scholarly journals Prevalence of potential mediators of artemisinin resistance in African isolates of Plasmodium falciparum

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Afolabi Owoloye ◽  
Michael Olufemi ◽  
Emmanuel T. Idowu ◽  
Kolapo M. Oyebola
Keyword(s):  
Plasmodium Falciparum ◽  
Partial Resistance ◽  
Meta Analysis ◽  
Artemisinin Resistance ◽  
Health Impact ◽  
Nucleotide Polymorphisms ◽  
African Countries ◽  
Effective Interventions ◽  
Resistance Markers

Abstract Background The devastating public health impact of malaria has prompted the need for effective interventions. Malaria control gained traction after the introduction of artemisinin-based combination therapy (ACT). However, the emergence of artemisinin (ART) partial resistance in Southeast Asia and emerging reports of delayed parasite sensitivity to ACT in African parasites signal a gradual trend towards treatment failure. Monitoring the prevalence of mutations associated with artemisinin resistance in African populations is necessary to stop resistance in its tracks. Mutations in Plasmodium falciparum genes pfk13, pfcoronin and pfatpase6 have been linked with ART partial resistance. Methods Findings from published research articles on the prevalence of pfk13, pfcoronin and pfatpase6 polymorphisms in Africa were collated. PubMed, Embase and Google Scholar were searched for relevant articles reporting polymorphisms in these genes across Africa from 2014 to August 2021, for pfk13 and pfcoronin. For pfatpase6, relevant articles between 2003 and August 2021 were retrieved. Results Eighty-seven studies passed the inclusion criteria for this analysis and reported 742 single nucleotide polymorphisms in 37,864 P. falciparum isolates from 29 African countries. Five validated-pfk13 partial resistance markers were identified in Africa: R561H in Rwanda and Tanzania, M476I in Tanzania, F446I in Mali, C580Y in Ghana, and P553L in an Angolan isolate. In Tanzania, three (L263E, E431K, S769N) of the four mutations (L263E, E431K, A623E, S769N) in pfatpase6 gene associated with high in vitro IC50 were reported. pfcoronin polymorphisms were reported in Senegal, Gabon, Ghana, Kenya, and Congo, with P76S being the most prevalent mutation. Conclusions This meta-analysis provides an overview of the prevalence and widespread distribution of pfk13, pfcoronin and pfatpase6 mutations in Africa. Understanding the phenotypic consequences of these mutations can provide information on the efficacy status of artemisinin-based treatment of malaria across the continent. Graphical Abstract

scholarly journals Prevalence of potential mediators of artemisinin resistance in African isolates of Plasmodium falciparum

2021 ◽  
Author(s):  
Afolabi Owoloye ◽  
Michael Juwon Olufemi ◽  
Emmanuel Taiwo Idowu ◽  
Kolapo Muyiwa Oyebola
Keyword(s):  
Plasmodium Falciparum ◽  
Gene Mutations ◽  
Artemisinin Resistance ◽  
Parasite Clearance ◽  
Health Impact ◽  
Nucleotide Polymorphisms ◽  
African Countries ◽  
Effective Interventions ◽  
Failure Monitoring ◽  
Published Research

Abstract The devastating public health impact of malaria has prompted the need for effective interventions. Malaria control gained traction after the introduction of artemisinin-based combination therapies (ACTs). However, the emergence of artemisinin (ART) resistance in South-East Asia and reports of delayed parasite sensitivity to ACTs in African parasites signal an imminent treatment failure. Monitoring the prevalence of mutations associated with artemisinin resistance in African populations is required to stop resistance in its tracks. Plasmodium falciparum Kelch-13 (Pfk13), Pfcoronin and PfATPase6 gene mutations have been associated with ART resistance. In this review, we collated findings from published research articles to establish the prevalence of Pfk13, Pfcoronin and PfATPase6 polymorphisms in Africa. We searched PubMed, Embase and Google Scholar for relevant articles reporting polymorphisms in these genes across Africa between 2014 to 2021. Seventy-two studies which passed the inclusion criteria reported 739 single nucleotide polymorphisms (331 unique variants) from 34,353 samples collected in 26 African countries. Four validated Pfk13 resistant markers linked with delayed parasite clearance were identified in Africa: R561H in Rwanda and Tanzania, M476I in Tanzania, and F446I in Mali, and P553L in Angola. In Tanzania, three (L263E, E431K, and S769N) of the four mutations (L263E, E431K, A623E, and S769N) in PfATPase6 gene previously associated with delayed parasite clearance in presence of artemisinin were reported. Pfcoronin polymorphisms were reported in Senegal, Gabon, Ghana, Kenya and Congo, with P76S being the most prevalent Pfcoronin mutation. Our findings demonstrate independent emergence and widespread distribution of Pfk13, Pfcoronin and PfATPase6 mutations in Africa. Understanding the phenotypic consequences of these mutations can provide information on the efficacy status of artemisinin-based treatment of malaria in Africa.

