scholarly journals Associations between Malaria-Preventive Regimens and Plasmodium falciparum Drug Resistance-Mediating Polymorphisms in Ugandan Pregnant Women

2020 ◽  
Vol 64 (12) ◽  
Author(s):  
Patience Nayebare ◽  
Victor Asua ◽  
Melissa D. Conrad ◽  
Richard Kajubi ◽  
Abel Kakuru ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Genetic Polymorphisms ◽  
Protective Efficacy ◽  
Intermittent Preventive Treatment ◽  
Preventive Treatment ◽  
Drug Susceptibility ◽  
Recent Trial ◽  
Content Type ◽  
High Level ◽  
Selection Of

ABSTRACT Intermittent preventive treatment in pregnancy (IPTp) with monthly sulfadoxine-pyrimethamine (SP) is recommended for malaria-endemic parts of Africa, but efficacy is compromised by resistance, and, in recent trials, dihydroartemisinin-piperaquine (DP) has shown better antimalarial protective efficacy. We utilized blood samples from a recent trial to evaluate selection by IPTp with DP or SP of Plasmodium falciparum genetic polymorphisms that alter susceptibility to these drugs. The prevalence of known genetic polymorphisms associated with altered drug susceptibility was determined in parasitemic samples, including 375 collected before IPTp drugs were administered, 125 randomly selected from those receiving SP, and 80 from those receiving DP. For women receiving DP, the prevalence of mixed/mutant sequences was greater in samples collected during IPTp than that in samples collected prior to the intervention for PfMDR1 N86Y (20.3% versus 3.9%; P < 0.001), PfMDR1 Y184F (73.0% versus 53.0%; P < 0.001), and PfCRT K76T (46.4% versus 24.0%; P < 0.001). Considering SP, prior to IPTp, the prevalence of all 5 common antifolate mutations was over 92%, and this prevalence increased following exposure to SP, although none of these changes were statistically significant. For two additional mutations associated with high-level SP resistance, the prevalence of PfDHFR 164L (13.7% versus 4.0%; P = 0.004), but not PfDHPS 581G (1.9% versus 3.0%; P = 0.74), was greater in samples collected during IPTp compared to those collected before the intervention. Use of IPTp in Uganda selected for parasites with mutations associated with decreased susceptibility to IPTp regimens. Thus, a potential drawback of IPTp is selection of parasites with decreased drug susceptibility.

scholarly journals Plasmodium falciparum and Plasmodium vivax Genotypes and Efficacy of Intermittent Preventive Treatment in Papua New Guinea

2014 ◽  
Vol 58 (11) ◽  
pp. 6958-6961 ◽  
Author(s):  
Celine Barnadas ◽  
Nicolas Senn ◽  
Jonah Iga ◽  
Lincoln Timinao ◽  
Sarah Javati ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Plasmodium Vivax ◽  
Papua New Guinea ◽  
Protective Efficacy ◽  
Intermittent Preventive Treatment ◽  
Preventive Treatment ◽  
New Guinea ◽  
Content Type ◽  
Resistance Markers ◽  
Childhood Malaria

ABSTRACTIntermittent preventive treatment of infants (IPTi) reduces early childhood malaria-related morbidity. While genotypic drug resistance markers have proven useful in predicting the efficacy of antimalarial drugs in case management, there are few equivalent data relating to their protective efficacy when used as IPTi. The present data from an IPTi trial in Papua New Guinea demonstrate how these markers can predict protective efficacy of IPTi for bothPlasmodium falciparumandPlasmodium vivax.

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 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 Plasmodium falciparum Polymorphisms Associated withEx VivoDrug Susceptibility and Clinical Effectiveness of Artemisinin-Based Combination Therapies in Benin

2013 ◽  
Vol 58 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Sabina Dahlström ◽  
Agnès Aubouy ◽  
Oumou Maïga-Ascofaré ◽  
Jean-François Faucher ◽  
Abel Wakpo ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Ex Vivo ◽  
Clinical Effectiveness ◽  
Drug Susceptibility ◽  
Fixed Dose ◽  
Enzyme Linked Immunosorbent Assay ◽  
Recurrent Infections ◽  
Combination Therapies ◽  
Content Type ◽  
Selection Of

