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BMJ Open Mar 2024Seasonal malaria chemoprevention (SMC) involves repeated administrations of sulfadoxine-pyrimethamine plus amodiaquine to children below the age of 5 years during the...
Understanding and maximising the community impact of seasonal malaria chemoprevention in Burkina Faso (INDIE-SMC): study protocol for a cluster randomised evaluation trial.
INTRODUCTION
Seasonal malaria chemoprevention (SMC) involves repeated administrations of sulfadoxine-pyrimethamine plus amodiaquine to children below the age of 5 years during the peak transmission season in areas of seasonal malaria transmission. While highly impactful in reducing malaria burden in controlled research settings, the impact of SMC on infection prevalence is moderate in real-life settings. It remains unclear what drives this efficacy decay. Recently, the WHO widened the scope for SMC to target all vulnerable populations. The Ministry of Health (MoH) in Burkina Faso is considering extending SMC to children below 10 years old. We aim to assess the impact of SMC on clinical incidence and parasite prevalence and quantify the human infectious reservoir for malaria in this population.
METHODS AND ANALYSIS
We will perform a cluster randomised trial in Saponé Health District, Burkina Faso, with three study arms comprising 62 clusters of three compounds: arm 1 (control): SMC in under 5-year-old children, implemented by the MoH without directly observed treatment (DOT) for the full course of SMC; arm 2 (intervention): SMC in under 5-year-old children, with DOT for the full course of SMC; arm 3 (intervention): SMC in under 10-year-old children, with DOT for the full course of SMC. The primary endpoint is parasite prevalence at the end of the malaria transmission season. Secondary endpoints include the impact of SMC on clinical incidence. Factors affecting SMC uptake, treatment adherence, drug concentrations, parasite resistance markers and transmission of parasites will be determined.
ETHICS AND DISSEMINATION
The London School of Hygiene & Tropical Medicine's Ethics Committee (29193) and the Burkina Faso National Medical Ethics Committee (Deliberation No 2023-05-104) approved this study. The findings will be presented to the community; disease occurrence data and study outcomes will also be shared with the Burkina Faso MoH. Findings will be published irrespective of their results.
TRIAL REGISTRATION NUMBER
NCT05878366.
Topics: Child, Preschool; Humans; Infant; Antimalarials; Burkina Faso; Chemoprevention; Drug Combinations; Malaria; Randomized Controlled Trials as Topic; Seasons; Child
PubMed: 38479748
DOI: 10.1136/bmjopen-2023-081682 -
Research Square Feb 2024Hard-to-reach communities represent Peru's main challenge for malaria elimination, but information about transmission in these areas is scarce. Here, we assessed (Pv)...
Hard-to-reach communities represent Peru's main challenge for malaria elimination, but information about transmission in these areas is scarce. Here, we assessed (Pv) and (Pf) transmission dynamics, resistance markers, and Pf deletions in Nueva Jerusalén (NJ), a remote, indigenous community in the Peruvian Amazon with high population mobility. We collected samples from November 2019 to May 2020 by active (ACD) and passive case detection (PCD) in NJ. Parasites were identified with microscopy and PCR. Then, we analyzed a representative set of positive-PCR samples (Pv = 68, Pf = 58) using highly-multiplexed deep sequencing assays (AmpliSeq) and compared NJ parasites with ones from other remote Peruvian areas using population genetics indexes. The ACD intervention did not reduce malaria cases in the short term, and persistent malaria transmission was observed (at least one Pv infection was detected in 96% of the study days). In Nueva Jerusalen, the Pv population had modest genetic diversity (He = 0.27). Pf population had lower diversity (He = 0.08) and presented temporal clustering, one of these clusters linked to an outbreak in February 2020. Moreover, Pv and Pf parasites from NJ exhibited variable levels of differentiation (Pv Fst = -0.52 & Pf Fst = 0.11-0.58) with parasites from other remote areas. No artemisin resistance mutations but chloroquine (57%) and sulfadoxine-pyrimethamine (35-67%) were detected in NJ's Pf parasites. Moreover, gene deletions were common (32-50% of parasites with one or both genes deleted). The persistent Pv transmission and the detection of a Pf outbreak with parasites genetically distinct from the local ones highlight the need for tailored interventions focusing on mobility patterns and imported infections in remote areas to eliminate malaria in the Peruvian Amazon.