scholarly journals Prevalence of Mutations in the pfcoronin Gene and Association with Ex Vivo Susceptibility to Common Quinoline Drugs against Plasmodium falciparum

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1273
Author(s):  
Océane Delandre ◽  
Mathieu Gendrot ◽  
Isabelle Fonta ◽  
Joel Mosnier ◽  
Nicolas Benoit ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Sanger Sequencing ◽  
Ex Vivo ◽  
Central Africa ◽  
Artemisinin Resistance ◽  
Current Data ◽  
Artemisinin Derivative ◽  
African Countries ◽  
Low Prevalence

Background: Artemisinin-based combination therapy (ACT) was recommended to treat uncomplicated falciparum malaria. Unlike the situation in Asia where resistance to ACT has been reported, artemisinin resistance has not yet emerged in Africa. However, some rare failures with ACT or patients continuing to be parasitaemic on day 3 after ACT treatment have been reported in Africa or in travellers returning from Africa. Three mutations (G50E, R100K, and E107V) in the pfcoronin gene could be responsible for artemisinin resistance in Africa. Methods: The aims of this study were first to determine the prevalence of mutations in the pfcoronin gene in African P. falciparum isolates by Sanger sequencing, by targeting the 874 samples collected from patients hospitalised in France after returning from endemic areas in Africa between 2018 and 2019, and secondly to evaluate their association with in vitro reduced susceptibility to standard quinoline antimalarial drugs, including chloroquine, quinine, mefloquine, desethylamodiaquine, lumefantrine, piperaquine, and pyronaridine. Results: The three mutations in the pfcoronin gene (50E, 100K, and 107V) were not detected in the 874 P. falciparum isolates. Current data show that another polymorphism (P76S) is present in many countries of West Africa (mean prevalence of 20.7%) and Central Africa (11.9%) and, rarely, in East Africa (4.2%). This mutation does not appear to be predictive of in vitro reduced susceptibility to quinolines, including artemisinin derivative partners in ACT such as amodiaquine, lumefantrine, piperaquine, pyronaridine, and mefloquine. Another mutation (V62M) was identified at low prevalence (overall prevalence of 1%). Conclusions: The 76S mutation is present in many African countries with a prevalence above 10%. It is reassuring that this mutation does not confer in vitro resistance to ACT partners.

scholarly journals Drug resistance markers within an evolving efficacy of anti-malarial drugs in Cameroon: a systematic review and meta-analysis (1998–2020)

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Peter Thelma Ngwa Niba ◽  
Akindeh M. Nji ◽  
Marie-Solange Evehe ◽  
Innocent M. Ali ◽  
Palmer Masumbe Netongo ◽  
...  
Keyword(s):  
Systematic Review ◽  
Drug Resistance ◽  
Resistance Genes ◽  
Meta Analysis ◽  
Gene Mutations ◽  
Artemisinin Resistance ◽  
Molecular Data ◽  
Nucleotide Polymorphisms ◽  
Pooled Prevalence ◽  
Resistance Markers

