Therapeutic efficacy and safety of artesunate + amodiaquine and artemether + lumefantrine in treating uncomplicated Plasmodium falciparum malaria in children on the rainy south-east coast of Madagascar.

Malaria is a major public health problem in Madagascar, particularly in coastal areas. We conducted a randomized, controlled, parallel-group study of artemisinin-based combination therapy (ACT) in Mananjary and Farafangana, two localities on the rainy south-east coast of Madagascar, from March to September 2018. The efficacy and safety of artesunate + amodiaquine (ASAQ) and artemether + lumefantrine (AL) were assessed according to the WHO protocol with a 28-day follow-up. Children aged 6 months to 14 years with uncomplicated Plasmodium falciparum malaria were randomized to receive ASAQ or AL for three days (1:1). 347/352 (98.5%) randomized patients reached the study endpoint on day 28. Crude adequate clinical and parasitological response (ACPR) rates were 100% (95% CI: 98.8-100%) in the ASAQ group and 96% (95% CI: 93.1-98.9%) in the AL group (per protocol population). However, the PCR-corrected ACPR rate was 97.7% (95% CI: 95.4-100%) in the AL group. Two cases of recrudescence and three of re-infection were observed. Mild and moderate adverse events, including gastrointestinal and/or nervous disorders, were reported in 11.9% (42/352) of patients. We found that ASAQ and AL were safe and efficacious for treating uncomplicated P. falciparum malaria. They may be used for treatment at health facilities and at the community level, and for mass drug administration campaigns.

Title: Efficacité thérapeutique et sécurité de l'artésunate + amodiaquine et de l'artéméther + luméfantrine pour le traitement du paludisme simple à Plasmodium falciparum chez les enfants sur la côte sud-est pluvieuse de Madagascar. Abstract: Le paludisme demeure un problème majeur de santé publique à Madagascar notamment dans les régions côtières. Nous avons réalisé une étude multisite, randomisée, contrôlée, en groupes parallèles sur la combinaison thérapeutique à base des dérivés d'artémisinine (CTA) à Mananjary et Farafangana, deux localités sur la côte sud-est pluvieuse de Madagascar, de mars au septembre 2018. L'efficacité et la sécurité de l'artésunate + amodiaquine (ASAQ) et de l'artéméther + luméfantrine (AL) ont été évaluées selon le protocole de l'OMS avec un suivi de 28 jours. Des enfants âgés de 6 mois à 14 ans souffrant de paludisme non compliqué à Plasmodium falciparum ont été randomisés (1:1) pour recevoir ASAQ ou AL pendant trois jours. 347/352 (98,5 %) des patients randomisés ont pu être suivis jusqu'au jour 28. Le taux de réponse clinique et parasitologique adéquate (RCPA) était de 100 % (95 % CI : 98,8 ­ 100 %) dans le bras thérapeutique ASAQ et de 96 % (95 % CI : 93,1 ­ 98,9 %) dans le bras thérapeutique AL (population per protocole). Cependant, après correction par PCR, le taux de RCPA était de 97,7 % (95 % CI : 95,4 ­ 100 %) dans le bras thérapeutique AL. Deux cas de recrudescence et trois cas de réinfections ont été observées. Des effets indésirables légers et modérés, notamment des troubles gastro-intestinaux et/ou nerveux, ont été rapportés chez 11,9 % (42/352) des patients. Nos résultats démontrent que l'ASAQ et l'AL sont sûrs et efficaces pour le traitement du paludisme non compliqué à P. falciparum. Ces deux CTA peuvent par conséquent être utilisés pour traiter le paludisme dans les centres de santé et au niveau communautaire, et aussi pendant les campagnes de traitement de masse.

Using routine health data to evaluate the impact of indoor residual spraying on malaria transmission in Madagascar.

INTRODUCTION: Indoor residual spraying (IRS) and insecticide-treated bed nets (ITNs) are cornerstone malaria prevention methods in Madagascar. This retrospective observational study uses routine data to evaluate the impacts of IRS overall, sustained IRS exposure over multiple years and level of spray coverage (structures sprayed/found) in nine districts where non-pyrethroid IRS was deployed to complement standard pyrethroid ITNs from 2017 to 2020. METHODS: Multilevel negative-binomial generalised linear models were fit to estimate the effects of IRS exposure overall, consecutive years of IRS exposure and spray coverage level on monthly all-ages population-adjusted malaria cases confirmed by rapid diagnostic test at the health facility level. The study period extended from July 2016 to June 2021. Facilities with missing data and non-geolocated communes were excluded. Facilities in IRS districts were matched with control facilities by propensity score analysis. Models were controlled for ITN survivorship, mass drug administration coverage, precipitation, enhanced vegetation index, seasonal effects and district. Predicted cases under a counterfactual no IRS scenario and number of cases averted by IRS were estimated using the fitted models. RESULTS: Exposure to IRS overall reduced case incidence by an estimated 30.3% from 165.8 cases per 1000 population (95% CI=139.7 to 196.7) under a counterfactual no IRS scenario, to 114.3 (95% CI=96.5 to 135.3) over 12 months post-IRS campaign in nine districts. A third year of IRS reduced malaria cases 30.9% more than a first year (incidence rate ratio (IRR)=0.578, 95% CI=0.578 to 0.825, p<0.001) and 26.7% more than a second year (IRR=0.733, 95% CI=0.611 to 0.878, p=0.001). There was no significant difference between the first and second year (p>0.05). Coverage of 86%-90% was associated with a 19.7% reduction in incidence (IRR=0.803, 95% CI=0.690 to 0.934, p=0.005) compared with coverage ≤85%, although these results were not robust to sensitivity analysis. CONCLUSION: This study demonstrates that non-pyrethroid IRS appears to substantially reduce malaria incidence in Madagascar and that sustained implementation of IRS over three years confers additional benefits.

Climatic, land-use and socio-economic factors can predict malaria dynamics at fine spatial scales relevant to local health actors: Evidence from rural Madagascar.

While much progress has been achieved over the last decades, malaria surveillance and control remain a challenge in countries with limited health care access and resources. High-resolution predictions of malaria incidence using routine surveillance data could represent a powerful tool to health practitioners by targeting malaria control activities where and when they are most needed. Here, we investigate the predictors of spatio-temporal malaria dynamics in rural Madagascar, estimated from facility-based passive surveillance data. Specifically, this study integrates climate, land-use, and representative household survey data to explain and predict malaria dynamics at a high spatial resolution (i.e., by Fokontany, a cluster of villages) relevant to health care practitioners. Combining generalized linear mixed models (GLMM) and path analyses, we found that socio-economic, land use and climatic variables are all important predictors of monthly malaria incidence at fine spatial scales, via both direct and indirect effects. In addition, out-of-sample predictions from our model were able to identify 58% of the Fokontany in the top quintile for malaria incidence and account for 77% of the variation in the Fokontany incidence rank. These results suggest that it is possible to build a predictive framework using environmental and social predictors that can be complementary to standard surveillance systems and help inform control strategies by field actors at local scales.