Monitoring the efficacy and safety of three artemisinin based-combinations therapies in Senegal: results from two years surveillance

BACKGROUND: Malaria remains a major public health problem in developing countries. Then in these countries prompt access to effective antimalarial treatment such as Artemisinin based-Combination Therapies (ACT) proves to be an essential tool for controlling the disease. In Senegal, since 2006 a nationwide scaling up program of ACT is being implemented. In this context it has become relevant to monitor ACT efficacy and provide recommendations for the Senegalese national malaria control program. METHODS: An open randomized trial was conducted during two malaria transmission seasons (2011 and 2012) to assess the efficacy and safety of three combinations: dihydro-artemisinin-piperaquine (DHAPQ), artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ). The primary end point of the study was represented by a PCR adjusted adequate clinical and parasitological response (ACPR) at day 28. Secondary end points included: (i) a ACPR at days 35 and 42, (ii) a parasite and fever clearance time, (iii) ACTs safety and tolerability. The 2003 WHO’s protocol for antimalarial drug evaluation was used to assess each outcome. RESULTS: Overall, 534 patients were randomized selected to receive, either ASAQ (n = 180), AL (n = 178) or DHAPQ (n = 176). The PCR adjusted ACPR at day 28 was 99.41% for the group ASAQ, while that was 100% in the AL and DHAPQ groups (p = 0.37). The therapeutic efficacy was evaluated at 99.37% in the ASAQ arm versus 100% in AL and DHAPQ arm at day 35 (p = 0.37). At day 42, the ACPR was 99.27% in the ASAQ group versus 100% for both AL and DHAPQ groups, (p = 0.36). No serious adverse event was noted during the study period. Also a similar safety profile was noted in the 3 study groups. CONCLUSION: In the context of scaling up of ACTs in Senegal, ASAQ, AL and DHAPQ are highly effective and safe antimalarial drugs. However, it’s remains important to continue to monitor their efficacy. TRIAL REGISTRATION: PACTR 201305000552290

Estimation of the number of seriously injured road users in France, 2006-2015

European Congress of Epidemiology, LYON, FRANCE, 04-/07/2018 - 06/07/2018Background The European Commission requests its member states to provide the number of serious road injuries, according to MAIS 3+=Maximum AIS 3+, where AIS=Abbreviated Injury Scale. This challenges in all countries the issue of under-reporting of road injuries in the official police data and the issue of using a medical trauma scale. Methods In France, as in most countries, police data provide the frequency of road casualties, but they suffer from large under-reporting and strong selection bias (on severity, mode of transport, etc). In the Rhone county (pop 1.6M inhabitants). Other data are available: a road trauma registry has been set up in 1996. It covers fatalities, hospitalized, and those attending the Emergency departments only. All injuries are directly coded into the Abbreviated Injury Scale, by the registry physician. At the Rhône county level, both databases are linked. Annually, on the 2006-2012 period, the police reports 2800 casualties, the road trauma registry 7400 by the registry and 1700 are identified as common to both sources. A capture-recapture approach is then used, so that we can estimate the real number of road casualties (in the Rhône). More importantly the corrections factors between the police data and the estimated real subgroup of road causalities in the Rhône. In particular, to account for some conditions for applying capture-recapture, a multivariate model is used, including the variables that are associated with lower probability of reporting by the police: type of police, road network, severity measured by hospitalised (yes/no), MAIS3+, road user type (pedestrian, cyclist, car occupant...), whether the crash involved a crash opponent or not, etc. The police correction factors are finally applied to the national police data with the assumption that police recording practices are rather homogenous across France, by type of police force, and type of road casualties, This corresponds to indirect standardization, not on age and sex as usual but on the characteristics influencing police reporting. Results The national number of injured road casualties, respectively for all severity, and for MAIS3+, are estimated at 285,000 and 24,000 resp. in 2015. The 2015 frequency of sMAIS3+ roadusers consists of 6850 motorized two-wheel users, 6500 car occupants, 3550 cyclists, 3500 pedestrians and 800 others (van, bus, truck users). This confirms the heavy burden suffered by Motorized two-wheel users. Moreover, they only account for 2% of traveled kilometers whereas car occupants account for 70% of traveled kilometers. Also, these results show a different pattern than the number of fatalities, where it is the number of killed car occupants that is the highest. Conclusions The frequency of injured road users, all severities, has been confirmed by other sources, namely: the French national Travel Survey, and by the annual firemen data (they provide first aid on crash scene). Concerning the number of seriously injured road users, the ratio of the number of MAIS3+ casualties divided by the number of fatalities enables country to country comparison

