum Isolates with Increased pfmdr1 Copy Number Circulate in West Africa

2010 ◽  
Vol 54 (7) ◽  
pp. 3049-3051 ◽  
Author(s):  
Benoit Witkowski ◽  
Marie-Laure Nicolau ◽  
Patrice Njomnang Soh ◽  
Xavier Iriart ◽  
Sandie Menard ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Combination Therapy ◽  
West Africa ◽  
Copy Number ◽  
Amino Alcohols ◽  
Pfmdr1 Copy Number

ABSTRACT Amplification of pfmdr1 in Plasmodium falciparum is linked to resistance to aryl-amino-alcohols and in reduced susceptibility to artemisinins. We demonstrate here that duplicated pfmdr1 genotypes circulate in West Africa. The monitoring of this prevalence in Africa appears essential for determining the antimalarial policy and to maintain the efficiency of artemisinin-based combination therapy (ACT) for as long as possible.

scholarly journals Molecular Detection of Mutations in the Propeller Domain of Kelch 13 and pfmdr1 Copy Number Variation in Plasmodium falciparum Isolates from Thailand Collected from 2002 to 2007

2021 ◽  
Author(s):  
Chaiyaporn Chaisatit ◽  
Piyaporn Sai-ngam ◽  
Sasikanya Thaloengsok ◽  
Sabaithip Sriwichai ◽  
Krisada Jongsakul ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Copy Number ◽  
Molecular Detection ◽  
Background Information ◽  
Southern Thailand ◽  
Geographic Diversity ◽  
Number Variation ◽  
Detection Of Mutations ◽  
Pfmdr1 Copy Number ◽  
Kelch 13

We determined the prevalence of Kelch 13 mutations and pfmdr1 copy number in samples collected from the Thailand–Myanmar border, the Thailand–Cambodia border, and southern Thailand from 2002 to 2007. C580Y was the most prevalent in Trat (Thailand–Cambodia border) and Ranong (Thailand–Myanmar border) at 42% (24/57) and 13% (6/48), respectively. Less predominant mutations were also identified including R539T (7%, 4/57) and Y493H (2%, 1/57) in Trat, P574L (6%, 3/48) and P553L (2%, 1/48) in Ranong, and N537I and D452E (7%, 1/15) in Sangkhlaburi (Thailand–Myanmar border). Samples from Mae sot (33%, 11/33) harbored the highest percentage of multiple pfmdr1 copies, followed by Trat (18%, 10/57), Chiang Dao in 2003 (13%, 4/30), Phang Nga (5%, 2/44), and Chiang Dao in 2002 (4%, 1/26). This retrospective study provides geographic diversity of K13 and pfmdr1 copies and the emergence of these molecular markers in Thailand, an important background information for future surveillance in the region.

scholarly journals A Major Genome Region Underlying Artemisinin Resistance in Malaria

Science ◽  
2012 ◽  
Vol 336 (6077) ◽  
pp. 79-82 ◽  
Author(s):  
Ian H. Cheeseman ◽  
Becky A. Miller ◽  
Shalini Nair ◽  
Standwell Nkhoma ◽  
Asako Tan ◽  
...  
Keyword(s):  
Genetic Basis ◽  
Selective Sweep ◽  
Strong Association ◽  
Artemisinin Resistance ◽  
Parasite Clearance ◽  
Nucleotide Polymorphisms ◽  
Two Phase ◽  
Single Nucleotide ◽  
Genome Region ◽  
Major Genome

Evolving resistance to artemisinin-based compounds threatens to derail attempts to control malaria. Resistance has been confirmed in western Cambodia and has recently emerged in western Thailand, but is absent from neighboring Laos. Artemisinin resistance results in reduced parasite clearance rates (CRs) after treatment. We used a two-phase strategy to identify genome region(s) underlying this ongoing selective event. Geographical differentiation and haplotype structure at 6969 polymorphic single-nucleotide polymorphisms (SNPs) in 91 parasites from Cambodia, Thailand, and Laos identified 33 genome regions under strong selection. We screened SNPs and microsatellites within these regions in 715 parasites from Thailand, identifying a selective sweep on chromosome 13 that shows strong association (P = 10−6 to 10−12) with slow CRs, illustrating the efficacy of targeted association for identifying the genetic basis of adaptive traits.

scholarly journals Counter-Selection of Antimalarial Resistance Polymorphisms by Intermittent Preventive Treatment in Pregnancy

