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The American Journal of Tropical... Feb 2024Despite marked progress in Senegal, three regions in the southeast part continue to have a high burden of malaria, but there have been no recent studies assessing the...
Despite marked progress in Senegal, three regions in the southeast part continue to have a high burden of malaria, but there have been no recent studies assessing the prevalence of malaria associated with pregnancy. This study aimed to determine the prevalence of malaria infection in pregnant women attending antenatal clinics in Senegal. During the malaria transmission season of 2019, pregnant women attending 11 health care facilities for a scheduled visit and those presenting unwell with signs of malaria were invited to participate in a malaria screening study. A finger prick blood sample was taken for malaria diagnosis by rapid diagnosis test (RDT) and polymerase chain reaction (PCR). A total of 877 pregnant women were enrolled, 787 for a scheduled antenatal consultation and 90 for an unscheduled consultation with signs of malaria. The prevalence of Plasmodium falciparum among the first group was 48% by PCR and 20% by RDT, and that among the second group was 86% by PCR and 83% by RDT. RDT sensitivity in capturing asymptomatic, PCR-positive infections was 9.2% but ranged from 83% to 94% among febrile women. The prevalence of infection by PCR in women who reported having received at least three doses of sulfadoxine pyrimethamine (SP) was 41.9% compared with 58.9% in women who reported they had not received any SP doses (prevalence ratio adjusted for gravidity and gestational age, 0.54; 95% CI, 0.41-0.73). The burden of P. falciparum infections remains high among pregnant women, the majority of which are not captured by RDT. More effective measures to prevent malaria infection in pregnancy are needed.
Topics: Humans; Female; Pregnancy; Infant; Antimalarials; Pregnant Women; Prevalence; Senegal; Sulfadoxine; Pyrimethamine; Malaria; Malaria, Falciparum; Drug Combinations; Asymptomatic Infections; Ambulatory Care Facilities
PubMed: 38167431
DOI: 10.4269/ajtmh.23-0164 -
BMC Public Health Jan 2024The uptake of Intermittent Preventive Treatment of malaria in pregnancy using Sulfadoxine-Pyrimethamine (IPTp-SP) remains unacceptably low, with more than two-thirds of...
Increasing the uptake of Intermittent Preventive Treatment of malaria in pregnancy using Sulfadoxine-Pyrimethamine (IPTp-SP) through seasonal malaria chemoprevention channel delivery: protocol of a multicenter cluster randomized implementation trial in Mali and Burkina Faso.
BACKGROUND
The uptake of Intermittent Preventive Treatment of malaria in pregnancy using Sulfadoxine-Pyrimethamine (IPTp-SP) remains unacceptably low, with more than two-thirds of pregnant women in sub-Saharan Africa still not accessing the three or more doses recommended by the World Health Organisation (WHO). In contrast, the coverage of Seasonal Malaria Chemoprevention (SMC), a more recent strategy recommended by the WHO for malaria prevention in children under five years living in Sahelian countries with seasonal transmission, including Mali and Burkina-Faso, is high (up to 90%). We hypothesized that IPTp-SP delivery to pregnant women through SMC alongside antenatal care (ANC) will increase IPTp-SP coverage, boost ANC attendance, and increase public health impact. This protocol describes the approach to assess acceptability, feasibility, effectiveness, and cost-effectiveness of the integrated strategy.
METHODS AND ANALYSIS
This is a multicentre, cluster-randomized, implementation trial of IPTp-SP delivery through ANC + SMC vs ANC alone in 40 health facilities and their catchment populations (20 clusters per arm). The intervention will consist of monthly administration of IPTp-SP through four monthly rounds of SMC during the malaria transmission season (July to October), for two consecutive years. Effectiveness of the strategy to increase coverage of three or more doses of IPTp-SP (IPTp3 +) will be assessed using household surveys and ANC exit interviews. Statistical analysis of IPT3 + and four or more ANC uptake will use a generalized linear mixed model. Feasibility and acceptability will be assessed through in-depth interviews and focus group discussions with health workers, pregnant women, and women with a child < 12 months.
