scholarly journals Effect of Drug Pressure on Promoting the Emergence of Antimalarial-Resistant Parasites among Pregnant Women in Ghana

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Bernard Tornyigah ◽  
Romain Coppée ◽  
Pascal Houze ◽  
Kwadwo A. Kusi ◽  
Bright Adu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Pregnant Women ◽  
Marker Gene ◽  
Intermittent Preventive Treatment ◽  
Artemisinin Resistance ◽  
Preventive Treatment ◽  
Drug Pressure ◽  
Gene Markers ◽  
Content Type ◽  
Artemisinin Derivatives

ABSTRACT The continuous spread of antimalarial drug resistance is a threat to current chemotherapy efficacy. Therefore, characterizing the genetic diversity of drug resistance markers is needed to follow treatment effectiveness and further update control strategies. Here, we genotyped Plasmodium falciparum resistance gene markers associated with sulfadoxine-pyrimethamine (SP) and artemisinin-based combination therapy (ACT) in isolates from pregnant women in Ghana. The prevalence of the septuple IRNI-A/FGKGS/T pfdhfr/pfdhps haplotypes, including the pfdhps A581G and A613S/T mutations, was high at delivery among post-SP treatment isolates (18.2%) compared to those of first antenatal care (before initiation of intermittent preventive treatment of malaria in pregnancy with sulfadoxine-pyrimethamine [IPTp-SP]; 6.1%; P = 0.03). Regarding the pfk13 marker gene, two nonsynonymous mutations (N458D and A481C) were detected at positions previously related to artemisinin resistance in isolates from Southeast Asia. These mutations were predicted in silico to alter the stability of the pfk13 propeller-encoding domain. Overall, these findings highlight the need for intensified monitoring and surveillance of additional mutations associated with increased SP resistance as well as emergence of resistance against artemisinin derivatives.

scholarly journals In Silico Investigation of the Decline in Clinical Efficacy of Artemisinin Combination Therapies Due to Increasing Artemisinin and Partner Drug Resistance

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
Sophie G. Zaloumis ◽  
Pengxing Cao ◽  
Saber Dini ◽  
Miles P. Davenport ◽  
Deborah Cromer ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Treatment Failure ◽  
In Silico ◽  
Artemisinin Resistance ◽  
Exact Nature ◽  
Artemisinin Derivative ◽  
Combination Therapies ◽  
Content Type ◽  
Artemisinin Derivatives ◽  
The Impact

ABSTRACT Antimalarial treatment currently relies on an artemisinin derivative and a longer-acting partner drug. With the emergence of resistance to the artemisinin derivatives and the potential pressure this exerts on the partner drugs, the impact of resistance to each drug on efficacy needs to be investigated. An in silico exploration of dihydroartemisinin-piperaquine and mefloquine-artesunate, two artemisinin-based combination therapies that are commonly used in Southeast Asia, was performed. The percentage of treatment failures was simulated from a within-host pharmacokinetic-pharmacodynamic (PKPD) model, assuming that parasites developed increasing levels of (i) artemisinin derivative resistance or (ii) concomitant resistance to both the artemisinin derivative and the partner drug. Because the exact nature of how resistant Plasmodium falciparum parasites respond to treatment is unknown, we examined the impact on treatment failure rates of artemisinin resistance that (i) reduced the maximal killing rate, (ii) increased the concentration of drug required for 50% killing, or (iii) shortened the window of parasite stages that were susceptible to artemisinin derivatives until the drugs had no effect on the ring stages. The loss of the ring-stage activity of the artemisinin derivative caused the greatest increase in the treatment failure rate, and this result held irrespective of whether partner drug resistance was assumed to be present or not. To capture the uncertainty regarding how artemisinin derivative and partner drug resistance affects the assumed concentration-killing effect relationship, a variety of changes to this relationship should be considered when using within-host PKPD models to simulate clinical outcomes to guide treatment strategies for resistant infections.

scholarly journals Molecular Epidemiology of Plasmodium falciparum kelch13 Mutations in Senegal Determined by Using Targeted Amplicon Deep Sequencing

