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Widespread of insecticide resistance amongst the species of the Anopheles gambiae complex continues to threaten vector control in Senegal. In this study, we investigated the presence and evolution of the Ace-1 and Gste2 resistance genes in natural populations of Anopheles gambiae s.l., the main malaria vector in Senegal. Using historical samples collected from ten sentinel health districts, this study focused on three different years (2013, 2017, and 2018) marking the periods of shift between the main public health insecticides families (pyrethroids, carbamates, organophosphates) used in IRS to track back the evolutionary history of the resistance mutations on the Ace-1 and Gste2 loci. The results revealed the presence of four members of the Anopheles gambiae complex, with the predominance of An. arabiensis followed by An. gambiae, An. coluzzii, and An. gambiae–coluzzii hybrids. The Ace-1 mutation was only detected in An. gambiae and An. gambiae–coluzzii hybrids at low frequencies varying between 0.006 and 0.02, while the Gste2 mutation was found in all the species with a frequency ranging between 0.02 and 0.25. The Ace-1 and Gste2 genes were highly diversified with twenty-two and thirty-one different haplotypes, respectively. The neutrality tests on each gene indicated a negative Tajima’s D, suggesting the abundance of rare alleles. The presence and spread of the Ace-1 and Gste2 resistance mutations represent a serious threat to of the effectiveness and the sustainability of IRS-based interventions using carbamates or organophosphates to manage the widespread pyrethroids resistance in Senegal. These data are of the highest importance to support the NMCP for evidence-based vector control interventions selection and targeting.

Despite the use of several effective control interventions in the central western Senegal, residual malaria transmission still occurring in some hotspots. In order to better understand the factors associated with this situation to better tailor targeted control actions, it is critical to unravel environmental and geographical factors underlying the persistence of the disease in study hotspot villages. Hotspots villages were defined as those reporting more than six indigenous malaria cases during the previous year. A total of ten villages, including seven hotspots and three non-hotspots, were surveyed. All potential mosquito breeding sites identified in and around the tenth study villages were regularly monitored between 2013 and 2017. This monitoring concerned the presence of anophelines larvae and the collection of epidemiological, hydrogeological, topographical and biogeographical data. Throughout the study area, the number of larval breeding sites inventoried and monitored over the study period ranged from 50 to 62. They were higher, with no significant difference, in hotspot sites than in non-hotspot sites for each year of monitoring with 62.3% (56/62) in 2013, 90.9% (50/55) in 2014, 90.3% (56/62) in 2015 and 86% (43/50) in 2017 (Fisher’s exact test; p = 1). The Hotspot villages were mostly characterized by saline or moderately saline hydro-morphic and halomorphic soils allowing water retention and a suitable presence of potential larval breeding sites. Whereas non-hotspot villages are characterized mainly by a high proportion of extremely permeable sandy-textured soils due to their porosity, which reduces water retention. The annual number of confirmed malaria cases was corelated relatively with the frequency and extent of breeding sites. Malaria cases were much more higher in the hamlets located near to the breeding sites of An. gambiae s.l then gradually decreases with their remoteness. This study has shown that the dynamics of larval breeding sites by their longevity, stability, proximity to houses and their positiveness rate for the presence of Anopheles larvae could be a determining factor in the persistence of malaria hotspots in central western Senegal. The results of this study shed more light on the environmental factors underlying the residual transmission and should make it possible to better organize vector control interventions for malaria elimination in west-central Senegal.

Resume Justificatif Les donnees relatives a la pneumonie a Pneumocystis en Afrique sub-saharienne ne sont pas bien connues. La faiblesse du plateau technique et l’utilisation d’outils de diagnostic biologique peu sensibles sont parmi les raisons evoquees. L’objectif de cette etude est de reactualiser les donnees de l’affection au centre hospitalier universitaire de Fann a Dakar et d’evaluer les methodes de diagnostic biologique utilisees. Materiel et methodes Une etude prospective descriptive est realisee du 5 janvier 2009 au 31 octobre 2011 au service de parasitologie-mycologie du centre hospitalier universitaire de Fann a Dakar. Les prelevements du liquide de lavage broncho-alveolaire recus au laboratoire sont examines au microscope par immunofluorescence indirecte ou apres coloration au Giemsa ou au bleu de toluidine O pour la mise en evidence de Pneumocystis jirovecii. Resultats Cent quatre-vingt-trois prelevements de liquide de lavage broncho-alveolaire provenant de 183 patients sont recus au laboratoire. Seize sont positifs pour la recherche de P. jirovecii , soit une frequence de 9 %. Quatre parmi eux sont infectes par le VIH. L’immunofluorescence indirecte a permis de retrouver P. jirovecii chez les 16 patients alors que la coloration au Giemsa n’a detecte P. jirovecii que chez un seul patient. Aucun cas n’est diagnostique par le bleu de toluidine O. Conclusion La pneumonie a Pneumocystis au laboratoire de parasitologie-mycologie du centre hospitalier universitaire de Fann a Dakar est majoritairement diagnostiquee chez des patients infectes par le VIH.

