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

Increased circulation time of Plasmodium falciparum underlies persistent asymptomatic infection in the dry season

The dry season is a major challenge for Plasmodium falciparum parasites in many malaria endemic regions, where water availability limits mosquito vectors to only part of the year. How P. falciparum bridges two transmission seasons months apart, without being cleared by the human host or compromising host survival, is poorly understood. Here we show that low levels of P. falciparum parasites persist in the blood of asymptomatic Malian individuals during the 5- to 6-month dry season, rarely causing symptoms and minimally affecting the host immune response. Parasites isolated during the dry season are transcriptionally distinct from those of individuals with febrile malaria in the transmission season, coinciding with longer circulation within each replicative cycle of parasitized erythrocytes without adhering to the vascular endothelium. Low parasite levels during the dry season are not due to impaired replication but rather to increased splenic clearance of longer-circulating infected erythrocytes, which likely maintain parasitemias below clinical and immunological radar. We propose that P. falciparum virulence in areas of seasonal malaria transmission is regulated so that the parasite decreases its endothelial binding capacity, allowing increased splenic clearance and enabling several months of subclinical parasite persistence

Trials on malaria economics in Sahel : case studies in Mali and Burkina Faso.

La mise en œuvre des objectifs du millénaire (OMDs) a permis de réaliser des progrès importants, mais irréguliers entre les pays. Les pays de l’Afrique sub-saharienne restent caractérisés par des proportions élevées d’enfants non scolarisés de mortalité infantile et un poids élevé de maladies transmissibles dans la charge globale de la maladie, dont le paludisme. A cela, s’ajoute un niveau de fécondité élevé avec ses conséquences économiques potentielles. Les Objectifs de Développement Durable, ciblent également le paludisme pour une élimination à l’horizon 2030 et prônent une éducation de qualité à tous, y compris l’encadrement de la petite enfance qui avait été occulté lors des OMDs. Cette thèse s’attache à analyser des aspects du développement liés à ces enjeux globaux. Le premier chapitre analyse l’impact des campagnes de lutte contre le paludisme sur la fécondité au Mali en utilisant les données d’Enquêtes Démographiques et de Santé de 2006 et 2012 et celles de Malaria Atlas Project de la même période. Les résultats montrent que le paludisme a un effet négatif sur la fécondité (-0,24 enfants). Parmi les mécanismes qui expliquent cet effet (décès infantiles, avortements), l’éducation des mères est le mécanisme le plus important. Le deuxième chapitre s’intéresse au lien entre le paludisme, le revenu du ménage et l’investissement dans l’éducation à travers un essai randomisé contrôlé dans un village du Mali. Des enquêtes ont été réalisées en juillet et décembre 2016 auprès des mêmes ménages, avec un dépistage du paludisme par la microscopie chez les enfants de 3 mois à 5 ans. Les résultats montrent que le relâchement des contraintes de pertes économiques liées au paludisme (coûts directs, dépenses de soins, et/ou perte de productivité) permettait aux ménages d’épargner 3194 F CFA (5 euros) et de faire des dépenses supplémentaires de 2863 F CFA (4 euros) dans l’éducation des enfants. Le troisième chapitre, un essai randomisé contrôlé également, analyse l’effet de messages de rappels et d’informations aux chefs des ménages sur l’utilisation et l’adoption de la stratégie moustiquaire imprégnée en utilisant une plateforme de téléphonie mobile à Bobo Dioulasso au Burkina Faso. Des enquêtes ont été réalisées en 2013, 2016 et 2017 pour recueillir les données auprès des mêmes ménages. Les résultats montrent que le problème d’utilisation inappropriée des soins préventifs du paludisme, peut être résolu au moyen de la méthode classique de sensibilisation en santé ou en diffusant des messages d’information auprès des chefs de ménages à travers leur diffusion par une plateforme de téléphonie mobile. L’effet était entre 4,6 et 6 points de pourcentage respectivement pour les messages textes et vocaux. Le quatrième chapitre analyse l’impact et le coût d’un ensemble de