Randomized Trial of Piperaquine with Sulfadoxine-Pyrimethamine or Dihydroartemisinin for Malaria Intermittent Preventive Treatment in Children

BACKGROUND: The long terminal half life of piperaquine makes it suitable for intermittent preventive treatment for malaria but no studies of its use for prevention have been done in Africa. We did a cluster randomized trial to determine whether piperaquine in combination with either dihydroartemisin (DHA) or sulfadoxine-pyrimethamine (SP) is as effective, and better tolerated, than SP plus amodiaquine (AQ), when used for intermittent preventive treatment in children delivered by community health workers in a rural area of Senegal. METHODS: Treatments were delivered to children 3-59 months of age in their homes once per month during the transmission season by community health workers. 33 health workers, each covering about 60 children, were randomized to deliver either SP+AQ, DHA+PQ or SP+PQ. Primary endpoints were the incidence of attacks of clinical malaria, and the incidence of adverse events. RESULTS: 1893 children were enrolled. Coverage of monthly rounds and compliance with daily doses was similar in all groups; 90% of children received at least 2 monthly doses. Piperaquine combinations were better tolerated than SP+AQ with a significantly lower risk of common, mild adverse events. 103 episodes of clinical malaria were recorded during the course of the trial. 68 children had malaria with parasitaemia >3000/microL, 29/671 (4.3%) in the SP+AQ group, compared with 22/604 (3.6%) in the DHA+PQ group (risk difference 0.47%, 95%CI -2.3%,+3.3%), and 17/618 (2.8%) in the SP+PQ group (risk difference 1.2%, 95%CI -1.3%,+3.6%). Prevalences of parasitaemia and the proportion of children carrying Pfdhfr and Pfdhps mutations associated with resistance to SP were very low in all groups at the end of the transmission season. CONCLUSIONS: Seasonal IPT with SP+PQ in children is highly effective and well tolerated; the combination of two long-acting drugs is likely to impede the emergence of resistant parasites. TRIAL REGISTRATION: ClinicalTrials.gov NCT00529620

Large-scale delivery of seasonal malaria chemoprevention to children under 10 in Senegal: an economic analysis.

Seasonal Malaria Chemoprevention (SMC) is recommended for children under 5 in the Sahel and sub-Sahel. The burden in older children may justify extending the age range, as has been done effectively in Senegal. We examine costs of door-to-door SMC delivery to children up to 10 years by community health workers (CHWs). We analysed incremental financial and economic costs at district level and below from a health service perspective. We examined project accounts and prospectively collected data from 405 CHWs, 46 health posts, and 4 district headquarters by introducing questionnaires in advance and completing them after each monthly implementation round. Affordability was explored by comparing financial costs of SMC to relevant existing health expenditure levels. Costs were disaggregated by administration month and by health service level. We used linear regression models to identify factors associated with cost variation between health posts. The financial cost to administer SMC to 180 000 children over one malaria season, reaching ∼93% of children with all three intended courses of SMC was $234 549 (constant 2010 USD) or$0.50 per monthly course administered. Excluding research-participation incentives, the financial cost was $0.32 per resident (all ages) in the catchment area, which is 1.2$278 922 or $0.59 per course administered and varied widely between health posts, from$0.38 to $2.74 per course administered. Substantial economies of scale across health posts were found, with the smallest health posts incurring highest average costs per monthly course administered. SMC for children up to 10 is likely to be affordable, particularly where it averts substantial curative care costs. Estimates of likely costs and cost-effectiveness of SMC in other contexts must account for variation in average costs across delivery months and health posts

Estimation du nombre de blessés graves de la route, au sens MAIS3+, en Ile de France

En termes de blessés de la route, la Commission Européenne demande dorénavant à ses États Membres d'estimer le nombre de blessés graves selon un critère médical, le MAIS3+ (Maximum Abbreviated Injury Score). Le Registre du Rhône des victimes d'accidents de la circulation fournit directement ce critère, et permet par modélisations successives, basées sur la coexistence de ce Registre et des données des forces de l'ordre, d'estimer le nombre de blessés graves MAIS3+ au niveau national. Il est ainsi estimé à 25 400 en 2016, au niveau national, et à 5000 en Ile de France. Les estimations sur l'Ile de France, et encore plus sur Paris, sont à lire avec prudence, car les pratiques d'enregistrement des forces de l'ordre, notamment de la préfecture de Police de Paris, peuvent différer de celles du Rhône. Il ressort un fort effectif de blessés graves des usagers de deux-roues motorisés, et un effectif important de blessés graves piétons et cyclistes