BACKGROUND Since 2006, artemisinin-based combination therapies (ACT) have been used to treat uncomplicated Plasmodium falciparum malaria in Senegal, as recommended by WHO. Recently, decreased parasite clearance with artemisinin derivatives has been reported in Cambodia and Thailand. The effectiveness of artemisinin derivatives in Africa must be monitored. This study was conducted to evaluate the efficacy and the tolerability of three ACT widely used in Senegal. METHODS From October 2010 to February 2011, a descriptive and analytical sequential study was conducted in adults and children to evaluate these three combinations: artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ), and dihydroartemisinin-piperaquine (DHAPQ). The study took place at the health posts of Deggo and Pikine and the health center of Guediawaye, in the suburbs of Dakar. The primary endpoint was the PCR-corrected adequate clinical and parasitological response (ACPR) at day 28 (D28); the secondary endpoints included ACPR at D42, clearance times for parasites, fever, and gametocytes, and the incidence of adverse events. RESULTS The study included 393 patients: 139 in the AL group, 130 in the ASAQ group, and 124 in the DHAPQ group. In the intent-to-treat population, PCR-corrected ACPR at day 28 was 92.8% in the AL, 89.2% in the ASAQ, and 91.1% in the DHAPQ (p = 0.58) groups, and in the per-protocol population, 98.4%, 98.3%, and 100% respectively (p = 0.39). At D42, ACPR was 99.2% in the AL, and 99.1% in each of the ASAQ and DHAPQ arms (p = 1). No early therapeutic failure (ETF) was observed. The combinations were well tolerated, with no serious adverse events reported during the follow-up period. CONCLUSION These combinations are still effective and well-tolerated. Continued monitoring is nonetheless essential to detect early artemisinin resistance in Africa.

Resume La regression de l’endemie palustre constatee dans certaines zones au centre du Senegal laisse entrevoir l’espoir d’une elimination de cette pathologie qui constitue un lourd fardeau en termes de morbidite et de mortalite. En effet dans les districts de Mbour, Fatick, Niakhar et Bambey, situes au centre-ouest du Senegal, le paludisme evolue en foyers de transmissions residuelles (hot spots) suite aux efforts de lutte realises ces dernieres annees. Le but de cet essai d’elimination est de mener une lutte intensifiee et ciblee sur les hot spots en utilisant des strategies a efficacite prouvee a savoir l’aspersion intradomiciliaire (AID) d’insecticide a effet remanent et la chimio prevention. L’AID est une intervention tres lourde dans sa mise en oeuvre et necessite une grande adhesion des populations. Apres sa mise en oeuvre en aout 2013 au niveau de 4 districts du centre-ouest du Senegal, une enquete d’acceptabilite de l’intervention a ete realisee sur un echantillon aleatoire de 370 menages. Les resultats de cette enquete ont revele une bonne acceptabilite de l’intervention avec 97,8 % des personnes interrogees qui jugent que l’AID est bien et meme excellente pour la communaute. Malgre les desagrements que peuvent engendrer cette activite, notamment la preparation des structures a traiter, 98 % des personnes interrogees estiment ne pas avoir ete perturbees dans leurs activites quotidiennes. Le comportement des applicateurs a ete juge exemplaire et professionnel par 98,6 % de l’echantillon de menages et la quasi-totalite (99,7 %) accepteraient que leurs structures soient traitees a nouveau l’annee suivante. Sur le plan pratique, la pulverisation avec l’Actellic ® 300 CS (pirimiphos-methyl, organophosphore) n’a pas occasionne de problemes majeurs aux populations beneficiaires. Au final, nous avons constate une grande satisfaction de la population des villages traites, en particulier en raison d’une forte reduction des nuisances causees par les insectes.