PubMed: 38464169
DOI: 10.21203/rs.3.rs-3979991/v1 -
Frontiers in Epidemiology 2024Antimalarial drugs including artemisinin-based combination therapy (ACT) regimens and sulphadoxine-pyrimethamine (SP) are used in Ghana for malaria therapeutics and...
INTRODUCTION
Antimalarial drugs including artemisinin-based combination therapy (ACT) regimens and sulphadoxine-pyrimethamine (SP) are used in Ghana for malaria therapeutics and prophylaxis respectively. The genetic basis of development of drug resistance involves single nucleotide polymorphisms in genes encoding proteins for multiple cellular and metabolic processes. The prevalence of single nucleotide polymorphisms in nine genes linked to ACT and SP resistance in the malaria parasite population was determined.
METHODS
Archived filter paper blood blot samples from patients aged 9 years and below with uncomplicated malaria reporting at 10 sentinel sites located in three ecological zones for the Malaria Therapeutic Efficacy Studies were used. The samples used were collected from 2007-2018 malaria transmission seasons and mutations in the genes were detected using PCR and Sanger sequencing.
RESULTS
In all 1,142 samples were used for the study. For falcipain-2 gene () Sanger sequencing was successful for 872 samples and were further analysed. The prevalence of the mutants was 45% (392/872) with markers V51I and S59F occurring in 15.0% (128/872) and 3.0% (26/872) of the samples respectively. Prevalence of other gene mutations: coronin () was 44.8% (37/90); cysteine desulfurase () was 73.9% (68/92); apicoplast ribosomal protein S10 () was 36.8% (35/95); ferredoxin () was 8.8% (8/91); multidrug resistance protein-1 () was 95.2.0% (80/84); multidrug resistance protein-2 () was 91.4% (32/35); dihydrofolate reductase () was 99.0% (84/85); dihydropteroate synthase () was 72% (68/95).
DISCUSSION
The observation of numerous mutations in these genes of interest in the Ghanaian isolates, some of which have been implicated in delayed parasite clearance is of great interest. The presence of these genotypes may account for the decline in the efficacies of ACT regimens being used to treat uncomplicated malaria in the country. The need for continuous monitoring of these genetic markers to give first-hand information on parasite susceptibility to antimalarial drugs to inform policy makers and stakeholders in malaria elimination in the country is further discussed.
PubMed: 38456076
DOI: 10.3389/fepid.2024.1279835 -
Tropical Parasitology 2024Resistance to antimalarial drugs is one of the major challenges for malaria elimination. In India, artemisinin combination therapy (artesunate-sulfadoxin pyrimethamine)...
Prevalence of polymorphisms in marker genes associated with antimalarial drug resistance in following 10 years of artemisinin-based combination therapy implementation in urban Kolkata.
CONTEXT
Resistance to antimalarial drugs is one of the major challenges for malaria elimination. In India, artemisinin combination therapy (artesunate-sulfadoxin pyrimethamine) was introduced in place of chloroquine (CQ) for the treatment of uncomplicated falciparum malaria in 2010. Periodical monitoring of polymorphisms in antimalarial drug resistance marker genes will be useful for assessing drug pressure, mapping and monitoring of drug resistance status; and will be helpful for searching alternative treatments.
OBJECTIVES
This study was conducted to study the polymorphisms in antimalarial drug resistance marker genes among clinical isolates collected from Kolkata after 10 years of artemisinin-based combination therapie (ACT) implementation.
MATERIALS AND METHODS
Blood samples were collected from mono-infected patients and polymorphisms in CQ resistance transporter , multidrug resistance , dihydrofolate reductase , dihydropteroate synthetase , and propeller genes were analysed by polymerase chain reaction and DNA sequencing.
RESULTS
In gene, C72S, and K76T mutation was recorded in 100% isolates and no mutations was detected in any of the targeted codons of gene. A double mutant haplotype SVMNT and wildtype haplotype NYD in were prevalent in 100% of study isolates. Triple mutant haplotype ANRNI-SGKAA was recorded. No polymorphism in gene was documented in any of the isolates.
CONCLUSIONS
Observed wild codon N86 along with Y184 and D1246 of gene might be an indication of the reappearance of CQ sensitivity. The absence of quadruple and quintuple haplotypes in gene along with the wild haplotype of pfK13 is evidence of ACT effectivity. Hence, similar studies with large sample size are highly suggested for monitoring the drug resistance status of .