Clinical tolerability of artesunate-amodiaquine versus comparator treatments for uncomplicated falciparum malaria: an individual-patient analysis of eight randomized controlled trials in sub-Saharan Africa

BACKGROUND: The widespread use of artesunate-amodiaquine (ASAQ) for treating uncomplicated malaria makes it important to gather and analyse information on its tolerability. METHODS: An individual-patient tolerability analysis was conducted using data from eight randomized controlled clinical trials conducted at 17 sites in nine sub-Saharan countries comparing ASAQ to other anti-malarial treatments. All patients who received at least one dose of the study drug were included in the analysis. Differences in adverse event (AE) and treatment emergent adverse event (TEAE) were analysed by Day 28. RESULTS: Of the 6,179 patients enrolled (74% <5 years of age), 50% (n = 3,113) received ASAQ, 20% (n = 1,217) another ACT, and 30% (n = 1,849) a non-ACT (combination or single-agent) treatment. Overall, 8,542 AEs were recorded. The proportion of patients experiencing at least one gastro-intestinal AE on ASAQ was 43% (and higher than that with artemether-lumefantrine and dihydroartemisinin-piperaquine at two sites), and was 23% for any other AEs (not different from other treatments). Specifically, the risk of diarrhoea, vomiting, cough and weakness was lower with artemether-lumefantrine; artemether-lumefantrine and dihydroartemisinin-piperaquine carried a higher risk of pruritus, chloroquine-SP had a higher risk of nausea. Parasitological recurrence increased the risk of occurrence of any AE. No other difference was detected. Comparing AE to TEAE in patients who had pre-treatment occurrence and grades of intensity recorded, AEs were significantly more related to the pre-treatment prevalence of the symptom (p = 0.001, Fisher test); AEs overestimated TEAEs by a factor ranging from none to five-fold. The overall incidence of serious AEs (SAEs) with ASAQ was nine per 1,000 (29/3,113) and mortality was one per 1,000 (three deaths, none drug-related); both were similar to other treatments. CONCLUSION: ASAQ was comparatively well-tolerated. Safety information is important, and must be collected and analysed in a standardized way. TEAEs are a more objective measure of treatment-induced toxicity

Safety and Efficacy of Adding a Single Low Dose of Primaquine to the Treatment of Adult Patients With Plasmodium falciparum Malaria in Senegal, to Reduce Gametocyte Carriage: A Randomized Controlled Trial.

Introduction: More information is needed about the safety of low-dose primaquine in populations where G6PD deficiency is common. Methods: Adults with Plasmodium falciparum malaria were randomized to receive 1 of 3 artemisinin combination therapies (ACTs) with or without primaquine (0.25 mg/kg). Glucose-6-phosphate dehydrogenase (G6PD) status was determined using a rapid test. Patients were followed for 28 days to record hemoglobin concentration, adverse events, and gametocyte carriage. The primary end point was the change in Hb at day 7. Results: In sum, 274 patients were randomized, 139 received an ACT alone, and 135 received an ACT + primaquine. The mean reduction in Hb at day 7 was similar in each group, a difference in the ACT + PQ versus the ACT alone group of -0.04 g/dL (95% confidence interval [CI] -0.23, 0.31), but the effect of primaquine differed according to G6PD status. In G6PD-deficient patients the drop in Hb was 0.63 g/dL (95% CI 0.03, 1.24) greater in those who received primaquine than in those who received an ACT alone. In G6PD-normal patients, the reduction in Hb was 0.22 g/dL (95% CI -0.08, 0.52) less in those who received primaquine (interaction P = .01). One G6PD normal patient who received primaquine developed moderately severe anaemia (Hb < 8 g/dL). Dark urine was more frequent in patients who received primaquine. Primaquine was associated with a 73% (95% CI 24-90) reduction in gametocyte carriage (P = .013). Conclusion: Primaquine substantially reduced gametocyte carriage. However, the fall in Hb concentration at day 7 was greater in G6PD-deficient patients who received primaquine than in those who did not and one patient who received primaquine developed moderately severe anemia. Clinical Trial registration: PACTR201411000937373 (www.pactr.org)

Application of geographically-weighted regression analysis to assess risk factors for malaria hotspots in Keur Soce health and demographic surveillance site.