2017 ◽  
Vol 61 (3) ◽  
Author(s):  
Eldin Talundzic ◽  
Yaye D. Ndiaye ◽  
Awa B. Deme ◽  
Christian Olsen ◽  
Dhruviben S. Patel ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Deep Sequencing ◽  
Artemisinin Resistance ◽  
Potential Drug ◽  
Drug Pressure ◽  
Low Frequencies ◽  
Content Type ◽  
Public Health Activity ◽  
Codon Positions

ABSTRACT The emergence of Plasmodium falciparum resistance to artemisinin in Southeast Asia threatens malaria control and elimination activities worldwide. Multiple polymorphisms in the P. falciparum kelch gene found in chromosome 13 (Pfk13) have been associated with artemisinin resistance. Surveillance of potential drug resistance loci within a population that may emerge under increasing drug pressure is an important public health activity. In this context, P. falciparum infections from an observational surveillance study in Senegal were genotyped using targeted amplicon deep sequencing (TADS) for Pfk13 polymorphisms. The results were compared to previously reported Pfk13 polymorphisms from around the world. A total of 22 Pfk13 propeller domain polymorphisms were identified in this study, of which 12 have previously not been reported. Interestingly, of the 10 polymorphisms identified in the present study that were also previously reported, all had a different amino acid substitution at these codon positions. Most of the polymorphisms were present at low frequencies and were confined to single isolates, suggesting they are likely transient polymorphisms that are part of naturally evolving parasite populations. The results of this study underscore the need to identify potential drug resistance loci existing within a population, which may emerge under increasing drug pressure.

scholarly journals Increasing Prevalence of a Novel Triple-Mutant Dihydropteroate Synthase Genotype in Plasmodium falciparum in Western Kenya

2015 ◽  
Vol 59 (7) ◽  
pp. 3995-4002 ◽  
Author(s):  
Naomi W. Lucchi ◽  
Sheila Akinyi Okoth ◽  
Franklin Komino ◽  
Philip Onyona ◽  
Ira F. Goldman ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Mutant Allele ◽  
Double Mutant ◽  
Intermittent Preventive Treatment ◽  
Preventive Treatment ◽  
Triple Mutant ◽  
Western Kenya ◽  
Content Type ◽  
Dihydropteroate Synthase

ABSTRACTThe molecular basis of sulfadoxine-pyrimethamine (SP) resistance lies in a combination of single-nucleotide polymorphisms (SNPs) in two genes coding forPlasmodium falciparumdihydrofolate reductase (Pfdhfr) andP. falciparumdihydropteroate synthase (Pfdhps), targeted by pyrimethamine and sulfadoxine, respectively. The continued use of SP for intermittent preventive treatment in pregnant women in many African countries, despite SP's discontinuation as a first-line antimalarial treatment option due to high levels of drug resistance, may further increase the prevalence of SP-resistant parasites and/or lead to the selection of new mutations. An antimalarial drug resistance surveillance study was conducted in western Kenya between 2010 and 2013. A total of 203 clinical samples from children with uncomplicated malaria were genotyped for SNPs associated with SP resistance. The prevalence of the triple-mutantPfdhfrC50I51R59N108I164genotype and the double-mutantPfdhpsS436G437E540A581A613genotype was high. Two triple-mutantPfdhpsgenotypes, S436G437E540G581A613andH436G437E540A581A613, were found, with the latter thus far being uniquely found in western Kenya. The prevalence of the S436G437E540G581A613genotype was low. However, a steady increase in the prevalence of thePfdhpstriple-mutantH436G437E540A581A613genotype has been observed since its appearance in early 2000. Isolates with these genotypes shared substantial microsatellite haplotypes with the most common double-mutant allele, suggesting that this triple-mutant allele may have evolved locally. Overall, these findings show that the prevalence of theH436G437E540A581A613triple mutant may be increasing in this population and could compromise the efficacy of SP for intermittent preventive treatment in pregnant women if it increases the resistance threshold further.

scholarly journals Prevalence of Plasmodium falciparum Resistance Markers to Sulfadoxine-Pyrimethamine among Pregnant Women Receiving Intermittent Preventive Treatment for Malaria in Uganda

2015 ◽  
Vol 59 (9) ◽  
pp. 5475-5482 ◽  
Author(s):  
Anthony K. Mbonye ◽  
Josephine Birungi ◽  
Stephanie K. Yanow ◽  
Sandra Shokoples ◽  
Samuel Malamba ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Birth Weight ◽  
Pregnant Women ◽  
Intermittent Preventive Treatment ◽  
Melting Curve ◽  
Preventive Treatment ◽  
Melting Curve Analysis ◽  
Content Type ◽  
Lower Birth Weight ◽  
Resistance Markers