PubMed: 38444799
DOI: 10.4103/tp.tp_43_23 -
Compliance With Guidelines on Seasonal Malaria Chemoprevention in Kwara State, Northcentral Nigeria.West African Journal of Medicine Jan 2024Seasonal malaria chemoprevention (SMC) is an effective strategy for reducing malaria morbidity and mortality in children aged 3-59 months in areas with seasonal malaria...
BACKGROUND
Seasonal malaria chemoprevention (SMC) is an effective strategy for reducing malaria morbidity and mortality in children aged 3-59 months in areas with seasonal malaria transmission. Sulphadoxine-pyrimethamine plus amodiaquine is given to an eligible child at monthly intervals during the peak malaria transmission season. The aim of this study was to determine the level of compliance with SMC guidelines by community drug distributors during SMC implementation in Kwara State.
METHOD
Caregivers of eligible children from six Local Government Areas were interviewed using a structured questionnaire on the KoboCollect app downloaded on hand-held android devices. The questionnaire was composed of questions on caregiver's demographics, SMC drug administration, and adherence to SMC protocol.
RESULTS
A total of 1,314 caregivers were interviewed, most of them were female 1076 (81.9%), married 1200 (91.3%) and literate 795 (60.5%). The mean SMC coverage for the 4 cycles was 1183(88.5%). SMC information was received by 1166 (88.7%) of caregivers. Most of the caregivers 1166 (88.7%) heard about SMC. Overall, SPAQ administration was directly observed in most cases 1169 (91.5%), second dose was given 1226 (96.0%) and drugs were fully ingested 1140(89.3%). Poor compliance was observed in home visits by lead mothers 988 (77.4%). The report of adverse drug reactions was low 132 (10.3% [95% CI: 8.8-12.3%]), the commonest being severe vomiting 50 (37.9%). There were significant (P<0.05) variations in SMC implementation across the 6 LGAs in virtually all the performance indicators. SPAQ administration to over-age children was low 128 (10.0%).
CONCLUSION
Overall, the compliance with SMC implementation guidelines in Kwara state was good though significant differences in performance were observed across the six LGAs. Home visits by lead mothers were generally poor. The self-reported coverage of SMC by caregivers was commendable.
Topics: Child; Female; Humans; Infant; Male; Antimalarials; Seasons; Nigeria; Malaria; Chemoprevention
PubMed: 38412205
DOI: No ID Found -
Antimicrobial Agents and Chemotherapy Apr 2024Malaria remains a leading cause of morbidity and mortality in Burkina Faso, which utilizes artemether-lumefantrine as the principal therapy to treat uncomplicated...
Malaria remains a leading cause of morbidity and mortality in Burkina Faso, which utilizes artemether-lumefantrine as the principal therapy to treat uncomplicated malaria and seasonal malaria chemoprevention with monthly sulfadoxine-pyrimethamine plus amodiaquine in children during the transmission season. Monitoring the activities of available antimalarial drugs is a high priority. We assessed the susceptibility of to 11 drugs in isolates from patients presenting with uncomplicated malaria in Bobo-Dioulasso in 2021 and 2022. IC values were derived using a standard 72 h growth inhibition assay. Parasite DNA was sequenced to characterize known drug resistance-mediating polymorphisms. Isolates were generally susceptible, with IC values in the low-nM range, to chloroquine (median IC10 nM, IQR 7.9-24), monodesethylamodiaquine (22, 14-46) piperaquine (6.1, 3.6-9.2), pyronaridine (3.0, 1.3-5.5), quinine (50, 30-75), mefloquine (7.1, 3.7-10), lumefantrine (7.1, 4.5-12), dihydroartemisinin (3.7, 2.2-5.5), and atovaquone (0.2, 0.1-0.3) and mostly resistant to cycloguanil (850, 543-1,290) and pyrimethamine (33,200, 18,400-54,200), although a small number of outliers were seen. Considering genetic markers of resistance to aminoquinolines, most samples had wild-type PfCRT K76T (87%) and PfMDR1 N86Y (95%) sequences. For markers of resistance to antifolates, established PfDHFR and PfDHPS mutations were highly prevalent, the PfDHPS A613S mutation was seen in 19% of samples, and key markers of high-level resistance (PfDHFR I164L; PfDHPS K540E) were absent or rare (A581G). Mutations in the PfK13 propeller domain known to mediate artemisinin partial resistance were not detected. Overall, our results suggest excellent susceptibilities to drugs now used to treat malaria and moderate, but stable, resistance to antifolates used to prevent malaria.