BACKGROUND: In Senegal, considerable efforts have been made to reduce malaria morbidity and mortality during the last decade. This resulted in a marked decrease of malaria cases. With the decline of malaria cases, transmission has become sparse in most Senegalese health districts. This study investigated malaria hotspots in Keur Soce sites by using geographically-weighted regression. Because of the occurrence of hotspots, spatial modelling of malaria cases could have a considerable effect in disease surveillance. METHODS: This study explored and analysed the spatial relationships between malaria occurrence and socio-economic and environmental factors in small communities in Keur Soce, Senegal, using 6 months passive surveillance. Geographically-weighted regression was used to explore the spatial variability of relationships between malaria incidence or persistence and the selected socio-economic, and human predictors. A model comparison of between ordinary least square and geographically-weighted regression was also explored. Vector dataset (spatial) of the study area by village levels and statistical data (non-spatial) on malaria confirmed cases, socio-economic status (bed net use), population data (size of the household) and environmental factors (temperature, rain fall) were used in this exploratory analysis. ArcMap 10.2 and Stata 11 were used to perform malaria hotspots analysis. RESULTS: From Jun to December, a total of 408 confirmed malaria cases were notified. The explanatory variables-household size, housing materials, sleeping rooms, sheep and distance to breeding site returned significant t values of -0.25, 2.3, 4.39, 1.25 and 2.36, respectively. The OLS global model revealed that it explained about 70 % (adjusted R(2) = 0.70) of the variation in malaria occurrence with AIC = 756.23. The geographically-weighted regression of malaria hotspots resulted in coefficient intercept ranging from 1.89 to 6.22 with a median of 3.5. Large positive values are distributed mainly in the southeast of the district where hotspots are more accurate while low values are mainly found in the centre and in the north. CONCLUSION: Geographically-weighted regression and OLS showed important risks factors of malaria hotspots in Keur Soce. The outputs of such models can be a useful tool to understand occurrence of malaria hotspots in Senegal. An understanding of geographical variation and determination of the core areas of the disease may provide an explanation regarding possible proximal and distal contributors to malaria elimination in Senegal

Haemoglobin changes and risk of anaemia following treatment for uncomplicated falciparum malaria in sub-Saharan Africa.

BACKGROUND: Anaemia is common in malaria. It is important to quantitate the risk of anaemia and to distinguish factors related to the natural history of disease from potential drug toxicity. METHODS: Individual-patient data analysis based on nine randomized controlled trials of treatments of uncomplicated falciparum malaria from 13 sub-Saharan African countries. Risk factors for reduced haemoglobin (Hb) concentrations and anaemia on presentation and after treatment were analysed using mixed effect models. RESULTS: Eight thousand eight hundred ninety-seven patients (77.0% <5 years-old) followed-up through 28 days treated with artemisinin combination therapy (ACT, 90%, n = 7968) or non-ACT. At baseline, under 5's had the highest risk of anaemia (77.6% vs. 32.8%) and higher parasitaemia (43,938 μl) than older subjects (2784 μl). Baseline anaemia increased the risk of parasitological recurrence. Hb began to fall after treatment start. In under 5's the estimated nadir was ~35 h (range 29-48), with a drop of -12.8% from baseline (from 9.8 g/dl to 8.7 g/dl, p = 0.001); in under 15's, the mean Hb decline between day 0-3 was -4.7% (from 9.4 to 9.0 g/dl, p = 0.001). The degree of Hb loss was greater in patients with high pre-treatment Hb and parasitaemia and with slower parasite reduction rates, and was unrelated to age. Subsequently, Hb increased linearly (+0.6%/day) until day 28, to reach +13.8% compared to baseline. Severe anaemia (<5 g/dl, 2 per 1000 patients) was transient and all patients recovered after day 14, except one case of very severe anaemia associated with parasite recurrence at day 28. There was no systematic difference in Hb concentrations between treatments and no case of delayed anaemia. CONCLUSION: On presentation with acute malaria young children with high parasitaemia have the highest risk of anaemia. The majority of patients experience a drop in Hb while on treatment as early as day 1-2, followed by a linear increase through follow-up. The degree of the early Hb dip is determined by pre-treatment parasitaemia and parasite clearance rates. Hb trends and rick of anaemia are independent of treatment