ABSTRACTArtemisinin-based combination therapies (ACTs) are the main option to treat malaria, and their efficacy and susceptibility must be closely monitored to avoid resistance. We assessed the association ofPlasmodium falciparumpolymorphisms andex vivodrug susceptibility with clinical effectiveness. Patients enrolled in an effectiveness trial comparing artemether-lumefantrine (n= 96), fixed-dose artesunate-amodiaquine (n= 96), and sulfadoxine-pyrimethamine (n= 48) for the treatment of uncomplicated malaria 2007 in Benin were assessed.pfcrt,pfmdr1,pfmrp1,pfdhfr, andpfdhpspolymorphisms were analyzed pretreatment and in recurrent infections. Drug susceptibility was determined in fresh baseline isolates byPlasmodiumlactate dehydrogenase enzyme-linked immunosorbent assay (ELISA). A majority had 50% inhibitory concentration (IC50) estimates (the concentration required for 50% growth inhibition) lower than those of the 3D7 reference clone for desethylamodiaquine, lumefantrine, mefloquine, and quinine and was considered to be susceptible, while dihydroartemisinin and pyrimethamine IC50s were higher. No association was found between susceptibility to the ACT compounds and treatment outcome. Selection was observed for thepfmdr1N86 allele in artemether-lumefantrine recrudescences (recurring infections) (4/7 [57.1%] versus 36/195 [18.5%]), and of the opposite allele, 86Y, in artesunate-amodiaquine reinfections (new infections) (20/22 [90.9%] versus 137/195 [70.3%]) compared to baseline infections. The importance ofpfmdr1N86 in lumefantrine tolerance was emphasized by its association with elevated lumefantrine IC50s. Genetic linkage between N86 and Y184 was observed, which together with the low frequency of 1246Y may explain regional differences in selection ofpfmdr1loci. Selection of opposite alleles in artemether-lumefantrine and artesunate-amodiaquine recurrent infections supports the strategy of multiple first-line treatment. Surveillance based on clinical,ex vivo, molecular, and pharmacological data is warranted.

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 Randomized, Double-Blind, Placebo-Controlled Trial of Monthly versus Bimonthly Dihydroartemisinin-Piperaquine Chemoprevention in Adults at High Risk of Malaria

2012 ◽  
Vol 56 (3) ◽  
pp. 1571-1577 ◽  
Author(s):  
Khin Maung Lwin ◽  
Aung Pyae Phyo ◽  
Joel Tarning ◽  
Warunee Hanpithakpong ◽  
Elizabeth A. Ashley ◽  
...  
Keyword(s):  
Placebo Group ◽  
High Risk ◽  
Protective Efficacy ◽  
Day Treatment ◽  
Controlled Trial ◽  
Intermittent Preventive Treatment ◽  
Preventive Treatment ◽  
Adult Males ◽  
Double Blind ◽  
Content Type

ABSTRACTIntermittent preventive treatment (IPT) is increasingly used to reduce malaria morbidity and mortality in children and pregnant women. The efficacy of IPT depends on the pharmacokinetic and pharmacodynamic properties of the antimalarial drugs used. Healthy adult male volunteers whose occupation put them at high risk of malaria on the Northwest border of Thailand were randomized to receive a 3-day-treatment dose of dihydroartemisinin-piperaquine monthly (DPm) or every 2 months (DPalt) or an identical placebo with or without fat (6.4g/dose) over a 9-month period. All volunteers were monitored weekly. One thousand adults were recruited. Dihydroartemisinin-piperaquine was well tolerated. There were 114 episodes of malaria (49Plasmodium falciparum, 63P. vivax, and 2P. ovale). The protective efficacy against all malaria at 36 weeks was 98% (95% confidence interval [CI], 96% to 99%) in the DPm group and 86% (95% CI, 81% to 90%) in the DPalt group (for both,P< 0.0001 compared to the placebo group). As a result, the placebo group also had lower hematocrits during the study (P< 0.0001). Trough plasma piperaquine concentrations were the main determinant of efficacy; no malaria occurred in participants with a trough concentration above 31 ng/ml. Neither plasma piperaquine concentration nor efficacy was influenced by the coadministration of fat. DPm is safe to use and is effective in the prevention of malaria in adult males living in an area whereP. vivaxand multidrug-resistantP. falciparummalaria are endemic.

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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