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The American Journal of Tropical... May 2024Surveillance for genetic markers of resistance can provide valuable information on the likely efficacy of antimalarials but needs to be targeted to ensure optimal use of...
Surveillance for genetic markers of resistance can provide valuable information on the likely efficacy of antimalarials but needs to be targeted to ensure optimal use of resources. We conducted a systematic search and review of publications in seven databases to compile resistance marker data from studies in India. The sample collection from the studies identified from this search was conducted between 1994 and 2020, and these studies were published between 1994 and 2022. In all, Plasmodium falciparum Kelch13 (PfK13), P. falciparum dihydropteroate synthase, and P. falciparum dihydrofolate reductase (PfDHPS) genotype data from 2,953, 4,148, and 4,222 blood samples from patients with laboratory-confirmed malaria, respectively, were extracted from these publications and uploaded onto the WorldWide Antimalarial Resistance Network molecular surveyors. These data were fed into hierarchical geostatistical models to produce maps with a predicted prevalence of the PfK13 and PfDHPS markers, and of the associated uncertainty. Zones with a predicted PfDHPS 540E prevalence of >15% were identified in central, eastern, and northeastern India. The predicted prevalence of PfK13 mutants was nonzero at only a few locations, but were within or adjacent to the zones with >15% prevalence of PfDHPS 540E. There may be a greater probability of artesunate-sulfadoxine-pyrimethamine failures in these regions, but these predictions need confirmation. This work can be applied in India and elsewhere to help identify the treatments most likely to be effective for malaria elimination.
Topics: Plasmodium falciparum; Pyrimethamine; Sulfadoxine; India; Drug Resistance; Antimalarials; Drug Combinations; Humans; Malaria, Falciparum; Artemisinins; Tetrahydrofolate Dehydrogenase; Genetic Markers; Dihydropteroate Synthase; Protozoan Proteins
PubMed: 38574550
DOI: 10.4269/ajtmh.23-0631 -
Malaria Journal Mar 2024A Stakeholder engagement meeting on the implementation of post-discharge malaria chemoprevention (PDMC) in Benin, Kenya, Malawi, and Uganda was held in Nairobi, Kenya,... (Meta-Analysis)
Meta-Analysis
A Stakeholder engagement meeting on the implementation of post-discharge malaria chemoprevention (PDMC) in Benin, Kenya, Malawi, and Uganda was held in Nairobi, Kenya, on 27 September 2023. Representatives from the respective National Malaria Control Programmes, the World Health Organization (WHO) Geneva, Africa Regional and Kenya offices, research partners, non-governmental organizations, and the Medicines for Malaria Venture participated. PDMC was recommended by the WHO in June 2022 and involves provision of a full anti-malarial treatment course at regular intervals during the post-discharge period in children hospitalized with severe anaemia in areas of moderate-to-high malaria transmission. The WHO recommendation followed evidence from a meta-analysis of three clinical trials and from acceptability, delivery, cost-effectiveness, and modelling studies. The trials were conducted in The Gambia using monthly sulfadoxine-pyrimethamine during the transmission season, in Malawi using monthly artemether-lumefantrine, and in Kenya and Uganda using monthly dihydroartemisinin-piperaquine, showing a significant reduction in all-cause mortality by 77% (95% CI 30-98) and a 55% (95% CI 44-64) reduction in all-cause hospital readmissions 6 months post-discharge. The recommendation has not yet been implemented in sub-Saharan Africa. There is no established platform for PDMC delivery. The objectives of the meeting were for the participating countries to share country contexts, plans and experiences regarding the adoption and implementation of PDMC and to explore potential delivery platforms in each setting. The meeting served as the beginning of stakeholder engagement within the PDMC Saves Lives project and will be followed by formative and implementation research to evaluate alternative delivery strategies in selected countries. Meeting highlights included country consensus on use of dihydroartemisinin-piperaquine for PDMC and expansion of the target group to "severe anaemia or severe malaria", in addition to identifying country-specific options for PDMC delivery for evaluation in implementation research. Further exploration is needed on whether the age group should be extended to school-age children.
Topics: Child; Humans; Antimalarials; Kenya; Uganda; Aftercare; Malawi; Benin; Patient Discharge; Stakeholder Participation; Artemether; Artemether, Lumefantrine Drug Combination; Malaria; Pyrimethamine; Drug Combinations; Chemoprevention; Anemia; Artemisinins
PubMed: 38539181
DOI: 10.1186/s12936-023-04810-0 -
PLOS Global Public Health 2024Malaria in pregnancy is a major public health concern that contributes to a significant increase in maternal and child mortality and morbidity. Intermittent preventive...