DISCUSSION
This multicentre cluster randomized implementation trial powered to detect a 45% and 22% increase in IPTp-SP3 + uptake in Mali and Burkina-Faso, respectively, will generate evidence on the feasibility, acceptability, effectiveness, and cost-effectiveness of IPTp-SP delivered through the ANC + SMC channel. The intervention is designed to facilitate scalability and translation into policy by leveraging existing resources, while strengthening local capacities in research, health, and community institutions. Findings will inform the local national malaria control policies.
TRIAL REGISTRATION
Retrospectively registered on August 11th, 2022; registration # PACTR202208844472053. Protocol v4.0 dated September 04, 2023. Trail sponsor: University of Sciences Techniques and Technologies of Bamako (USTTB), Mali.
Topics: Child; Female; Pregnancy; Humans; Child, Preschool; Seasons; Antimalarials; Burkina Faso; Mali; Sulfadoxine; Pyrimethamine; Malaria; Drug Combinations; Pregnancy Complications, Parasitic; Chemoprevention; Randomized Controlled Trials as Topic; Multicenter Studies as Topic
PubMed: 38166711
DOI: 10.1186/s12889-023-17529-z -
International Journal of Antimicrobial... Mar 2024India is on track to eliminate malaria by 2030 but emerging resistance to first-line antimalarials is a recognised threat. Two instances of rapid development, spread,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
India is on track to eliminate malaria by 2030 but emerging resistance to first-line antimalarials is a recognised threat. Two instances of rapid development, spread, and natural selection of drug-resistant mutant parasites in India (chloroquine across the country and artesunate + sulfadoxine-pyrimethamine [AS+SP] in the northeastern states) translated into drug policy changes for Plasmodium falciparum malaria in 2010 and 2013, respectively. Considering these rapid changes in the SP drug resistance-conferring mutation profile of P. falciparum, there is a need to systematically monitor the validated mutations in Pfdhfr and Pfdhps genes across India alongside AS+SP therapeutic efficacy studies. There has been no robust, systematic countrywide surveillance reported for these parameters in India, hence the current study was undertaken.
METHODS
Studies that reported data on WHO-validated SP resistance markers in P. falciparum across India from 2008 to January 2023 were included. Five major databases, PubMed, Web of Science, Scopus, Embase, and Google Scholar, were exhaustively searched. Individual and pooled prevalence estimates of mutations were obtained through random- and fixed-effect models. Data were depicted using forest plots created with a 95% confidence interval. The study is registered with PROSPERO (CRD42021236012).
RESULTS
A total of 37 publications, and 533 Pfdhfr and 134 Pfdhps National Centre of Biotechnology Information (NCBI) DNA sequences were included from >4000 samples. The study included information from 80 districts, 21 states and 3 union territories (UTs) from India. The two PfDHFR mutations, C59R (62%) and S108N (74%), were the most prevalent mutations (pooled estimates 61% and 71%, respectively) and appeared to be stabilised/fixed. Although rarest overall, the prevalence of I164L was observed to be as high as 32%. The PfDHFR double mutants were the most prevalent overall (51%; pooled 42%). The prevalence of triple and quadruple mutations was 6% and 5%, respectively, and is an immediate concern for some states. The most prevalent PfDHPS mutation was A437G (39%), followed by K540E (25%) and A581G (12%). There was a low overall prevalence of PfDHFR/PfDHPS quintuple and sextuple mutations but surveillance for these mutations is critical for some areas.
CONCLUSION
The analyses span the two critical policy changes, highlight the areas of concern, and guide policymakers in strategising and refining the anti-malaria drug policy for malaria elimination. The results of the analyses also highlight the SP-resistance hot spots, critical gaps and challenges, and indicate that focal and local malaria genetic surveillance (including drug-resistance markers) is needed until malaria is successfully eliminated.
Topics: Humans; Plasmodium falciparum; Pyrimethamine; Malaria, Falciparum; Antimalarials; India; Artesunate; Drug Combinations; Sulfadoxine
PubMed: 38154659
DOI: 10.1016/j.ijantimicag.2023.107071 -
The American Journal of Tropical... Mar 2024Malaria in pregnancy (MiP) intervention coverage, especially intermittent preventive treatment in pregnancy (IPTp), lags behind other global malaria indicators. In 2020,...
