Efficacy of non-artemisinin- and artemisinin-based combination therapies for uncomplicated falciparum malaria in Cameroon

<p>Abstract</p> <p>Background</p> <p>The use of drug combinations, including non-artemisinin-based and artemisinin-based combination therapy (ACT), is a novel strategy that enhances therapeutic efficacy and delays the emergence of multidrug-resistant <it>Plasmodium falciparum</it>. Its use is strongly recommended in most sub-Saharan African countries, namely Cameroon, where resistance to chloroquine is widespread and antifolate resistance is emerging.</p> <p>Methods</p> <p>Studies were conducted in Cameroonian children with acute uncomplicated <it>P. falciparum </it>malaria according to the standard World Health Organization protocol at four sentinel sites between 2003 and 2007. A total of 1,401 children were enrolled, of whom 1,337 were assigned to randomized studies and 64 were included in a single non-randomized study. The proportions of adequate clinical and parasitological response (PCR-uncorrected on day 14 and PCR-corrected on day 28) were the primary endpoints to evaluate treatment efficacy on day 14 and day 28. The relative effectiveness of drug combinations was compared by a multi-treatment Bayesian random-effect meta-analysis.</p> <p>Findings</p> <p>The results based on the meta-analysis suggested that artesunate-amodiaquine (AS-AQ) is as effective as other drugs (artesunate-sulphadoxine-pyrimethamine [AS-SP], artesunate-chlorproguanil-dapsone [AS-CD], artesunate-mefloquine [AS-MQ], dihydroartemisinin-piperaquine [DH-PP], artemether-lumefantrine [AM-LM], amodiaquine, and amodiaquine-sulphadoxine-pyrimethamine [AQ-SP]). AM-LM appeared to be the most effective with no treatment failure due to recrudescence, closely followed by DH-PP.</p> <p>Conclusion</p> <p>Although AM-LM requires six doses, rather than three doses for other artemisinin-based combinations, it has potential advantages over other forms of ACT. Further studies are needed to evaluate the clinical efficacy and tolerance of these combinations in different epidemiological context.</p

Methodological approaches for analysing data from therapeutic efficacy studies

International audienceSeveral anti-malarial drugs have been evaluated in randomized clinical trials to treat acute uncomplicated Plasmodium falciparum malaria. The outcome of anti-malarial drug efficacy studies is classified into one of four possible outcomes defined by the World Health Organization: adequate clinical and parasitological response, late parasitological failure, late clinical failure, early treatment failure. These four ordered categories are ordinal data, which are reduced to either a binary outcome (i.e., treatment success and treatment failure) to calculate the proportions of treatment failure or to time-to-event outcome for Kaplan–Meier survival analysis. The arbitrary transition from 4-level ordered categories to 2-level type categories results in a loss of statistical power. In the opinion of the authors, this outcome can be considered as ordinal at a fixed endpoint or at longitudinal endpoints. Alternative statistical methods can be applied to 4-level ordinal categories of therapeutic response to optimize data exploitation. Furthermore, network meta-analysis is useful not only for direct comparison of drugs which were evaluated together in a randomized design, but also for indirect comparison of different artemisinin-based combinations across different clinical studies using a common drug comparator, with the aim to determine the ranking order of drug efficacy. Previous works conducted in Cameroonian children served as data source to illustrate the feasibility of these novel statistical approaches. Data analysis based on ordinal end-point may be helpful to gain further insight into anti-malarial drug efficacy

Multiple treatment comparisons in a series of anti-malarial trials with an ordinal primary outcome and repeated treatment evaluations

<p>Abstract</p> <p>Background</p> <p>Artemisinin-based combination therapies (ACT) are widely used in African countries, including Cameroon. Between 2005 and 2007, five randomized studies comparing different treatment arms among artesunate-amodiaquine and other ACT were conducted in Cameroonian children aged two to 60 months who had uncomplicated <it>Plasmodium falciparum</it> malaria. In these studies, the categorical criterion proposed by the World Health Organization (WHO) to assess the relative effectiveness of anti-malarial drugs was repeatedly evaluated on Days 14, 21 and 28 after treatment initiation. The aim of the present study was to compare the effects of different treatments on this repeated ordinal outcome, hence using the fully available information.</p> <p>Methods</p> <p>The quantitative synthesis was based on individual patient data. Due to the incomplete block design concerning treatment arms between different trials, a mixed treatment comparison (MTC) meta-analysis approach was adopted. The repeated ordinal outcome was modelled through a latent variable, as a proportional odds mixed model with trial, period and treatment arms as covariates. The model was further complexified to account for the variance heterogeneity, and the individual log-residual variance was modelled as a linear mixed model, as well. The effects of individual covariates at inclusion, such as parasitaemia, fever, gender and weight, were also tested. Model parameters were estimated using a Bayesian approach <it>via</it> the WinBUGS software. After selecting the best model using Deviance Information Criterion (DIC), mixed treatment comparisons were based on the estimated treatment effects.</p> <p>Results</p> <p>Modeling the residual variance improved the model ability to adjust the data. The results showed that, compared to artesunate-amodiaquine (ASAQ), dihydroartemisinin-piperaquine (DHPP) was significantly more efficacious. Artesunate-chlorproguanil-dapsone (ASCD) was less efficacious than artesunate-sulphadoxine-pyrimethamine (ASSP), artemether-lumefantrine (AMLM) and DHPP, the difference with the latter being significant. No difference in efficacy was found between ASAQ and AMLM.</p> <p>Conclusions</p> <p>Bayesian mixed treatment comparisons of a network of connected randomized trials with repeated measurements of the primary categorical outcome allowed to take into account both the individual- and between- studies sources of heterogeneity. The results of the present study complete the previous quantitative review based on a binary outcome at a fixed time point, suggesting that DHPP represents an alternative for the treatment of uncomplicated <it>P. falciparum</it> malaria in Cameroonian children.</p