Abstract Background Malaria remains highly endemic in Cameroon. The rapid emergence and spread of drug resistance was responsible for the change from monotherapies to artemisinin-based combinations. This systematic review and meta-analysis aimed to determine the prevalence and distribution of Plasmodium falciparum drug resistance markers within an evolving efficacy of anti-malarial drugs in Cameroon from January 1998 to August 2020. Methods The PRISMA-P and PRISMA statements were adopted in the inclusion of studies on single nucleotide polymorphisms (SNPs) of P. falciparum anti-malarial drug resistance genes (Pfcrt, Pfmdr1, Pfdhfr, Pfdhps, Pfatp6, Pfcytb and Pfk13). The heterogeneity of the included studies was evaluated using the Cochran’s Q and I2 statistics. The random effects model was used as standard in the determination of heterogeneity between studies. Results Out of the 902 records screened, 48 studies were included in this aggregated meta-analysis of molecular data. A total of 18,706 SNPs of the anti-malarial drug resistance genes were genotyped from 47,382 samples which yielded a pooled prevalence of 35.4% (95% CI 29.1–42.3%). Between 1998 and 2020, there was significant decline (P < 0.0001 for all) in key mutants including Pfcrt 76 T (79.9%-43.0%), Pfmdr1 86Y (82.7%-30.5%), Pfdhfr 51I (72.2%-66.9%), Pfdhfr 59R (76.5%-67.8%), Pfdhfr 108 N (80.8%-67.6%). The only exception was Pfdhps 437G which increased over time (30.4%-46.9%, P < 0.0001) and Pfdhps 540E that remained largely unchanged (0.0%-0.4%, P = 0.201). Exploring mutant haplotypes, the study observed a significant increase in the prevalence of Pfcrt CVIET mixed quintuple haplotype from 57.1% in 1998 to 57.9% in 2020 (P < 0.0001). In addition, within the same study period, there was no significant change in the triple Pfdhfr IRN mutant haplotype (66.2% to 67.3%, P = 0.427). The Pfk13 amino acid polymorphisms associated with artemisinin resistance were not detected. Conclusions This review reported an overall decline in the prevalence of P. falciparum gene mutations conferring resistance to 4-aminoquinolines and amino alcohols for a period over two decades. Resistance to artemisinins measured by the presence of SNPs in the Pfk13 gene does not seem to be a problem in Cameroon. Systematic review registration PROSPERO CRD42020162620

scholarly journals K13 Propeller Mutations in Plasmodium falciparum Populations in Regions of Malaria Endemicity in Vietnam from 2009 to 2016

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Nguyen Thuy-Nhien ◽  
Nguyen Kim Tuyen ◽  
Nguyen Thanh Tong ◽  
Nguyen Tuong Vy ◽  
Ngo Viet Thanh ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Artemisinin Resistance ◽  
Parasite Clearance ◽  
Single Strain ◽  
Content Type ◽  
Reduced Ring ◽  
Resistance Markers ◽  
Multiple Strains

ABSTRACT The spread of artemisinin-resistant Plasmodium falciparum compromises the therapeutic efficacy of artemisinin combination therapies (ACTs) and is considered the greatest threat to current global initiatives to control and eliminate malaria. This is particularly relevant in Vietnam, where dihydroartemisinin-piperaquine (DP) is the recommended ACT for P. falciparum infection. The propeller domain gene of K13, a molecular marker of artemisinin resistance, was successfully sequenced in 1,060 P. falciparum isolates collected at 3 malaria hot spots in Vietnam between 2009 and 2016. Eight K13 propeller mutations (Thr474Ile, Tyr493His, Arg539Thr, Ile543Thr, Pro553Leu, Val568Gly, Pro574Leu, and Cys580Tyr), including several that have been validated to be artemisinin resistance markers, were found. The prevalences of K13 mutations were 29% (222/767), 6% (11/188), and 43% (45/105) in the Binh Phuoc, Ninh Thuan, and Gia Lai Provinces of Vietnam, respectively. Cys580Tyr became the dominant genotype in recent years, with 79.1% (34/43) of isolates in Binh Phuoc Province and 63% (17/27) of isolates in Gia Lai Province carrying this mutation. K13 mutations were associated with reduced ring-stage susceptibility to dihydroartemisinin (DHA) in vitro and prolonged parasite clearance in vivo. An analysis of haplotypes flanking K13 suggested the presence of multiple strains with the Cys580Tyr mutation rather than a single strain expanding across the three sites.