2019 ◽  
Author(s):  
Silvie Huijben ◽  
Eusebio Macete ◽  
Ghyslain Mombo-Ngoma ◽  
Michael Ramharter ◽  
Simon Kariuki ◽  
...  
Keyword(s):  
Pregnancy Outcomes ◽  
Copy Number ◽  
Intermittent Preventive Treatment ◽  
Preventive Treatment ◽  
Antimalarial Resistance ◽  
Resistance Markers ◽  
The Impact ◽  
Pfmdr1 Copy Number ◽  
Selection Of ◽  
In Pregnancy

Abstract Background Innovative approaches are needed to limit antimalarial resistance evolution. Understanding the role of intermittent preventive treatment in pregnancy (IPTp) on the selection for resistance and the impact such selection has on pregnancy outcomes can guide future interventions. Methods Plasmodium falciparum isolates (n = 914) from 2 randomized clinical trials were screened for pfmdr1 copy number variation and pfcrt, pfmdr1, pfdhfr, and pfdhps resistance markers. The trials were conducted between 2010 and 2013 in Benin, Gabon, Kenya, and Mozambique to establish the efficacy of IPTp-mefloquine (MQ) compared with IPTp-sulphadoxine-pyrimethamine (SP) in human immunodeficiency virus (HIV)-uninfected and to IPTp-placebo in HIV-infected women. Results In HIV-uninfected women, the prevalence of pfcrt mutants, pfdhfr/pfdhps quintuple mutants, and pfmdr1 copy number was similar between women receiving IPT-SP and IPTp-MQ. However, prevalence of pfmdr1 polymorphism 86Y was lower in the IPTp-MQ group than in the IPTp-SP group, and within the IPTp-MQ group it was lower at delivery compared with recruitment. No effect of IPTp-MQ on resistance markers was observed among HIV-infected women. The carriage of resistance markers was not associated with pregnancy outcomes. Conclusions Selection of wild-type pfmdr1 polymorphism N86 by IPTp-MQ highlights the strong selective pressure IPTp can exert and the opportunity for using negative cross-resistance in drug choice for clinical treatment and IPTp.

scholarly journals No evidence of amplified Plasmodium falciparum plasmepsin II gene copy number in an area with artemisinin-resistant malaria along the China–Myanmar border

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Fang Huang ◽  
Biraj Shrestha ◽  
Hui Liu ◽  
Lin-Hua Tang ◽  
Shui-Sen Zhou ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Markers ◽  
Therapeutic Efficacy ◽  
Copy Number ◽  
Copy Number Variants ◽  
Gene Copy Number ◽  
Artemisinin Resistance ◽  
World Health ◽  
Gene Copy ◽  
Synonymous Mutations

Abstract Background The emergence and spread of artemisinin resistance in Plasmodium falciparum poses a threat to malaria eradication, including China’s plan to eliminate malaria by 2020. Piperaquine (PPQ) resistance has emerged in Cambodia, compromising an important partner drug that is widely used in China in the form of dihydroartemisinin (DHA)-PPQ. Several mutations in a P. falciparum gene encoding a kelch protein on chromosome 13 (k13) are associated with artemisinin resistance and have arisen spread in the Great Mekong subregion, including the China–Myanmar border. Multiple copies of the plasmepsin II/III (pm2/3) genes, located on chromosome 14, have been shown to be associated with PPQ resistance. Methods The therapeutic efficacy of DHA-PPQ for the treatment of uncomplicated P. falciparum was evaluated along the China–Myanmar border from 2010 to 2014. The dry blood spots samples collected in the efficacy study prior DHA-PPQ treatment and from the local hospital by passive detection were used to amplify k13 and pm2. Polymorphisms within k13 were genotyped by capillary sequencing and pm2 copy number was quantified by relative-quantitative real-time polymerase chain reaction. Treatment outcome was evaluated with the World Health Organization protocol. A linear regression model was used to estimate the association between the day 3 positive rate and k13 mutation and the relationship of the pm2 copy number variants and k13 mutations. Results DHA-PPQ was effective for uncomplicated P. falciparum infection in Yunnan Province with cure rates > 95%. Twelve non synonymous mutations in the k13 domain were observed among the 268 samples with the prevalence of 44.0% and the predominant mutation was F446I with a prevalence of 32.8%. Only one sample was observed with multi-copies of pm2, including parasites with and without k13 mutations. The therapeutic efficacy of DHA-PPQ was > 95% along the China–Myanmar border, consistent with the lack of amplification of pm2. Conclusion DHA-PPQ for uncomplicated P. falciparum infection still showed efficacy in an area with artemisinin-resistant malaria along the China–Myanmar border. There was no evidence to show PPQ resistance by clinical study and molecular markers survey. Continued monitoring of the parasite population using molecular markers will be important to track emergence and spread of resistance in this region.