Monitoring the Efficacy and Safety of Artemisinin-Based Combination Therapies: A Review and Network Meta-analysis of Antimalarial Therapeutic Efficacy Trials in Cameroon

International audienc

Comparison of anti-malarial drugs efficacy in the treatment of uncomplicated malaria in African children and adults using network meta-analysis

International audienceBackground: Artemisinin-based combination therapy (ACT) and novel drug combinations are available and used in African countries to treat uncomplicated malaria. Network meta-analysis methods are rarely and poorly applied for the comparison of their efficacies. This method was applied on a set of randomized controlled trials to illustrate its usefulness. Methods: A literature review available in Pubmed was conducted in July 2016. Eligible studies, conducted in sub-Saharan Africa, published between 2002 and 2016, focused on randomized controlled trials of at least two artemisinin-based combinations to treat uncomplicated malaria in children and adults. Agglomerate data were: the number of PCR-corrected adequate clinical and parasitological response (ACPR) on day 28, used as the primary enDHAPoint in all interventions, the number of participants and the list of treatments. A Bayesian random effect meta-analysis using a binary outcome was the method to compare the efficacy. Ranking measure was used to obtain a hierarchy of the competing interventions. Results: In total, 76 articles were included; 13 treatment regimens were involved and tested in 36,001 patients. Using artemether-lumefantrine (AL) as the common comparator for the entire network, 12 relative treatment effects were estimated and indirect comparisons were obtained. Dihydroartemisinin-piperaquine (DHAP) was shown to be more effective than AL (odds ratio [OR] = 1.92; 95% CI 1.30-2.82; 19,163 patients), ASAQ (OR = 1.70; 95% CI 1.10-2.64; 14,433 patients), and amodiaquine-sulfadoxine-pyrimethamine (AQSP): OR = 2.20; 95% CI 1.21-3.96; 8863 patients. Artesunate-amodiaquine (ASAQ) was comparable to AL (OR = 1.11; 95% CI 0.84-1.45; 21,235 patients). No significant difference was found between artesunate and mefloquine (ASMQ) and AL (OR = 1.20; 95% CI = 0.52-2.8; 13,824 participants). According to treatment ranking, among the WHO-recommended ACT medicines, DHAP was shown to be the most efficacious. Conclusions: Based on the available evidence, this study demonstrated the superiority of DHAP among currently recommended artemisinin-based combinations. The application of the methods described here may be helpful to gain better understanding of treatment efficacy and improve future decisions. However, more data are needed to allow robust conclusions about the results in comparison with novel drugs. Further surveillance of the efficacy of anti-malarial drugs and clinical trials are needed to closely follow the evolution of the epidemiology of drug-resistant malaria in Africa

Coding for dummies

Additional file 3. Forest plots and other direct and indirect comparisons. Direct and indirect comparisons are extracted from the model with inconsistency

MOESM3 of Comparison of anti-malarial drug efficacy in the treatment of uncomplicated malaria in African children and adults using network meta-analysis

Additional file 3. Forest plots and other direct and indirect comparisons. Direct and indirect comparisons are extracted from the model with inconsistency

Timeliness and missed opportunities for vaccination among children aged 0 to 23 months in Dschang health district, West region, Cameroon: A cross-sectional survey.