stratégies en santé et éducation (micronutriments, CPS, déparasitage) sur l’amélioration du développement de la petite enfance. Il s’agissait d’un essai randomisé contrôlé avec comme unité de randomisation des villages, réalisé en 2016 dans une zone de forte transmission du paludisme et de prévalence élevée de l’anémie, à Sikasso au sud du Mali. Le coût des différentes stratégies a été évalué dans la perspective du fournisseur pour un horizon relativement court. Les stratégies intégrées n’ont pas eu d’impact sur le développement de la petite enfance. Le coût de la mise en œuvre de ces stratégies était cependant limité. En conclusion, le paludisme constitue un poids pour le développement économique, à travers des effets sur la fécondité et le revenu, pénalisant ainsi potentiellement l’investissement dans l’éducation. Nos résultats contribuent donc à la littérature existante sur l’effet du paludisme sur le développement économique.The implementation of the Millennium Development Goals (MDGs) has led to significant but uneven progress between countries. Sub-Saharan African countries continue to be characterized by high proportion of out-of-school children, high child mortality and a high burden of communicable diseases in the overall disease burden, including malaria. Added to this is a high fertility level with its potential economic consequences. The Sustainable Development Goals also target malaria for elimination by 2030 and advocate for quality education for all, including early childhood care, which had been overlooked in the MDGs. This thesis focuses on analysing aspects of development linked to these global challenges. This thesis focuses on analyzing aspects of development related to these global challenges.The first chapter analyses the impact of malaria control campaigns on fertility in Mali using data from the Demographic and Health Surveys of 2006 and 2012 and those of the Malaria Atlas Project for the same period. The results show that malaria has a negative effect on fertility (-0.24 children). Among the mechanisms that explain this effect (infant deaths, abortions), mother’s education is more important. The second chapter examines the relationship between malaria, household income and investment in education through a randomized controlled trial in a village in Mali. Surveys were conducted in July and December 2016 within the same households, with microscopic screening for malaria in children aged 3 months to 5 years. The results show that relaxing the constraints of economic losses linked to malaria (direct costs, care expenses, and/or loss of productivity) allowed households to save 3194 F CFA (5 euros) and to make additional expenditures of 2863 F CFA (4 euros) in children's education. The third chapter, also a randomized controlled trial, analyses the effect of reminder messages and information to household heads on the use and adoption of the ITN strategy using a mobile phone platform in Bobo Dioulasso, Burkina Faso. Surveys were conducted in 2013, 2016 and 2017 to collect data within the same households. The results show that the problem of inappropriate use of preventive malaria care can be solved by using the traditional method of health awareness or by disseminating information messages to heads of households through a mobile phone platform. The effect was between 4.6 and 6 percentage points for text and voice messages respectively. The fourth chapter analyses the impact and cost of a set of health and education strategies (micronutrients, CPS, deworming) on improving early childhood development. This was a randomized controlled trial with villages as the randomization unit, conducted in 2016 in an area of high malaria transmission and high prevalence of anaemia, in Sikasso in southern Mali. The cost of the different strategies was evaluated from the provider's perspective for a relatively short time horizon. The integrated disease control strategies, the implementation of Early Childhood Development Centres and parental education did not have an impact on early childhood development. However, the cost of implementing these strategies was limited.In conclusion, malaria is a burden on economic development through its effects on fertility and income, potentially penalising investment in education. Our results therefore contribute to the existing literature on the effect of malaria on economic development

