Increase in Kelch 13 Polymorphisms in Plasmodium falciparum, Southern Rwanda

Abstract According to the WHO, almost two thirds of the Ethiopian population are at risk of contracting malaria, where infection with Plasmodium falciparum accounts for approximately 60% of cases today. The risk of artemisinin resistance spreading from SE Asia to Africa is a major concern. We conducted a 28-day in vivo efficacy trial of Artemether-Lumefantrine (Co-Artem) for treatment of uncomplicated malaria (n = 97) in the Gondar Region, North West Ethiopia in 2017–2018. Our results confirmed 100% adequate clinical and parasitological response (ACPR) with no parasites observed at day 3 by microscopy. Further analysis of day 0 samples showed the expansion of a kelch13 mutation R622I to 9.5% from 2.4% of isolates reported three years earlier. Closer examination of the R622I mutation in vitro is warranted.

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Efficacy of Artemether-Lumefantrine on various Plasmodium falciparum Kelch 13 and Pfmdr1 genes isolated in Ghana

Parasite Epidemiology and Control ◽

10.1016/j.parepi.2020.e00190 ◽

2020 ◽

Vol 11 ◽

pp. e00190

Author(s):

Enoch Aninagyei ◽

Comfort Dede Tetteh ◽

Martin Oppong ◽

Alex Boye ◽

Desmond Omane Acheampong

Keyword(s):

Plasmodium Falciparum ◽

Kelch 13

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Polymorphisms in Plasmodium falciparum Kelch 13 and P. vivax Kelch 12 Genes in Parasites Collected from Three South Pacific Countries Prior to Extensive Exposure to Artemisinin Combination Therapies

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00536-19 ◽

2019 ◽

Vol 63 (7) ◽

Cited By ~ 1

Author(s):

Karryn Gresty ◽

Karen Anderson ◽

Cielo Pasay ◽

Norman C. Waters ◽

Qin Cheng

Keyword(s):

Plasmodium Falciparum ◽

Papua New Guinea ◽

Solomon Islands ◽

Artemisinin Resistance ◽

South Pacific ◽

New Guinea ◽

Combination Therapies ◽

Baseline Information ◽

Artemisinin Combination Therapies ◽

Kelch 13

ABSTRACT The South Pacific countries Solomon Islands, Vanuatu, and Papua New Guinea (PNG) adopted artemisinin-based combination therapies (ACTs) in 2008. We examined Kelch 13 and Kelch 12 genes in parasites originating from these countries before or at ACT introduction. Four Kelch 13 and two Kelch 12 novel sequence polymorphisms, not associated with artemisinin resistance, were observed in parasites from Solomon Islands and Vanuatu. No polymorphisms were observed in PNG parasites. The findings provide useful baseline information.

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Continued Sensitivity of Plasmodium falciparum to Artemisinin in Guyana, With Absence of Kelch Propeller Domain Mutant Alleles

Open Forum Infectious Diseases ◽

10.1093/ofid/ofw185 ◽

2016 ◽

Vol 3 (3) ◽

Cited By ~ 6

Author(s):

Reyaud Rahman ◽

Maria Jesus Sanchez Martin ◽

Shamdeo Persaud ◽

Nicolas Ceron ◽

Dwayne Kellman ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Confidence Interval ◽

Clearance Rate ◽

Artemisinin Resistance ◽

Parasite Clearance ◽

Wild Type ◽

Resistance Monitoring ◽

Mining Areas ◽

Widespread Availability ◽

Kelch 13

Abstract Because of concerns about possible emergence of artemisinin resistance strains of Plasmodium falciparum in mining areas of the interior of Guyana, a 7-day artesunate trial was conducted from March to December 2014. The day-3 parasite clearance rate, the efficacy of artesunate at day 28, and polymorphism of Kelch 13 (PfK13)—the marker of artemisinin resistance—were assessed. The study confirmed the continued sensitivity of P falciparum to artemisinin. A 7-day course of artesunate was 100% efficacious with only 2% (95% confidence interval, .1%–10.9%) of enrolled subjects positive at day 3. All day-0 parasite samples were wild type. Continued resistance monitoring is nevertheless recommended, given the widespread availability and uncontrolled use of artemisinin drugs in mining areas of Guyana.

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Plasmodium falciparum kelch 13: a potential molecular marker for tackling artemisinin-resistant malaria parasites

Expert Review of Anti-infective Therapy ◽

10.1586/14787210.2016.1106938 ◽

2015 ◽

Vol 14 (1) ◽

pp. 125-135 ◽

Cited By ~ 11

Author(s):

Toshihiro Mita ◽

Shin-Ichiro Tachibana ◽

Muneaki Hashimoto ◽

Makoto Hirai

Keyword(s):

Plasmodium Falciparum ◽

Molecular Marker ◽

Malaria Parasites ◽

Kelch 13

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Kelch 13 propeller gene polymorphism among Plasmodium falciparum isolates in Lagos, Nigeria: Molecular Epidemiologic Study

Tropical Medicine & International Health ◽

10.1111/tmi.13273 ◽

2019 ◽

Vol 24 (8) ◽

pp. 1011-1017 ◽

Cited By ~ 1

Author(s):

Uche Igbasi ◽

Wellington Oyibo ◽

Sunday Omilabu ◽

Hong Quan ◽

Shen‐Bo Chen ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Gene Polymorphism ◽

Epidemiologic Study ◽

Molecular Epidemiologic Study ◽

Kelch 13

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Imidazolopiperazines Kill both Rings and Dormant Rings in Wild-Type and K13 Artemisinin-Resistant Plasmodium falciparum In Vitro

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02235-17 ◽

2018 ◽

Vol 62 (5) ◽

Cited By ~ 5

Author(s):

Laurent Dembele ◽

Devendra Kumar Gupta ◽

Michelle Yi-Xiu Lim ◽

Xiaoman Ang ◽

Jeremy J. Selva ◽

...

Keyword(s):

Clinical Trials ◽

Plasmodium Falciparum ◽

Southeast Asia ◽

Active Metabolite ◽

Parasite Clearance ◽

Ring Stage ◽

Wild Type ◽

Content Type ◽

Kelch 13

ABSTRACT Artemisinin (ART) resistance has spread through Southeast Asia, posing a serious threat to the control and elimination of malaria. ART resistance has been associated with mutations in the Plasmodium falciparum kelch-13 ( Pfk13 ) propeller domain. Phenotypically, ART resistance is defined as delayed parasite clearance in patients due to the reduced susceptibility of early ring-stage parasites to the active metabolite of ART dihydroartemisinin (DHA). Early rings can enter a state of quiescence upon DHA exposure and resume growth in its absence. These quiescent rings are referred to as dormant rings or DHA-pretreated rings (here called dormant rings). The imidazolopiperazines (IPZ) are a novel class of antimalarial drugs that have demonstrated efficacy in early clinical trials. Here, we characterized the stage of action of the IPZ GNF179 and evaluated its activity against rings and dormant rings in wild-type and ART-resistant parasites. Unlike DHA, GNF179 does not induce dormancy. We show that GNF179 is more rapidly cidal against schizonts than against ring and trophozoite stages. However, with 12 h of exposure, the compound effectively kills rings and dormant rings of both susceptible and ART-resistant parasites within 72 h. We further demonstrate that in combination with ART, GNF179 effectively prevents recrudescence of dormant rings, including those bearing pfk13 propeller mutations.

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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

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.21-0303 ◽

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.

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