scholarly journals Efficacy of Three Antimalarial Regimens for Uncomplicated Plasmodium Falciparum Malaria in Cambodia, 2009 – 2011: A Randomized Control Trial

2021 ◽  
Author(s):  
Dysoley Lek ◽  
Agus Rachmat ◽  
Dustin Harrison ◽  
Geoffrey Chin ◽  
Suwanna Chaoratanakawee ◽  
...  
Keyword(s):  
Falciparum Malaria ◽  
Copy Number ◽  
Controlled Trial ◽  
Artemisinin Resistance ◽  
Uncomplicated Falciparum Malaria ◽  
Multi Drug Resistance ◽  
Directly Observed Therapy ◽  
Open Label ◽  
Northern Border

Abstract Background: Antimalarial resistance remains an important public health challenge in Cambodia. The effectiveness of three therapies for uncomplicated Falciparum malaria were evaluated in Oddar Meanchey province in Northern Cambodia from 2009 – 2011.Methods: In this randomized, open-label, parallel group controlled trial, 211 subjects at least 5 years old with uncomplicated Falciparum malaria were treated with directly observed therapy. Over 3 days, 63 received artesunate-mefloquine (AS/MQ), 77 received dihydroartemisinin-piperaquine (DHA/PPQ), and 71 received atovaquone-proguanil (ATQ/PG). Subjects were followed for 42 days or until recurrent parasitemia. Genotyping of msp1, msp2, and glurp among individual parasite isolates distinguished recrudescence from reinfection. Pfmdr1 copy number was measured by real-time PCR and half-maximal parasite inhibitory concentrations (IC50) was measured in vitro by 48-hour isotopic hypoxanthine incorporation assay.Results: The primary outcome of per-protocol PCR-adjusted efficacy at 42 days was analyzed for 190 (90.0%) of the enrolled subjects. PCR-adjusted efficacy (95% confidence interval) at 42 days was 80.6% (70.8 – 90.5%) for AS/MQ, 97.2% (93.3 – 100%) for DHA/PPQ, and 92.9% (86.1 – 99.6%) for ATQ/PG. On day 3, 59.3% remained parasitemic. At baseline, 46.9% had microscopic P. falciparum gametocytemia. Both recurrences in the DHA/PPQ arm lost Pfmdr1 copy number amplification at recrudescence. All four recurrences in the ATQ/PG arm were wild-type for cytochrome bc1. One subject withdrew from the ATQ/PG arm due to drug allergy.Conclusions: This previously unpublished study was conducted at the epicenter of substantial multi-drug resistance that emerged soon thereafter. Occurring early in the national transition from AS/MQ to DHA/PPQ, both DHA/PPQ and ATQ/PG had acceptable efficacy against uncomplicated falciparum malaria. However, efficacy of AS/MQ was only 80% with apparent mefloquine resistance based on elevated Pfmdr1 copy number and IC50. By 2009, there was already significant evidence of artemisinin resistance not previously reported at the Northern Cambodia-Thai border. This study suggests the basis for early development of significant DHA/PPQ failures within 3 years of introduction. Artemisinin resistance likely occurred on the Northern border concurrently with that reported along the Western border in Pailin.Trial Registration: This legacy trial was conducted prior to International Committee of Medical Journal Editors’ requirements for preregistration on ClinicalTrials.gov. The full protocol has been provided.

scholarly journals K13 mutations and pfmdr1 copy number variation in Plasmodium falciparum malaria in Myanmar

2016 ◽  
Vol 15 (1) ◽  
Author(s):  
Aye A. Win ◽  
Mallika Imwong ◽  
Myat P. Kyaw ◽  
Charles J. Woodrow ◽  
Kesinee Chotivanich ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Copy Number Variation ◽  
Falciparum Malaria ◽  
Copy Number ◽  
Plasmodium Falciparum Malaria ◽  
Number Variation ◽  
Pfmdr1 Copy Number
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