Malaria in pregnancy (MiP) intervention coverage, especially intermittent preventive treatment in pregnancy (IPTp), lags behind other global malaria indicators. In 2020, across Africa, only 32% of eligible pregnant women received at least three IPTp doses, despite high antenatal care attendance. We conducted a secondary analysis of data collected during Outreach Training and Supportive Supervision visits from 2019 to 2020 to assess quality of care and explore factors contributing to providers' competence in providing IPTp, insecticide-treated nets, malaria case management, and respectful maternity care. Data were collected during observations of provider-patient interactions in six countries (Cameroon, Cote d'Ivoire, Ghana, Kenya, Mali, and Niger). Competency scores (i.e., composite scores of supervisory checklist observations) were calculated across three domains: MiP prevention, MiP treatment, and respectful maternity care. Scores are used to understand drivers of competency, rather than to assess individual health worker performance. Country-specific multilinear regressions were used to assess how competency score was influenced by commodity availability, training, provider gender and cadre, job aid availability, and facility type. Average competency scores varied across countries: prevention (44-90%), treatment (78-90%), and respectful maternity care (53-93%). The relative association of each factor with competency score varied. Commodity availability, training, and access to job aids correlated positively with competency in multiple countries. To improve MiP service quality, equitable access to training opportunities for different cadres, targeted training, and access to job aids and guidelines should be available for providers. Collection and analysis of routine supervision data can support tailored actions to improve quality MiP services.
Topics: Female; Pregnancy; Humans; Antimalarials; Pyrimethamine; Sulfadoxine; Maternal Health Services; Malaria; Prenatal Care; Pregnancy Complications, Parasitic; Kenya; Quality of Health Care; Drug Combinations
PubMed: 38150728
DOI: 10.4269/ajtmh.23-0206 -
ELife Dec 2023Pathogen evolution of drug resistance often occurs in a stepwise manner via the accumulation of multiple mutations that in combination have a non-additive impact on...
Pathogen evolution of drug resistance often occurs in a stepwise manner via the accumulation of multiple mutations that in combination have a non-additive impact on fitness, a phenomenon known as epistasis. The evolution of resistance via the accumulation of point mutations in the DHFR genes of () and () has been studied extensively and multiple studies have shown epistatic interactions between these mutations determine the accessible evolutionary trajectories to highly resistant multiple mutations. Here, we simulated these evolutionary trajectories using a model of molecular evolution, parameterised using Rosetta Flex ddG predictions, where selection acts to reduce the target-drug binding affinity. We observe strong agreement with pathways determined using experimentally measured IC50 values of pyrimethamine binding, which suggests binding affinity is strongly predictive of resistance and epistasis in binding affinity strongly influences the order of fixation of resistance mutations. We also infer pathways directly from the frequency of mutations found in isolate data, and observe remarkable agreement with the most likely pathways predicted by our mechanistic model, as well as those determined experimentally. This suggests mutation frequency data can be used to intuitively infer evolutionary pathways, provided sufficient sampling of the population.
Topics: Antimalarials; Pyrimethamine; Mutation; Point Mutation; Evolution, Molecular; Plasmodium falciparum; Drug Resistance; Tetrahydrofolate Dehydrogenase
PubMed: 38132182
DOI: 10.7554/eLife.84756 -
EBioMedicine Jan 2024Sulfadoxine-pyrimethamine (SP) antimalarial therapy has been suggested to potentially increase the birth weight of infants in pregnant women in sub-Saharan Africa,...
BACKGROUND
Sulfadoxine-pyrimethamine (SP) antimalarial therapy has been suggested to potentially increase the birth weight of infants in pregnant women in sub-Saharan Africa, independently of malarial infection. Here, we utilized female intestinal organoid-derived cells cultured within microfluidic Organ Chips to investigate whether SP could directly impact intestinal function and thereby improve the absorption of essential fats and nutrients crucial for fetal growth.
METHODS
Using a human organ-on-a-chip model, we replicated the adult female intestine with patient organoid-derived duodenal epithelial cells interfaced with human intestinal endothelial cells. Nutrient-deficient (ND) medium was perfused to simulate malnutrition, resulting in the appearance of enteric dysfunction indicators such as villus blunting, reduced mucus production, impaired nutrient absorption, and increased inflammatory cytokine secretion. SP was administered to these chips in the presence or absence of human peripheral blood mononuclear cells (PBMCs).