Factors associated with the uptake of intermittent preventive treatment for malaria during pregnancy in Cameroon: An analysis of data from the 2018 Cameroon Demographic and Health Survey.
Malaria in pregnancy is a major public health concern that contributes to a significant increase in maternal and child mortality and morbidity. Intermittent preventive treatment of malaria during pregnancy using sulfadoxine-pyrimethamine (IPTp-SP) is a key intervention recommended by the World Health Organization (WHO) and implemented in Cameroon to reduce the morbidity associated with malaria during pregnancy. This study aimed to assess the distribution of the poor uptake of IPTp-SP (i.e. fewer than three doses) in Cameroon and the factors associated. We conducted a secondary analysis of data extracted from the 2018 Cameroon Demographic and Health Survey. Data was collected using a face-to-face questionnaire administered to mothers with at least one child under the age of five. The participants were selected using a two-stage stratified sampling process. We estimated the frequencies of mothers receiving fewer than three doses of IPTp-SP. Multilevel logistic regression modeling was used to assess the associations between key suspected determinants and uptake of fewer than three doses of IPTp-SP. Crude and adjusted Odds-Ratio (ORs) were estimated. A total of 13,527 women of childbearing age were interviewed, of whom 5,528 (40.9%) met our selection criteria. Among them, 845 (15.3%) women had no antenatal consultation (ANC) visit, 1,109 (20%) had 1-3 visits, 3,379 (61.1%) had 4-7 visits, and only 195 (3.5%) had at least eight visits. Moreover, 3,398 (61.5%, CI: 60.2-62.8) had received fewer than three doses of IPTp-SP. Our findings show that the predictors of poor uptake of IPTp-SP include attending the first ANC visit after the third month of pregnancy (aOR = 1.52, CI: 1.30-1.77), attending fewer than four ANC visits (aOR = 1.29, CI: 1.06-1.56), and not being attended to by a healthcare professional during the prenatal period (aOR = 4.63, CI: 2.81-7.64). Residing in the Sahelian regions was not increasing the risk of poor IPTp-SP uptake on its own but was positively modifying the effect of not being attended by a healthcare professional (p < 0.001). We did not find a significant association between a higher level of education and the uptake of IPTp-SP (aOR = 1.10, CI: 0.90-1.32). Nearly two third of the pregnant women in Cameroon have a poor uptake of IPTp-SP. Interventions focused on ANC provision ought to be explored and tested to address this gap, with priority assigned to the Sahelian region.
PubMed: 38536856
DOI: 10.1371/journal.pgph.0001245 -
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 -
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 -
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 -
Infection and Drug Resistance 2024Due to the increasing resistance of to chloroquine (CQ) in Sudan, a shift from CQ to artesunate combined with sulfadoxine/pyrimethamine as a first-line treatment for...
BACKGROUND
Due to the increasing resistance of to chloroquine (CQ) in Sudan, a shift from CQ to artesunate combined with sulfadoxine/pyrimethamine as a first-line treatment for uncomplicated falciparum malaria was adopted in 2004. This study aimed to determine the frequency distribution of K76T and N86Y mutations in chloroquine resistance transporter () and multidrug resistance 1 () genes as key markers of resistance to CQ among isolates from patients in Nyala district of South Darfur state, west of Sudan.
METHODS
A descriptive, cross-sectional study was conducted among 75 P. falciparum isolates from Sudanese patients diagnosed with falciparum malaria mono-infection. Parasite DNA was extracted from dried blood spots and amplified using a nested polymerase chain reaction (PCR). Then, restriction fragment length polymorphism (RFLP) was used to detect the genetic polymorphisms in codons 76 of and 86 of . PCR-RFLP products were analyzed using 1.5% gel electrophoresis to identify the genetic polymorphisms in the studied codons. The wild-type (pfcrt K76 and pfmdr1 N86), mutant ( 76T and 86Y) and mixed-type ( K76T and N86Y) alleles were expressed as frequencies and proportions.
RESULTS
The wild-type K76 allele was observed among 34.7% of isolates and the mutant 76T allele among 20% of isolates, while the mixed-type K76T allele was observed among 45.3% of isolates. On the other hand, 54.7% of isolates harbored the wild-type N86 allele and 5.3% of isolates had the mutant 86Y allele, while the mixed-type N86Y allele was observed among 40% of isolates.
CONCLUSION
The key molecular markers associated with CQ resistance ( 76T and 86Y) are still circulating in high frequency among isolates in South Darfur state, about twelve years after the official withdrawal of the drug as a treatment for uncomplicated falciparum malaria.
PubMed: 38283109
DOI: 10.2147/IDR.S439875