Malaria transmission is in decline in some parts of Africa, partly due to the scaling up of control measures. If the goal of elimination is to be achieved, additional control measures including an effective and durable vaccine will be required. Studies utilising the prime-boost approach to deliver viral vectors encoding the pre-erythrocytic antigen ME-TRAP (multiple epitope thrombospondin-related adhesion protein) have shown promising safety, immunogenicity and efficacy in sporozoite challenge studies. More recently, a study in Kenyan adults, similar to that reported here, showed substantial efficacy against P. falciparum infection. One hundred and twenty healthy male volunteers, living in a malaria endemic area of Senegal were randomised to receive either the Chimpanzee adenovirus (ChAd63) ME-TRAP as prime vaccination, followed eight weeks later by modified vaccinia Ankara (MVA) also encoding ME-TRAP as booster, or two doses of anti-rabies vaccine as a comparator. Prior to follow-up, antimalarials were administered to clear parasitaemia and then participants were monitored by PCR for malaria infection for eight weeks. The primary endpoint was time-to-infection with P. falciparum malaria, determined by two consecutive positive PCR results. Secondary endpoints included adverse event reporting, measures of cellular and humoral immunogenicity and a meta-analysis of combined vaccine efficacy with the parallel study in Kenyan adults.We show that this pre-erythrocytic malaria vaccine is safe and induces significant immunogenicity, with a peak T-cell response at seven days after boosting of 932 Spot Forming Cells (SFC)/106 Peripheral Blood Mononuclear Cells(PBMC) compared to 57 SFC/ 106 PBMCs in the control group. However, a vaccine efficacy was not observed: 12 of 57 ME-TRAP vaccinees became PCR positive during the intensive monitoring period as compared to 13 of the 58 controls (P = 0.80). This trial confirms that vaccine efficacy against malaria infection in adults may be rapidly assessed using this efficient and cost-effective clinical trial design. Further efficacy evaluation of this vectored candidate vaccine approach in other malaria transmission settings and age-de-escalation into the main target age groups for a malaria vaccine is in progress.

Background It is recommended that children aged 3 months to five years of age living in areas of seasonal transmission in the sub-Sahel should receive Seasonal Malaria Chemoprevention (SMC) with sulfadoxine-pyrimethamine plus amodiaquine (SPAQ) during the malaria transmission season. The purpose of this study was to evaluate the safety of SMC with SPAQ in children when delivered by community health workers in three districts in Senegal where SMC was introduced over three years, in children from 3 months of age to five years of age in the first year, then in children up to 10 years of age. Methods A surveillance system was established to record all deaths and all malaria cases diagnosed at health facilities and a pharmacovigilance system was established to detect adverse drug reactions. Health posts were randomized to introduce SMC in a stepped wedge design. SMC with SPAQ was administered once per month from September to November, by nine health-posts in 2008, by 27 in 2009 and by 45 in 2010. Results After three years, 780,000 documented courses of SMC had been administered. High coverage was achieved. No serious adverse events attributable to the intervention were detected, despite a high level of surveillance. Conclusions SMC is being implemented in countries of the sub-Sahel for children under 5 years of age, but in some areas the age distribution of cases of malaria may justify extending this age limit, as has been done in Senegal. Our results show that SMC is well tolerated in children under five and in older children. However, pharmacovigilance should be maintained where SMC is implemented and provision for strengthening national pharmacovigilance systems should be included in plans for SMC implementation. Trial Registration ClinicalTrials.gov NCT 00712374

Physicochemical Problems of Mineral Processing; ISSN 2083-3989

WWARN Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group; International audience; Background: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs). Methods: A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in included studies was evaluated based on study design, methodology and missing data. Results: In total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine (n = 13,664), artesunate-amodiaquine (n = 11,337) and dihydroartemisinin-piperaquine (n = 4,492). The overall parasite clearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5–64.9) on day 1 to 6.7 % (95 % CI: 4.8–8.7) on day 2 and 0.9 % (95 % CI: 0.5–1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %. Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08–1.25); per 2-fold increase in parasite density, P 37.5 °C) (AOR = 1.50 (95 % CI: 1.06–2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21–3.44), P = 0.008); areas of low/moderate transmission setting (AOR = 2.71 (95 % CI: 1.38–5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR = 2.27 (95 % CI: 1.14–4.51), P = 0.020, compared to dihydroartemisinin-piperaquine). Conclusions: The three ACTs assessed in this analysis continue to achieve rapid early parasitological clearance across the sites assessed in Sub-Saharan Africa. A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility.

Background Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria. Methods Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites. Results Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P