FINDINGS
Our findings revealed that SP treatment effectively reversed multiple intestinal absorptive abnormalities observed in malnourished female Intestine Chips, as validated by transcriptomic and proteomic analyses. SP also reduced the production of inflammatory cytokines and suppressed the recruitment of PBMCs in ND chips.
INTERPRETATION
Our results indicate that SP could potentially increase birth weights by preventing enteric dysfunction and suppressing intestinal inflammation. This underscores the potential of SP as a targeted intervention to improve maternal absorption, subsequently contributing to healthier fetal growth. While SP treatment shows promise in addressing malabsorption issues that can influence infant birth weight, we did not model pregnancy in our chips, and thus its usefulness for treatment of malnourished pregnant women requires further investigation through clinical trials.
FUNDING
The Bill and Melinda Gates Foundation, and the Wyss Institute for Biologically Inspired Engineering at Harvard University, and the HDDC Organoid Core of the P30 DK034854.
Topics: Adult; Female; Humans; Pregnancy; Birth Weight; Endothelial Cells; Leukocytes, Mononuclear; Proteomics; Pregnancy Complications, Parasitic; Pyrimethamine; Antimalarials; Drug Combinations; Intestines; Malnutrition; Sulfadoxine
PubMed: 38101300
DOI: 10.1016/j.ebiom.2023.104921 -
The Lancet. Global Health Jan 2024Severe anaemia is associated with high in-hospital mortality among young children. In malaria-endemic areas, surviving children also have an increased risk of mortality... (Meta-Analysis)
Meta-Analysis
Post-discharge malaria chemoprevention in children admitted with severe anaemia in malaria-endemic settings in Africa: a systematic review and individual patient data meta-analysis of randomised controlled trials.
BACKGROUND
Severe anaemia is associated with high in-hospital mortality among young children. In malaria-endemic areas, surviving children also have an increased risk of mortality or readmission after hospital discharge. We conducted a systematic review and individual patient data meta-analysis to determine the efficacy of monthly post-discharge malaria chemoprevention in children recovering from severe anaemia.
METHODS
This analysis was conducted according to PRISMA-IPD guidelines. We searched multiple databases on Aug 28, 2023, without date or language restrictions, for randomised controlled trials comparing monthly post-discharge malaria chemoprevention with placebo or standard of care among children (aged <15 years) admitted with severe anaemia in malaria-endemic Africa. Trials using daily or weekly malaria prophylaxis were not eligible. The investigators from all eligible trials shared pseudonymised datasets, which were standardised and merged for analysis. The primary outcome was all-cause mortality during the intervention period. Analyses were performed in the modified intention-to-treat population, including all randomly assigned participants who contributed to the endpoint. Fixed-effects two-stage meta-analysis of risk ratios (RRs) was used to generate pooled effect estimates for mortality. Recurrent time-to-event data (readmissions or clinic visits) were analysed using one-stage mixed-effects Prentice-Williams-Peterson total-time models to obtain hazard ratios (HRs). This study is registered with PROSPERO, CRD42022308791.
FINDINGS
Our search identified 91 articles, of which 78 were excluded by title and abstract, and a further ten did not meet eligibility criteria. Three double-blind, placebo-controlled trials, including 3663 children with severe anaemia, were included in the systematic review and meta-analysis; 3507 (95·7%) contributed to the modified intention-to-treat analysis. Participants received monthly sulfadoxine-pyrimethamine until the end of the malaria transmission season (mean 3·1 courses per child [range 1-6]; n=1085; The Gambia), monthly artemether-lumefantrine given at the end of weeks 4 and 8 post discharge (n=1373; Malawi), or monthly dihydroartemisinin-piperaquine given at the end of weeks 2, 6, and 10 post discharge (n=1049; Uganda and Kenya). During the intervention period, post-discharge malaria chemoprevention was associated with a 77% reduction in mortality (RR 0·23 [95% CI 0·08-0·70], p=0·0094, I=0%) and a 55% reduction in all-cause readmissions (HR 0·45 [95% CI 0·36-0·56], p<0·0001) compared with placebo. The protective effect was restricted to the intervention period and was not sustained after the direct pharmacodynamic effect of the drugs had waned. The small number of trials limited our ability to assess heterogeneity, its sources, and publication bias.