scholarly journals Absence of Plasmodium falciparum artemisinin resistance gene mutations eleven years after the adoption of artemisinin-based combination therapy in Nigeria

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Moses Ikegbunam ◽  
Johnson A. Ojo ◽  
Kossiwa Kokou ◽  
Ugonna Morikwe ◽  
Chukwuemeka Nworu ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Combination Therapy ◽  
Gene Mutations ◽  
Artemisinin Resistance ◽  
Cross Sectional Study ◽  
Nucleotide Polymorphisms ◽  
Cross Sectional ◽  
Two Samples ◽  
Group A

Abstract Background The occurrence of artemisinin resistance (ART)-associated polymorphism of Plasmodium falciparum K13-propeller (pfk13) gene before and after the introduction of artemisinin-based combination therapy (ACT) in two regions of Nigeria was investigated in this study. Regular surveillance is necessary to make a definite conclusion on the emergence and pattern of possible resistance to ART. Methods This cross-sectional study was carried out in the Southwestern and Southeastern geopolitical zones of Nigeria. A total of 150, 217, and 475 participants were enrolled for the study in the Southwest (2004_Group A), Southwest (2015_Group B), and southeast (2015_Group C), respectively. Blood samples were collected from the study participants for DNA extraction and a nested PCR for P. falciparum identification. Samples that were positive for P. falciparum were genotyped for the pfk13 gene using the Sanger sequencing method. The single nucleotide polymorphisms were analysed using the Bioedit software. Results A total of 116, 125, and 83 samples were positive for P. falciparum, respectively for the samples collected from the Southwest (2004 and 2015) and southeast (2015). Parasite DNA samples collected from febrile children in 2004 (Group A; n = 71) and 2015 (Group B; n = 73) in Osogbo Western Nigeria and 2015_Group C (n = 36) in southeast Nigeria were sequenced successfully. This study did not observe mutations associated with the in vitro resistance in southeast Asia, such as Y493H, R539T, I543T, and C580Y. Two new polymorphisms V520A and V581I were observed in two samples collected in Osogbo, Southwest Nigeria. These two mutations occurred in the year 2004 (Group A) before the introduction of ACT. Six mutations were identified in 17% of the samples collected in southeast Nigeria. One of these mutations (D547G) was non-synonymous, while the remaining (V510V, R515R, Q613Q, E688E, and N458N) were synonymous. Also, one (2%) heterozygote allele was identified at codon 458 in the 2015 (Group C) samples. Conclusions None of the mutations observed in this study were previously validated to be associated with ART resistance. These results, therefore, suggest that artemisinin is likely to remain highly effective in treating malaria in the study areas that are malarious zone.

scholarly journals Mutation in Plasmodium falciparum BTB/POZ domain of K13 protein confers artemisinin resistance

2021 ◽  
Author(s):  
Lucie Paloque ◽  
Romain Coppée ◽  
Barbara H. Stokes ◽  
Nina F. Gnädig ◽  
Karamoko Niaré ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Artemisinin Resistance ◽  
Parasite Clearance ◽  
West African ◽  
Whole Genome Sequence ◽  
Drug Pressure ◽  
Synonymous Mutations ◽  
Survival Assay ◽  
One Year

Partial artemisinin resistance, defined in patients as a delayed parasite clearance following artemisinin-based treatment, is conferred by non-synonymous mutations in the Kelch beta-propeller domain of the Plasmodium falciparum k13 ( pfk13 ) gene. Here, we carried out in vitro selection over a one-year period on a West African P. falciparum strain isolated from Kolle (Mali) under a dose-escalating artemisinin regimen. After 18 cycles of sequential drug pressure, the selected parasites exhibited enhanced survival to dihydroartemisinin in the ring-stage survival assay (RSA 0-3h = 9.2%). Sanger and whole-genome sequence analyses identified the PfK13 P413A mutation, localized in the BTB/POZ domain, upstream of the propeller domain. This mutation was sufficient to confer in vitro artemisinin resistance when introduced into the PfK13 coding sequence of the parasite strain Dd2 by CRISPR/Cas9 gene editing. These results together with structural studies of the protein demonstrate that the propeller domain is not the sole in vitro mediator of PfK13-mediated artemisinin resistance, and highlight the importance of monitoring for mutations throughout PfK13.