Topics: Child; Humans; Antimalarials; Plasmodium falciparum; Malaria, Falciparum; Artemether, Lumefantrine Drug Combination; Folic Acid Antagonists; Burkina Faso; Artemether; Pyrimethamine; Malaria; Lumefantrine; Drug Combinations; Polymorphism, Genetic; Drug Resistance; Protozoan Proteins
PubMed: 38411062
DOI: 10.1128/aac.01534-23 -
MedRxiv : the Preprint Server For... Feb 2024Genomic surveillance plays a critical role in monitoring malaria transmission and understanding how the parasite adapts in response to interventions. We conducted...
Genomic surveillance plays a critical role in monitoring malaria transmission and understanding how the parasite adapts in response to interventions. We conducted genomic surveillance of malaria by sequencing 241 genomes from regions with varying levels of malaria transmission across Zambia. We found genomic evidence of high levels of within-host polygenomic infections, regardless of epidemiological characteristics, underscoring the extensive and ongoing endemic malaria transmission in the country. We identified country-level clustering of parasites from Zambia and neighboring countries, and distinct clustering of parasites from West Africa. Within Zambia, our identity by descent (IBD) relatedness analysis uncovered spatial clustering of closely related parasite pairs at the local level and rare cases of long-distance sharing. Genomic regions with large shared IBD segments and strong positive selection signatures identified genes involved in sulfadoxine-pyrimethamine and artemisinin combination therapies drug resistance, but no signature related to chloroquine resistance. Together, our findings enhance our understanding of transmission nationwide in Zambia and highlight the urgency of strengthening malaria control programs and surveillance of antimalarial drug resistance.
PubMed: 38370674
DOI: 10.1101/2024.02.09.24302570 -
Chemosphere Mar 2024The occurrence of antibiotic residues in the environment has received considerable attention because of their potential to select for bacterial resistance. The overuse...
The occurrence of antibiotic residues in the environment has received considerable attention because of their potential to select for bacterial resistance. The overuse of antibiotics in human medicine and animal production results in antibiotic residues entering the aquatic environment, but concentrations are currently not well determined. This study investigates the occurrence of antibiotics in groundwater in areas strongly related to agriculture and the antibiotic treatment of animals. A multiresidue method was validated according to EU Regulation 2021/808, to allow (semi-)quantitative analysis of 78 antibiotics from 10 different classes: β-lactams, sulfonamides, tetracyclines, lincosamides, amphenicols, (fluoro)quinolones, macrolides, pleuromutilins, ansamycins and diaminopyrimidines using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). This method was used to test different storage conditions of these water samples during a stability study over a period of 2 weeks. Sulfonamides, lincosamides and pleuromutilins were the most stable. Degradation was most pronounced for β-lactam antibiotics, macrolides and ansamycins. To maintain stability, storage of samples at -18 °C is preferred. With the validated method, antibiotic residues were detected in groundwater, sampled from regions associated with intensive livestock farming in Flanders (Belgium). Out of 50 samples, 14% contained at least one residue. Concentrations were low, ranging from < LOD to 0.03 μg/L. Chloramphenicol, oxolinic acid, tetracycline and sulfonamides (sulfadiazine, sulfadoxine, sulfamethazine and sulfisoxazole) were detected. This study presents a new method for the quantification of antibiotic residues, which was applied to investigate the presence of antibiotic residues in groundwater in Flanders.
Topics: Animals; Humans; Anti-Bacterial Agents; Chromatography, High Pressure Liquid; Tandem Mass Spectrometry; Lactams, Macrocyclic; Sulfanilamide; Chloramphenicol; Sulfonamides; Lincosamides; Pleuromutilins; Groundwater; Macrolides; Drug Residues
PubMed: 38367872
DOI: 10.1016/j.chemosphere.2024.141455 -
The Lancet. Global Health Mar 2024Seasonal malaria chemoprevention (SMC) is recommended for disease control in settings with moderate to high Plasmodium falciparum transmission and currently depends on...