INTERPRETATION
In malaria-endemic Africa, post-discharge malaria chemoprevention reduces mortality and readmissions in recently discharged children recovering from severe anaemia. Post-discharge malaria chemoprevention could be a valuable strategy for the management of this group at high risk. Future research should focus on methods of delivery, options to prolong the protection duration, other hospitalised groups at high risk, and interventions targeting non-malarial causes of post-discharge morbidity.
FUNDING
The Research-Council of Norway and the Bill-&-Melinda-Gates-Foundation through the Worldwide-Antimalarial-Research-Network.
Topics: Child; Humans; Child, Preschool; Antimalarials; Patient Discharge; Aftercare; Artemether; Artemether, Lumefantrine Drug Combination; Malaria; Anemia; Drug Combinations; Kenya; Chemoprevention; Randomized Controlled Trials as Topic
PubMed: 38097295
DOI: 10.1016/S2214-109X(23)00492-8 -
The American Journal of Tropical... Jan 2024Seasonal malaria chemoprevention (SMC) for children under 5 years of age for up to four monthly cycles during malaria transmission season was recommended by the WHO in... (Meta-Analysis)
Meta-Analysis
Seasonal malaria chemoprevention (SMC) for children under 5 years of age for up to four monthly cycles during malaria transmission season was recommended by the WHO in 2012 and has been implemented in 13 countries in the Sahel, reaching more than 30 million children annually. Malaria control programs implementing SMC have asked the WHO to consider expanding the age range or number of monthly cycles. We conducted a systematic review and meta-analysis of SMC among children up to 15 years of age and up to six monthly cycles. Twelve randomized studies were included, with outcomes stratified by age (< 5/≥ 5 years), by three or four versus five or six cycles, and by drug where possible. Drug regimens included sulfadoxine-pyrimethamine + amodiaquine, amodiaquine-artesunate, and sulfadoxine-pyrimethamine + artesunate. Included studies were all conducted in Sahelian countries in which high-grade resistance to sulfadoxine-pyrimethamine was rare and in zones with parasite prevalence ranging from 1% to 79%. Seasonal malaria chemoprevention resulted in substantial reductions in uncomplicated malaria incidence measured during that transmission season (rate ratio: 0.27, 95% CI: 0.25-0.29 among children < 5 years; rate ratio: 0.27, 95% CI: 0.25-0.30 among children ≥ 5 years) and in the prevalence of malaria parasitemia measured within 4-6 weeks from the final SMC cycle (risk ratio: 0.38, 95% CI: 0.34-0.43 among children < 5 years; risk ratio: 0.23, 95% CI: 0.11-0.48 among children ≥ 5 years). In high-transmission zones, SMC resulted in a moderately reduced risk of any anemia (risk ratio: 0.77, 95% CI: 0.72-0.83 among children < 5 years; risk ratio: 0.70, 95% CI: 0.52-0.95 among children ≥ 5 years [one study]). Children < 10 years of age had a moderate reduction in severe malaria (risk ratio: 0.53, 95% CI: 0.37-0.76) but no evidence of a mortality reduction. The evidence suggests that in areas in which sulfadoxine-pyrimethamine and amodiaquine remained efficacious, SMC effectively reduced malaria disease burden among children both < 5 and ≥ 5 years old and that the number of cycles should be commensurate with the length of the transmission season, up to six cycles.
Topics: Child; Child, Preschool; Humans; Amodiaquine; Antimalarials; Artesunate; Chemoprevention; Drug Combinations; Malaria; Pyrimethamine; Seasons; Sulfadoxine; Adolescent
PubMed: 38081050
DOI: 10.4269/ajtmh.23-0481 -
Malaria Journal Dec 2023Resistance against artemisinin-based combination therapy is one of the challenges to malaria control and elimination globally. Mutations in different genes (Pfdhfr,...