Malaria and Education: Evidence from Mali

We are very grateful to the editor, John Hoddinott, and two anonymous referees, Hoyt Bleakley, Lauwrence Katz, Maria Kuecken, Nigel Rice, Andrew Street, Marie-Anne Valfort and numerous seminar participants for helpful comments and advice. We especially thank the children of Diankabou and their families for their cooperation. We are also grateful to Diankabou school teachers, the Malaria Research and Training Center employees for expert research assistance, for help acquiring the necessary data and for answering our many questions. In particular, we would like to thank Prof. Abdoulaye Djimdé Dr Alasseini Balam, Dr Yamoussa Keita, Dr Abdoul Karim Sangaré Saïla Doumbo, Ismaila Théra; and the Department of Immunology of Stockholm University, especially Stéphanie Bostrm, Leif Rogell and Marita Troye Blomberg. We thank the European Research Council (ERC Starting Grant DU 283953), the French School of Public Health, the Fondation pour les Études et Recherches sur le Développement International and University Paris 1 for financial support. This work also benefited from the support of the French National Research Agency, as part of the programme ‘Investissements d'avenir’, ANR-10-LABX-14–01. The usual caveat applies.International audienceThis article examines the influence of malaria on human capital accumulation in the village of Diankabou in Mali. To account for malaria endogeneity and its interaction with unobservable risk factors, we exploit natural variations in malaria immunity across individuals of several sympatric ethnic groups—the Fulani and the non-Fulani—who differ in their susceptibility to malaria. The Fulani are known to be less susceptible to malaria infections, despite living with a similar malaria transmission intensity to those seen among other ethnic groups. We also use natural variation of malaria intensity in the area (during and after the malaria transmission season) and utilise this seasonal change as a treatment. We found that malaria has an impact on cognitive and educational outcomes in this village

A randomized trial of dihydroartemisinin–piperaquine versus artemether–lumefantrine for treatment of uncomplicated Plasmodium falciparum malaria in Mali

Abstract Background Artemether–lumefantrine (AL) and artesunate–amodiaquine are first-line treatment for uncomplicated malaria in many endemic countries, including Mali. Dihydroartemisinin–piperaquine (DHA–PQ) is also an alternative first-line artemisinin-based combination therapy, but only few data are available on DHA–PQ efficacy in sub-Saharan Africa. The main aim of this study was to compare clinical efficacy of DHA–PQ versus AL, using the World Health Organization (WHO) 42-day in vivo protocol. Methods The efficacy of three-dose regimens of DHA–PQ was compared to AL combination in a randomized, comparative open label trial using the WHO 42-day follow-up protocol from 2013 to 2015 in Doneguebougou and Torodo, Mali. The primary endpoint was to access the PCR-corrected Adequate Clinical and Parasitological Responses at day 28. Results A total of 317 uncomplicated malaria patients were enrolled, with 159 in DHA–PQ arm and 158 in AL arm. The parasite positivity rate decreased from 68.4% (95% CI 60.5–75.5) on day 1 to 3.8% (95% CI 1.4–8.1) on day 2 for DHA–PQ and 79.8% (95% CI 72.3–85.7) on day 1 to 9.5% (95% CI 5.4–15.2) on day 2 for AL, (p = 0.04). There was a significant difference in the uncorrected ACPR between DHA–PQ and AL, both at 28-day and 42-day follow-up with 97.4% (95% CI 93.5–99.3) in DHA–PQ vs 84.5% (95% CI 77.8–89.8) in AL (p < 0.001) and 94.2% (95% CI 89.3–97.3) in DHA–PQ vs 73.4% (95% CI 65.7–80.2) in AL, respectively (p < 0.001). After molecular correction, there was no significant difference in ACPRc between DHA–PQ and AL, both at the 28-day and 42-day follow-up with 99.4% (95% CI 96.5–100) in DHA–PQ versus 98.1% (95% CI 94.5–99.6) in AL (p = 0.3) and 99.3% (95% CI 96.5–100) in DHA–PQ vs 97.4% (95% CI 93.5–99.3) in AL (p = 0.2). There was no significant difference between DHA–PQ and AL in QTc prolongation 12.1% vs 7%, respectively (p = 0.4). Conclusion The results showed that dihydroartemisinin–piperaquine and artemether–lumefantrine were clinically efficacious on Plasmodium falciparum parasites in Mali

Relationship between weight status and anti-malarial drug efficacy and safety in children in Mali