ABSTRACTThe aim of this study was to assess the prevalence of mutations inPlasmodium falciparumdihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes among pregnant women using sulfadoxine-pyrimethamine (SP) as an intermittent preventive treatment (IPTp). A molecular epidemiological study ofP. falciparumparasite resistance markers to SP was conducted from August 2010 to February 2012 in Mukono district in central Uganda. DNA was extracted from 413P. falciparum-positive samples. Real-time PCR, followed by melting curve analysis, was used to characterize point mutations in thePfdhfrandPfdhpsgenes that are associated with SP resistance. The prevalence of the single-nucleotide mutations inPfdhfrat codons 51I, 59R, and 108N and inPfdhpsat codons 437G and 540E was high (>98%), reaching 100% fixation after one dose of SP, while the prevalence of 581G was 3.3% at baseline, reaching 12.5% after one dose of SP. At baseline, the prevalence ofPfdhfrandPfdhpsquintuple mutations was 89%, whereas the sextuple mutations (including 581G) were not prevalent (3.9%), reaching 16.7% after one dose of SP. However, the numbers of infections at follow-up visits were small, and hence there was insufficient statistical power to test whether there was a true rise in the prevalence of this allele. The overall high frequency ofPfdhfrandPfdhpsquintuple mutations throughout pregnancy excluded further analyses of possible associations between certain haplotypes and the risk of lower birth weight and anemia. However, women infected withP. falciparumhad 1.3-g/dl-lower hemoglobin levels (P= 0.001) and delivered babies with a 400-g-lower birth weight (P= 0.001) compared to nonparasitemic women. Despite this, 44 women who wereP. falciparumpositive at baseline became negative after one or two doses of SP (i.e., 50.5%), implying that SP-IPTp still has some efficacy.P. falciparumresistance markers to SP are high in this population, whereasP. falciparuminfection was associated with poor birth outcomes.

scholarly journals Intermittent Preventive Treatment with Dihydroartemisinin-Piperaquine in Ugandan Schoolchildren Selects for Plasmodium falciparum Transporter Polymorphisms That Modify Drug Sensitivity

2016 ◽  
Vol 60 (10) ◽  
pp. 5649-5654 ◽  
Author(s):  
Joaniter I. Nankabirwa ◽  
Melissa D. Conrad ◽  
Jennifer Legac ◽  
Stephen Tukwasibwe ◽  
Patrick Tumwebaze ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Sensitivity ◽  
Selective Pressure ◽  
Intermittent Preventive Treatment ◽  
Preventive Treatment ◽  
Drug Pressure ◽  
Content Type ◽  
The Past ◽  
The Impact ◽  
Selection Of

ABSTRACTDihydroartemisinin-piperaquine (DP) offers prolonged protection against malaria, but its impact onPlasmodium falciparumdrug sensitivity is uncertain. In a trial of intermittent preventive treatment in schoolchildren in Tororo, Uganda, in 2011 to 2012, monthly DP for 1 year decreased the incidence of malaria by 96% compared to placebo; DP once per school term offered protection primarily during the first month after therapy. To assess the impact of DP on selection of drug resistance, we compared the prevalence of key polymorphisms in isolates that emerged at different intervals after treatment with DP. Blood obtained monthly and at each episode of fever was assessed forP. falciparumparasitemia by microscopy. Samples from 160 symptomatic and 650 asymptomatic episodes of parasitemia were assessed at 4 loci (N86Y, Y184F, and D1246Y inpfmdr1and K76T inpfcrt) that modulate sensitivity to aminoquinoline antimalarials, utilizing a ligase detection reaction-fluorescent microsphere assay. Forpfmdr1N86Y andpfcrtK76T, but not the other studied polymorphisms, the prevalences of mutant genotypes were significantly greater in children who had received DP within the past 30 days than in those not treated within 60 days (86Y, 18.0% versus 8.3% [P= 0.03]; 76T, 96.0% versus 86.1% [P= 0.05]), suggesting selective pressure of DP. Full sequencing ofpfcrtin a subset of samples did not identify additional polymorphisms selected by DP. In summary, parasites that emerged soon after treatment with DP were more likely than parasites not under drug pressure to harborpfmdr1andpfcrtpolymorphisms associated with decreased sensitivity to aminoquinoline antimalarials. (This study has been registered at ClinicalTrials.gov under no. NCT01231880.)

