Le paludisme demeure un des principaux fardeaux de l'humanité en dépit d'une évolution générale favorable du nombre de cas de paludisme. Les travaux contenus dans cette thèse concernent le déploiement d'une combinaison antipaludique à base de dérivés de l'artémisinine en zone rurale à transmission modérée. Le choix du traitement à adopter doit reposer sur l'évidence, dont la forme la plus aboutie demeure la revue systématique et méta-analyse. Cependant, la présentation des résultats peut être améliorée dans le but de faciliter la prise de décision. En outre pour compléter cette preuve expérimentale, il est nécessaire d’étudier l’utilisation des médicaments en pratique courante, dans une approche de médecine factuelle et d’en effectuer le suivi sur plusieurs années concernant l'efficacité, tolérance, sensibilité in vitro, qualité de la prise en charge, épidémiologie du paludisme.Un programme pilote de prise en charge du paludisme intégré dans le système de santé publique a été mis en place au dispensaire de Mlomp, Sénégal à partir de l’année 2000 : un traitement avec la combinaison artésunate + amodiaquine après confirmation parasitologique (en lieu et place d'un traitement présomptif par mono-thérapie). Ces travaux d'accompagnement de la mise à l'échelle des nouvelles directives de prise en charge du paludisme ont permis d'apporter des éléments pour améliorer la qualité des soins ainsi que permettre une meilleure compréhension des obstacles à la mise en place de la nouvelle stratégie et ses effets sur la santé de la population. / Malaria remains a major health burden for mankind despite trends towards a decrease in the number of cases in most endemic areas. The research summarized in this thesis concerns the deployment of an artemisinin-containing antimalarial drug combination (ACT) in a rural district of moderately intense transmission. The choice of an adapted treatment must be evidence based. Systematic reviews and meta-analysis are considered the most robust form of evidence. However, visual displays should be improved in order to improve decision making.Furthermore, to complement evidence from clinical trials, drugs should be studied when used in real-life conditions and followed-up over time for their efficacy, safety, parasite susceptibility, quality of case management, malaria epidemiology.A pilot programme to change case management modalities was started in 2000 in Mlomp, Senegal. The programme was embedded in the public health system and aimed at replacing the previous policy (single-agent treatment on clinical grounds) with the new policy (ACT for parasitologically confirmed malaria). The work conducted to support the scaling-up of the new policy allows improving case management and provides elements towards a better understanding of obstacles to the deployment of the new strategy and its effects on the health of populations.

The World Health Organization estimates that about 10-30% of pharmaceuticals in the world are either substandard or counterfeit. The number is even higher in the developing countries. From a public health perspective, a key contributor to the development and proliferation drug resistant strains of infections, including tuberculosis (TB), malaria and other infections that are leading killers in resource limited settings is poor quality medicines. Most of the main causes are profit driven corruption in many pharmaceutical companies, the poor manufacture and quality control, and/or the inappropriate storage conditions. Poor quality drugs lead to loss of life, create morbidity, strain the financial structure of the health system and lead to long-term drug resistance that affects us all. The current technology for screening poor quality drugs can be divided into 2 categories: the high end, precise and high cost technologies (such as High Performance Liquid Chromatography) and lower cost and qualitative technologies (such as Thin-Layered Chromatography). The high-end methods can give a precise measurement of active pharmaceutical ingredient (API) concentration and the presence of impurities in the tablets, but require trained personnel, advanced machine and lab set up, not suitable for field testing where most of poor quality pharmaceuticals have been found. The lower cost techniques require little training and simple equipment to operate at a relatively inexpensive price, but only gives qualitative results. In addition, most of current methods do not look at the dissolution profile of the tablets simultaneously with the concentration of API. Therefore, we propose to develop an assay that can quantify the concentrations of multiple APIs simultaneously and measure dissolution rates. In order to address current gaps in knowledge, my research proposal has three main parts in the assay development: 1) Development of an fluorescent/luminescent assay for detection of counterfeit/substandard antimalarial using small-molecules-based methods and field testing in Ghana; 2) Development of a fluorescent assay for detection of water-soluble pharmaceuticals using SELEX; and 3) Design a detection platform using microfluidic chips for real time quantification of multiple active pharmaceutical ingredients. For proof-of-concept, an antimalarial drug (artesunate and amodiaquine) and antibacterial antibiotics (sulfamethoxazole and trimethoprim) are selected to demonstrate the probe development and test the chip performance. Overall, the assay will be rapid, robust, portable, inexpensive, multiplexed, quantitative, specific, and sensitive. At a big picture level, emphasizing drug quality and creating robust mechanisms of drug testing will improve health outcomes and enhance treatment efficacy in resource limited settings.

Introduction: Emergence of resistance to artemisinin-based combination therapy (ACT) is a major threat to combat Plasmodium falciparum malaria. Regular therapeutic studies to monitor treatment efficacy is essential, and genotyping of molecular makers is useful for mapping development and spread of resistance. Aims: The study aims are to assess efficacy of artesunate-amodiquine (ASAQ) and prevalence of molecular markers of drug resistance in Zanzibar in 2017. Methods: Treatment efficacy of the clinical trial conducted in 2017 was compared with efficacies in 2002 and 2005. A total of 142 samples were genotyped for single nucleotide polymorphisms (SNPs) in the P. falciparum chloroquine resistance transporter gene (pfcrt) gene, the P. falciparum multi drug resistance 1 (pfmdr1) gene, and in the P. falciparum Kelch 13 (PfK13) propeller region. Prevalence of SNPs were assessed during the period 2002-2017. Results: Cure rate was 100% in 2017, compared to 94% and 96%, in 2002-2003 and 2005, respectively. Day 3 fever clearance rate were also high 93% (2002-3), 99% (2005) and 98% (2017) in all studies. Prevalence of pfcrt 76T, pfmdr1 86Y, 184Y and 1246Y and pfmdr1 (86Y, 184Y and 1246Y) YYY haplotypes were significantly decreased between 2002-3 and 2017 (p &lt; 0.001). No SNP in the PfK13 gene related to artemisinin resistance was identified. Conclusion: Efficacy of ASAQ remains high after fourteen years as first-line treatment, despite the wide-scale use of ASAQ, and there is no evidence of selection of resistance markers in Zanzibar. Continuous monitoring of drug efficacy and resistance markers is recommended. / <p>This master thesis is a collaboration project between Institutionen för kvinnors och barns hälsa, Department of Women's and Children's Health, Uppsala Universtiy and Anders Björkman group, Department of Microbiology, Tumor and Cell Biology (MTC), C1, Karolinska Institutet. Laboratory examinations were mainly conducted at MTC house, Karolinska Institutet.</p>