Abstract Background Anti-malarial treatments effectiveness remains a critical challenge for control programmes. However, when drug efficacy is established, the dose is calculated based on a predefined weight according to the patient age. Based on the hypothesis that the standard assumption of weight according to the age when administering the drug could lead to a therapeutic failure potentially due to under-dosing (in the case of overweight) or over-dosing (in case of underweight). In this study, the relationship between weight status and malaria drug efficacy in clearing current Plasmodium falciparum infection and preventing reinfection after treatment was investigated. Methods Data were drown from a clinical trial conducted previously to investigate malaria drug efficacy in 749 children from Mali (2002–2004). Participants were treated either with artesunate + amodiaquine (AS + AQ, n1 = 250), artesunate + sulfadoxine–pyrimethamine (AS + SP, n2 = 248) or artesunate (AS, n3 = 251) and followed for 28 days after treatment. The World Health Organization (WHO) z-score was used to define weight status. A Chi square test was used to compare outcomes according to drugs, weight status and the dynamic of ALAT, ASAT, creatinine and haemoglobin level. Logistic regression models were developed to determine the effect of baseline parameters (weight status, aspartate transaminase, alanine aminotransferase, creatinine and haemoglobin level) on drug efficacy as per WHO criteria. Results Without molecular correction, in AS + AQ arm, the rate of adequate clinical and parasitological response (ACPR) was higher in the group of underweight children 94.74% compared to children with normal and overweight (91.24% and 80.43% respectively, p = 0.03). After PCR correction, treatment efficacy was similar in the three groups of patients and was above 98% (p = 0.4). Overweight was observed to have no impact on recrudescence. However, it was associated with an increased risk of new infections in the (AS + AQ) arm (OR = 0.21, 95% CI [0.06; 0.86], p = 0.03). Conclusions The findings suggest that weight deficiency has no deleterious effect on anti-malarial drug efficacy. An increase in the rate of reinfection in overweight children treated by AS + AQ should be further explored in larger studies

Reduced ex vivo susceptibility of Plasmodium falciparum after oral artemether–lumefantrine treatment in Mali

International audienceBackground: Artemisinin-based combination therapy is the recommended first-line treatment for uncomplicated falciparum malaria worldwide. However, recent studies conducted in Mali showed an increased frequency of recurrent parasitaemia following artemether-lumefantrine (AL) treatment. Methods: Study samples were collected during a large WANECAM study. Ex-vivo Plasmodium falciparum sensitivity to artemether and lumefantrine was assessed using the tritiated hypoxanthine-based assay. The prevalence of molecular markers of anti-malarial drug resistance (pfcrt K76T, pfmdr1 N86Y and K13-propeller) were measured by PCR and/or sequencing. Results: Overall 61 samples were successfully analysed in ex vivo studies. Mean IC 50 s increased significantly between baseline and recurrent parasites for both artemether (1.6 nM vs 3.2 nM, p < 0.001) and lumefantrine (1.4 nM vs 3.4 nM, p = 0.004). Wild type Pfmdr1 N86 allele was selected after treatment (71 vs 91%, 112 of 158 vs 95 of 105, p < 0.001) but not the wild type pfcrt K76 variant (23.5 vs 24.8%, 40 of 170 vs 26 of 105, p = 0.9). Three non-synonymous K13-propeller SNPs (A522C, A578S, and G638R) were found with allele frequencies <2%. Conclusion: Malian postAL P. falciparum isolates were less susceptible to artemether and lumefantrine than baseline isolates

Coxiella burnetii-positive PCR in febrile patients in rural and urban Africa

Objectives: Q fever has been reported throughout the African continent. The objective of this study was to detect the presence of Coxiella burnetii in febrile patients from Africa. Methods: Blood samples from febrile and non-febrile patients from six African countries and from France were investigated retrospectively for Q fever infection by molecular assays targeting the IS1111 and IS30A spacers. Results: We tested 1888 febrile patients from Senegal, Mali, Tunisia, Algeria, Gabon, and Morocco and found one male adult patient (0.3%) infected with C. burnetii in Algeria and six positive patients (0.5%) in Senegal. For one patient from Senegal we determined that the infection was caused by C. burnetii genotype 35. In Senegal, more patients were infected with C. burnetii in Keur Momar Sarr (p = 0.002) than in the other locations. Blood samples taken from 500 (51% males) non-febrile people from Senegal and France were all negative. Conclusions: The installation of point-of-care laboratories in rural Africa can be a very effective tool for studying the epidemiology of many infectious diseases