scholarly journals Artemisinin-Resistant Plasmodium falciparum Parasites Exhibit Altered Patterns of Development in Infected Erythrocytes

2015 ◽  
Vol 59 (6) ◽  
pp. 3156-3167 ◽  
Author(s):  
Amanda Hott ◽  
Debora Casandra ◽  
Kansas N. Sparks ◽  
Lindsay C. Morton ◽  
Geocel-Grace Castanares ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Artemisinin Resistance ◽  
Drug Pressure ◽  
Content Type ◽  
Phenotypic Resistance ◽  
Artemisinin Derivatives ◽  
Stage Of Development ◽  
Clinical Resistance

ABSTRACTArtemisinin derivatives are used in combination with other antimalarial drugs for treatment of multidrug-resistant malaria worldwide. Clinical resistance to artemisinin recently emerged in southeast Asia, yetin vitrophenotypes for discerning mechanism(s) of resistance remain elusive. Here, we describe novel phenotypic resistance traits expressed by artemisinin-resistantPlasmodium falciparum. The resistant parasites exhibit altered patterns of development that result in reduced exposure to drug at the most susceptible stage of development in erythrocytes (trophozoites) and increased exposure in the most resistant stage (rings). In addition, a novelin vitrodelayed clearance assay (DCA) that assesses drug effects on asexual stages was found to correlate with parasite clearance half-lifein vivoas well as with mutations in the Kelch domain gene associated with resistance (Pf3D7_1343700). Importantly, all of the resistance phenotypes were stable in cloned parasites for more than 2 years without drug pressure. The results demonstrate artemisinin-resistantP. falciparumhas evolved a novel mechanism of phenotypic resistance to artemisinin drugs linked to abnormal cell cycle regulation. These results offer insights into a novel mechanism of drug resistance inP. falciparumand new tools for monitoring the spread of artemisinin resistance.

scholarly journals Modeling Prevention of Malaria and Selection of Drug Resistance with Different Dosing Schedules of Dihydroartemisinin-Piperaquine Preventive Therapy during Pregnancy in Uganda

2018 ◽  
Vol 63 (2) ◽  
pp. e01393-18
Author(s):  
Erika Wallender ◽  
Nan Zhang ◽  
Melissa Conrad ◽  
Abel Kakuru ◽  
Mary Muhindo ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Intermittent Preventive Treatment ◽  
Preventive Treatment ◽  
Preventive Therapy ◽  
Wild Type ◽  
Content Type ◽  
Mixed Effects Modeling ◽  
Selection For ◽  
Log Linear ◽  
Selection Of

ABSTRACT Dihydroartemisinin-piperaquine (DHA-PQ) is under study for intermittent preventive treatment during pregnancy (IPTp), but it may accelerate selection for drug resistance. Understanding the relationships between piperaquine concentration, prevention of parasitemia, and selection for decreased drug sensitivity can inform control policies and optimization of DHA-PQ dosing. Piperaquine concentrations, measures of parasitemia, and Plasmodium falciparum genotypes associated with decreased aminoquinoline sensitivity in Africa (pfmdr1 86Y, pfcrt 76T) were obtained from pregnant Ugandan women randomized to IPTp with sulfadoxine-pyrimethamine (SP) or DHA-PQ. Joint pharmacokinetic/pharmacodynamic models described relationships between piperaquine concentration and the probability of genotypes of interest using nonlinear mixed effects modeling. An increase in the piperaquine plasma concentration was associated with a log-linear decrease in risk of parasitemia. Our models predicted that higher median piperaquine concentrations would be required to provide 99% protection against mutant infections than against wild-type infections (pfmdr1: N86, 9.6 ng/ml; 86Y, 19.6 ng/ml; pfcrt: K76, 6.5 ng/ml; 76T, 19.6 ng/ml). Comparing monthly, weekly, and daily dosing, daily low-dose DHA-PQ was predicted to result in the fewest infections and the fewest mutant infections per 1,000 pregnancies (predicted mutant infections for pfmdr1 86Y: SP monthly, 607; DHA-PQ monthly, 198; DHA-PQ daily, 1; for pfcrt 76T: SP monthly, 1,564; DHA-PQ monthly, 283; DHA-PQ daily, 1). Our models predict that higher piperaquine concentrations are needed to prevent infections with the pfmdr1/pfcrt mutant compared to those with wild-type parasites and that, despite selection for mutants by DHA-PQ, the overall burden of mutant infections is lower for IPTp with DHA-PQ than for IPTp with SP. (This study has been registered at ClinicalTrials.gov under identifier NCT02282293.)