Missed opportunities for vaccination (MOV) reflect quality of immunization service. The objective of this study was to assess vaccination timeliness, prevalence, and characteristics of MOVs among children aged 0-23 months, as well as knowledge, attitude and practice of health workers towards immunization. An exit interview method was used to select caregivers and health personnel. Selection took place in 26 health facilities within 14 health areas in the Dshcang Health district. Data were collected using two face-to-face questionnaires adapted from the World Health Organization (WHO) tools. We conducted an evaluation of all free vaccines in the Expanded Programme on Immunisation (EPI). We studied timeliness, assessed MOV, and knowledge, behaviour and attitude of health workers on immunization. Basic statistical tests were used to study the association between MOV and socio demographic characteristics. A total of 363 children aged 0 to 23 months were surveyed. A total of 88 (91.66%) of health personnel agreed to participate in our study. A total of 298 (82.1%) children had vaccination cards with dates, leading to 18% not completely vaccinated. Vaccination timeliness ranged from 20% to 77%. Overall MOV estimated was 23.83%, range from 0% to 16.4% among all vaccines. Among health workers, 70.45% (62/88) had insufficient knowledge on vaccination, 73.86% assessed the vaccination status of children during any routine visit and 74% ask parents to bring the child's vaccination record to any health facility visit. The study highlighted presence of MOV among children. Strategies for remedying this includes strengthening parents' knowledge, organizing refresher courses for health workers on vaccination, and systematically assessing children's vaccination status

Méthodologies d'évaluation de l'efficacité thérapeutique des antipaludiques (application à des données du Cameroun)

Le sujet de cette thèse s'inscrit dans un contexte commun aux pays d'Afrique sub-saharienne, celui des évaluations des stratégies thérapeutiques et des choix des politiques de santé publique dans la lutte contre le paludisme. Il concerne les méthodes d'évaluation globale de l'efficacité thérapeutique des antipaludiques qui s'attachent aux techniques de méta-analyse de comparaisons mixtes de traitements. D'une part, le critère principal préconisé par l'OMS dans les essais d'antipaludiques est un critère ordinal. D'autre part, les différents bras thérapeutiques dans les essais ne concernent pas toujours les mêmes bras de combinaisons thérapeutiques et la durée totale d'évaluation entre essais a changé au cours des années. Enfin, le critère ordinal d'évaluation préconisé entraine des répartitions déséquilibrées dans les réponses. Nous avons travaillé sur un jeu de données correspondant à une série d'essais menés entre 2003 et 2007, chez l'enfant de moins de 5 ans au Cameroun, suivant les recommandations OMS. La première étape du travail a emprunté des techniques d'analyse classique de meta-analyse sur un critère binaire pour comparer l'ensemble des traitements de tous les essais. Le caractère ordinal de la réponse dans des essais à plus de 2 bras de traitement et temps unique d'évaluation de ce critère a été ensuite analysé, en s'appuyant sur une étude par simulation pour évaluer les risques associés de première et seconde espèces en fonction de l'amplitude de l'effet traitement. La méthode a été étendue aux données répétées dans le temps à 14, 21 et 28 jours de traitement.La prise en compte de l'ordinalité du critère a permis d'obtenir des résultats significatifsThis work was motivated by a health context which is common to all subsaharian African countries. It is directly related to the evaluation of the therapeutical strategies and the public health decisions in the fight against malaria. It concerns the quantitative methods for pooling randomised trials and estimating the efficacy of the various antimalarial drugs.First, the primary outcome developed by the WHO is an ordinal one. Second, the different treatment arms between the trials are not always the same combined treatments and, the follow up durations changed over the years. Third, the observed counts between the different categories of responses are highly unbalanced. In the first step method, a global classical meta-analysis pooling all the trials was carried out using as primary outcome a binarised WHO outcome. In a second step, the primary outcome was analysed as an ordinal outcome at a fixed time endpoint in a single three- arm randomised clinical trial. A simulation study was performed to assess the type- 1 and type-2 errors in relation to the treatment effect. In a third step, the 28- day trials were pooled by extending the previous methodology to the repeated measurements on days 14, 21 and 28. Significant results were obtained when analyzing the WHO outcome as ordinal.PARIS5-BU Saints-Pères (751062109) / SudocSudocFranceF

Midlife Dietary Vitamin D Intake and Subsequent Performance in Different Cognitive Domains

International audienceBackground/Aims: We evaluated the cross-time association between midlife dietary vitamin D intake and subsequent cognitive performance in a French general-population sample. Methods: Data from participants in both the SU.VI.MAX trial (1994-2002) and the SU.VI.MAX 2 observational study (2007-2009) were used. Dietary intake was estimated at baseline from 6 or more 24-hour records. Cognitive performance was evaluated 13 years later with a comprehensive neuropsychological battery. Parameter estimates of cognitive performance according to quartiles (Q) of vitamin D intake were estimated via ANCOVA. Results: In a sample of 1,990 aging adults, principal component analyses yielded two cognitive factors - for episodic/semantic memory and short-term memory/executive function; however, neither one displayed associations with dietary vitamin D intake. Midlife vitamin D intake was significantly and positively associated with scores on the forward digit span task measuring short-term memory (fully adjusted model: mean difference, Q4 vs. Q1 = 1.95; 95% CI 0.37-3.53; p(trend) = 0.03). No significant interaction with either sex or lifetime sun exposure was found. Conclusions: Midlife vitamin D intake exhibited a cross-time and domain-specific association with cognition in the context of aging. Further investigations in this area of prevention are warranted given the rapidly expanding elderly population and the absence of curative treatment for dementia