scholarly journals Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda

2020 ◽  
Vol 26 (10) ◽  
pp. 1602-1608 ◽  
Author(s):  
Aline Uwimana ◽  
Eric Legrand ◽  
Barbara H. Stokes ◽  
Jean-Louis Mangala Ndikumana ◽  
Marian Warsame ◽  
...  
Keyword(s):  
Phylogenetic Analysis ◽  
Plasmodium Falciparum ◽  
Gene Editing ◽  
De Novo ◽  
Artemisinin Resistance ◽  
Clonal Expansion ◽  
Efficacy Trials ◽  
Cure Rates ◽  
Antimalarial Chemotherapy

Abstract Artemisinin resistance (delayed P. falciparum clearance following artemisinin-based combination therapy), is widespread across Southeast Asia but to date has not been reported in Africa1–4. Here we genotyped the P. falciparum K13 (Pfkelch13) propeller domain, mutations in which can mediate artemisinin resistance5,6, in pretreatment samples collected from recent dihydroarteminisin-piperaquine and artemether-lumefantrine efficacy trials in Rwanda7. While cure rates were >95% in both treatment arms, the Pfkelch13 R561H mutation was identified in 19 of 257 (7.4%) patients at Masaka. Phylogenetic analysis revealed the expansion of an indigenous R561H lineage. Gene editing confirmed that this mutation can drive artemisinin resistance in vitro. This study provides evidence for the de novo emergence of Pfkelch13-mediated artemisinin resistance in Rwanda, potentially compromising the continued success of antimalarial chemotherapy in Africa.

scholarly journals Delayed Parasite Clearance after Treatment with Dihydroartemisinin-Piperaquine in Plasmodium falciparum Malaria Patients in Central Vietnam

2014 ◽  
Vol 58 (12) ◽  
pp. 7049-7055 ◽  
Author(s):  
Kamala Thriemer ◽  
Nguyen Van Hong ◽  
Anna Rosanas-Urgell ◽  
Bui Quang Phuc ◽  
Do Manh Ha ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Clearance Rate ◽  
Artemisinin Resistance ◽  
Parasite Clearance ◽  
Clearance Time ◽  
Sensitivity Testing ◽  
Content Type ◽  
Parasite Clearance Time ◽  
Central Vietnam

ABSTRACTReduced susceptibility ofPlasmodium falciparumtoward artemisinin derivatives has been reported from the Thai-Cambodian and Thai-Myanmar borders. Following increasing reports from central Vietnam of delayed parasite clearance after treatment with dihydroartemisinin-piperaquine (DHA-PPQ), the current first-line treatment, we carried out a study on the efficacy of this treatment. Between September 2012 and February 2013, we conducted a 42-dayin vivoandin vitroefficacy study in Quang Nam Province. Treatment was directly observed, and blood samples were collected twice daily until parasite clearance. In addition, genotyping, quantitative PCR (qPCR), andin vitrosensitivity testing of isolates was performed. The primary endpoints were parasite clearance rate and time. The secondary endpoints included PCR-corrected and uncorrected cure rates, qPCR clearance profiles,in vitrosensitivity results (for chloroquine, dihydroartemisinin, and piperaquine), and genotyping for mutations in the Kelch 13 propeller domain. Out of 672 screened patients, 95 were recruited and 89 available for primary endpoint analyses. The median parasite clearance time (PCT) was 61.7 h (interquartile range [IQR], 47.6 to 83.2 h), and the median parasite clearance rate had a slope half-life of 6.2 h (IQR, 4.4 to 7.5 h). The PCR-corrected efficacy rates were estimated at 100% at day 28 and 97.7% (95% confidence interval, 91.2% to 99.4%) at day 42. At day 3, theP. falciparumprevalence by qPCR was 2.5 times higher than that by microscopy. The 50% inhibitory concentrations (IC50s) of isolates with delayed clearance times (≥72 h) were significantly higher than those with normal clearance times for all three drugs. Delayed parasite clearance (PCT, ≥72 h) was significantly higher among day 0 samples carrying the 543 mutant allele (47.8%) than those carrying the wild-type allele (1.8%;P= 0.048). In central Vietnam, the efficacy of DHA-PPQ is still satisfactory, but the parasite clearance time and rate are indicative of emerging artemisinin resistance. (This study has been registered at ClinicalTrials.gov under registration no. NCT01775592.)