scholarly journals Emergence and Spread of kelch13 Mutations Associated with Artemisinin Resistance in Plasmodium falciparum Parasites in 12 Thai Provinces from 2007 to 2016

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Theerayot Kobasa ◽  
Eldin Talundzic ◽  
Rungniran Sug-aram ◽  
Patcharida Boondat ◽  
Ira F. Goldman ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Gene Mutations ◽  
Artemisinin Resistance ◽  
Parasite Clearance ◽  
Resistance Mutations ◽  
Content Type ◽  
Artemisinin Derivatives ◽  
Reduced Ring ◽  
Control And Prevention ◽  
Greater Mekong Subregion

ABSTRACT Artemisinin-based combination therapy (ACT) is the most effective and widely used treatment for uncomplicated Plasmodium falciparum malaria and is a cornerstone for malaria control and prevention globally. Resistance to artemisinin derivatives has been confirmed in the Greater Mekong Subregion (GMS) and manifests as slow parasite clearance in patients and reduced ring stage susceptibility to artemisinins in survival assays. The P. falciparum kelch13 gene mutations associated with artemisinin-resistant parasites are now widespread in the GMS. We genotyped 277 samples collected during an observational study from 2012 to 2016 from eight provinces in Thailand to identify P. falciparum kelch13 mutations. The results were combined with previously reported genotyping results from Thailand to construct a map illustrating the evolution of P. falciparum kelch13 mutations from 2007 to 2016 in that country. Different mutant alleles were found in strains with different geographical origins. The artemisinin resistance-conferring Y493H and R539T mutations were detected mainly in eastern Thailand (bordering Cambodia), while P574L was found only in western Thailand and R561H only in northwestern Thailand. The C580Y mutation was found across the entire country and was nearing fixation along the Thai-Cambodia border. Overall, the prevalence of artemisinin resistance mutations increased over the last 10 years across Thailand, especially along the Thai-Cambodia border. Molecular surveillance and therapeutic efficacy monitoring should be intensified in the region to further assess the extent and spread of artemisinin resistance.

scholarly journals Malaria intermittent preventive treatment in Nigeria: a qualitative study to explore barriers

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Fatima Mahmud Muhammad ◽  
Saharnaz Nedjat ◽  
Haniye Sadat Sajadi ◽  
Mahboubeh Parsaeian ◽  
Abraham Assan ◽  
...  
Keyword(s):  
Qualitative Study ◽  
Pregnant Women ◽  
Intermittent Preventive Treatment ◽  
Sampling Strategy ◽  
Preventive Treatment ◽  
Group Discussions ◽  
Content Analysis Method ◽  
Conventional Content Analysis ◽  
Sulphadoxine Pyrimethamine ◽  
Selection Of

Abstract Background While the use of sulphadoxine pyrimethamine (SP) is effective in preventing malaria infection during pregnancy, there are challenges limiting its uptake in Nigeria. This study aimed at exploring the barriers to IPTp usage among pregnant women in Kano state - Nigeria. Methods This is a qualitative study. The purposive sampling strategy was used for identification and selection of 14 key informants for interviews. In addition, six focus group discussions (FGDs) were conducted with pregnant women (3 FGDs) and married men (3 FGDs). The conventional content analysis method was used to interpret meaning from the content of the data. MAXQDA 10 software was used for data management and analysis. Results Poor policy implementation, poor antenatal care attendance, inadequate access to intermittent preventive treatment at the community levels, lack of sustainable funding, and poor community engagement emerged as major barriers to IPTp use in Nigeria. Conclusion While the political will to allocate sufficient financial resources could help improve service delivery and IPTp usage among pregnant women, community participation is critical to sustain the gains.

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