BACKGROUND
Seasonal malaria chemoprevention (SMC) is recommended for disease control in settings with moderate to high Plasmodium falciparum transmission and currently depends on the administration of sulfadoxine-pyrimethamine plus amodiaquine. However, poor regimen adherence and the increased frequency of parasite mutations conferring sulfadoxine-pyrimethamine resistance might threaten the effectiveness of SMC. Guidance is needed to de-risk the development of drug compounds for malaria prevention. We aimed to provide guidance for the early prioritisation of new and alternative SMC drugs and their target product profiles.
METHODS
In this modelling study, we combined an individual-based malaria transmission model that has explicit parasite growth with drug pharmacokinetic and pharmacodynamic models. We modelled SMC drug attributes for several possible modes of action, linked to their potential public health impact. Global sensitivity analyses identified trade-offs between drug elimination half-life, maximum parasite killing effect, and SMC coverage, and optimisation identified minimum requirements to maximise malaria burden reductions.
FINDINGS
Model predictions show that preventing infection for the entire period between SMC cycles is more important than drug curative efficacy for clinical disease effectiveness outcomes, but similarly important for impact on prevalence. When children younger than 5 years receive four SMC cycles with high levels of coverage (ie, 69% of children receiving all cycles), drug candidates require a duration of protection half-life higher than 23 days (elimination half-life >10 days) to achieve reductions higher than 75% in clinical incidence and severe disease (measured over the intervention period in the target population, compared with no intervention across a range of modelled scenarios). High coverage is crucial to achieve these targets, requiring more than 60% of children to receive all SMC cycles and more than 90% of children to receive at least one cycle regardless of the protection duration of the drug.
INTERPRETATION
Although efficacy is crucial for malaria prevalence reductions, chemoprevention development should select drug candidates for their duration of protection to maximise burden reductions, with the duration half-life determining cycle timing. Explicitly designing or selecting drug properties to increase community uptake is paramount.
FUNDING
Bill & Melinda Gates Foundation and the Swiss National Science Foundation.
Topics: Child; Humans; Infant; Antimalarials; Pharmaceutical Preparations; Public Health; Seasons; Malaria; Drug Combinations; Chemoprevention
PubMed: 38365418
DOI: 10.1016/S2214-109X(23)00550-8 -
Molecular Ecology Mar 2024Malaria cases are frequently recorded in the Ethiopian highlands even at altitudes above 2000 m. The epidemiology of malaria in the Ethiopian highlands, and, in...
Malaria cases are frequently recorded in the Ethiopian highlands even at altitudes above 2000 m. The epidemiology of malaria in the Ethiopian highlands, and, in particular, the role of importation by human migration from the highly endemic lowlands is not well understood. We sequenced 187 Plasmodium falciparum samples from two sites in the Ethiopian highlands, Gondar (n = 159) and Ziway (n = 28), using a multiplexed droplet digital PCR (ddPCR)-based amplicon sequencing method targeting 35 microhaplotypes and drug resistance loci. Here, we characterize the parasite population structure and genetic relatedness. We identify moderate parasite diversity (mean H : 0.54) and low infection complexity (74.9% monoclonal). A significant percentage of infections share microhaplotypes, even across transmission seasons and sites, indicating persistent local transmission. We identify multiple clusters of clonal or near-clonal infections, highlighting high genetic relatedness. Only 6.3% of individuals diagnosed with P. falciparum reported recent travel. Yet, in clonal or near-clonal clusters, infections of travellers were frequently observed first in time, suggesting that parasites may have been imported and then transmitted locally. 31.1% of infections are pfhrp2-deleted and 84.4% pfhrp3-deleted, and 28.7% have pfhrp2/3 double deletions. Parasites with pfhrp2/3 deletions and wild-type parasites are genetically distinct. Mutations associated with resistance to sulphadoxine-pyrimethamine or suggested to reduce sensitivity to lumefantrine are observed at near-fixation. In conclusion, genomic data corroborate local transmission and the importance of intensified control in the Ethiopian highlands.
Topics: Animals; Humans; Plasmodium falciparum; Parasites; Protozoan Proteins; Antigens, Protozoan; Ethiopia; Gene Deletion; Malaria, Falciparum; Malaria
PubMed: 38339833
DOI: 10.1111/mec.17292