BACKGROUND
Resistance against artemisinin-based combination therapy is one of the challenges to malaria control and elimination globally. Mutations in different genes (Pfdhfr, Pfdhps, Pfk-13 and Pfmdr1) confer resistance to artesunate and sulfadoxine-pyrimethamine (AS + SP) were analysed from Mandla district, Madhya Pradesh, to assess the effectiveness of the current treatment regimen against uncomplicated Plasmodium falciparum.
METHODS
Dried blood spots were collected during the active fever survey and mass screening and treatment activities as part of the Malaria Elimination Demonstration Project (MEDP) from 2019 to 2020. Isolated DNA samples were used to amplify the Pfdhfr, Pfdhps, Pfk13 and Pfmdr1 genes using nested PCR and sequenced for mutation analysis using the Sanger sequencing method.
RESULTS
A total of 393 samples were subjected to PCR amplification, sequencing and sequence analysis; 199, 215, 235, and 141 samples were successfully sequenced for Pfdhfr, Pfdhps, Pfk13, Pfmdr1, respectively. Analysis revealed that the 53.3% double mutation (C59R, S108N) in Pfdhfr, 89.3% single mutation (G437A) in Pfdhps, 13.5% single mutants (N86Y), and 51.1% synonymous mutations in Pfmdr1 in the study area. Five different non-synonymous and two synonymous point mutations found in Pfk13, which were not associated to artemisinin resistance.
CONCLUSION
The study has found that mutations linked to SP resistance are increasing in frequency, which may reduce the effectiveness of this drug as a future partner in artemisinin-based combinations. No evidence of mutations linked to artemisinin resistance in Pfk13 was found, suggesting that parasites are sensitive to artemisinin derivatives in the study area. These findings are a baseline for routine molecular surveillance to proactively identify the emergence and spread of artemisinin-resistant parasites.
Topics: Humans; Plasmodium falciparum; Antimalarials; Pyrimethamine; Sulfadoxine; Artemisinins; Malaria; Biomarkers; Drug Resistance; India; Drug Combinations; Malaria, Falciparum; Protozoan Proteins
PubMed: 38072967
DOI: 10.1186/s12936-023-04817-7 -
Parasites, Hosts and Diseases Nov 2023Since 2015, countries in the Sahel region have implemented large-scale seasonal malaria chemoprevention (SMC). However, the mass use of sulfadoxine-pyrimethamine (SP)...
Since 2015, countries in the Sahel region have implemented large-scale seasonal malaria chemoprevention (SMC). However, the mass use of sulfadoxine-pyrimethamine (SP) plus amodiaquine impacts the genetic diversity of malaria parasites and their sensitivity to antimalarials. This study aimed to describe and compare the genetic diversity and SP resistance of Plasmodium falciparum strains in Mali and Niger. We collected 400 blood samples in Mali and Niger from children aged 3-59 months suspected of malaria. Of them, 201 tested positive (Niger, 111, 55.2%; Mali, 90, 44.8%). Polymorphism of merozoite surface protein 1 (msp1) genetic marker showed 201 allotypes. The frequency of the RO33 allotype was significantly higher in Niger (63.6%) than in Mali (39.3%). There was no significant difference in the frequency of the K1 and MAD20 allotypes between the 2 countries. The multiplicity of infection was 2 allotypes per patient in Mali and one allotype per patient in Niger. The prevalence of strains with the triple mutants Pfdhfr51I/Pfdhfr59R/Pfdhps436A/F/H and Pfdhfr51I/Pfdhfr59R/Pfdhps437G was 18.1% and 30.2%, respectively, and 7.7% carried the quadruple mutant Pfdhfr51I/Pfdhfr59R/Pfdhps436A/F/H/Pfdhps437G. Despite the significant genetic diversity of parasite populations, the level of SP resistance was comparable between Mali and Niger. The frequency of mutations conferring resistance to SP still allows its effective use in intermittent preventive treatment in pregnant women and in SMC.
Topics: Child; Female; Humans; Pregnancy; Folic Acid Antagonists; Malaria; Malaria, Falciparum; Mali; Merozoite Surface Protein 1; Niger; Plasmodium falciparum; Polymorphism, Genetic; Drug Resistance
PubMed: 38043541
DOI: 10.3347/PHD.23049