scholarly journals Molecular Profile of Malaria Drug Resistance Markers of Plasmodium falciparum in Suriname

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
Stella M. Chenet ◽  
Sheila Akinyi Okoth ◽  
Julia Kelley ◽  
Naomi Lucchi ◽  
Curtis S. Huber ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Therapeutic Efficacy ◽  
Artemisinin Resistance ◽  
Molecular Profile ◽  
Resistance Mutations ◽  
Molecular Surveillance ◽  
Content Type ◽  
Resistance Markers ◽  
High Parasite

ABSTRACT In Suriname, an artesunate monotherapy therapeutic efficacy trial was recently conducted to evaluate partial artemisinin resistance emerging in Plasmodium falciparum. We genotyped the PfK13 propeller domain of P. falciparum in 40 samples as well as other mutations proposed to be associated with artemisinin-resistant mutants. We did not find any mutations previously associated with artemisinin resistance in Southeast Asia, but we found fixed resistance mutations for chloroquine (CQ) and sulfadoxine-pyrimethamine. Additionally, the PfCRT C350R mutation, associated with reversal of CQ resistance and piperaquine-selective pressure, was present in 62% of the samples. Our results from neutral microsatellite data also confirmed a high parasite gene flow in the Guiana Shield. Although recruiting participants for therapeutic efficacy studies is challenging in areas where malaria endemicity is very low due to the low number of malaria cases reported, conducting these studies along with molecular surveillance remains essential for the monitoring of artemisinin-resistant alleles and for the characterization of the population structure of P. falciparum in areas targeted for malaria elimination.

scholarly journals Plasmodium falciparum K13 mutations in Africa and Asia present varying degrees of artemisinin resistance and an elevated fitness cost in African parasites

2021 ◽  
Author(s):  
Barbara H. Stokes ◽  
Kelly Rubiano ◽  
Satish K. Dhingra ◽  
Sachel Mok ◽  
Judith Straimer ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Southeast Asia ◽  
Survival Rates ◽  
Point Mutations ◽  
Artemisinin Resistance ◽  
Parasite Clearance ◽  
Definitive Evidence ◽  
The Impact

AbstractThe emergence of artemisinin (ART) resistance in Plasmodium falciparum parasites has led to increasing rates of treatment failure with first-line ART-based combination therapies (ACTs) in Southeast Asia. In this region, select mutations in K13 can result in delayed parasite clearance rates in vivo and enhanced survival in the ring-stage survival assay (RSA) in vitro. Our genotyping of 3,299 P. falciparum isolates across 11 sub-Saharan countries reveals the continuing dominance of wild-type K13 and confirms the emergence of a K13 R561H variant in Rwanda. Using gene editing, we provide definitive evidence that this mutation, along with M579I and C580Y, can confer variable degrees of in vitro ART resistance in African P. falciparum strains. C580Y and M579I were both associated with substantial fitness costs in African parasites, which may counter-select against their dissemination in high-transmission settings. We also report the impact of multiple K13 mutations, including the predominant variant C580Y, on RSA survival rates and fitness in multiple Southeast Asian strains. No change in ART susceptibility was observed upon editing point mutations in ferrodoxin or mdr2, earlier associated with ART resistance in Southeast Asia. These data point to the lack of an evident biological barrier to mutant K13 mediating ART resistance in Africa, while identifying their detrimental impact on parasite growth.

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