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Denoeud-Ndam et al. BMC Medicine (2016) 14:167 DOI /s RESEARCH ARTICLE Open Access Efficacy of artemether-lumefantrine in relation to drug exposure in children with and without severe
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Denoeud-Ndam et al. BMC Medicine (2016) 14:167 DOI /s RESEARCH ARTICLE Open Access Efficacy of artemether-lumefantrine in relation to drug exposure in children with and without severe acute malnutrition: an open comparative intervention study in Mali and Niger Lise Denoeud-Ndam 1*, Alassane Dicko 2, Elisabeth Baudin 1, Ousmane Guindo 3, Francesco Grandesso 1, Halimatou Diawara 2, Sibiri Sissoko 2, Koualy Sanogo 2, Seydou Traoré 2, Sekouba Keita 2, Amadou Barry 2, Martin de Smet 4, Estrella Lasry 5, Michiel Smit 6, Lubbe Wiesner 6, Karen I. Barnes 6,7, Abdoulaye A. Djimde 2, Philippe J. Guerin 7,8, Rebecca F. Grais 1, Ogobara K. Doumbo 2 and Jean-François Etard 1,9 Abstract Background: Severe acute malnutrition (SAM) affects almost all organs and has been associated with reduced intestinal absorption of medicines. However, very limited information is available on the pharmacokinetic properties of antimalarial drugs in this vulnerable population. We assessed artemether-lumefantrine (AL) clinical efficacy in children with SAM compared to those without. Methods: Children under 5 years of age with uncomplicated P. falciparum malaria were enrolled between November 2013 and January 2015 in Mali and Niger, one third with uncomplicated SAM and two thirds without. AL was administered under direct observation with a fat intake consisting of ready-to-use therapeutic food (RUTF Plumpy Nut ) in SAM children, twice daily during 3 days. Children were followed for 42 days, with PCR-corrected adequate clinical and parasitological response (ACPR) at day 28 as the primary outcome. Lumefantrine concentrations were assessed in a subset of participants at different time points, including systematic measurements on day 7. Results: A total of 399 children (360 in Mali and 39 in Niger) were enrolled. Children with SAM were younger than their non-sam counterparts (mean 17 vs. 28 months, P ). PCR-corrected ACPR was 100 % (95 % CI, %) in SAM at both day 28 and 42, versus 98.8 % ( %) at day 28 and 98.3 % ( %) at day 42 in non-sam (P = and 0.168, respectively). Compared to younger children, children older than 21 months experienced more reinfections and SAM was associated with a greater risk of reinfection until day 28 (adjusted hazard ratio = 2.10 ( ), P = 0.038). Day 7 lumefantrine concentrations were significantly lower in SAM than non-sam (median 251 vs. 365 ng/ml, P =0.049). Conclusions: This study shows comparable therapeutic efficacy of AL in children without SAM and in those with SAM when given in combination with RUTF, but a higher risk of reinfection in older children suffering from SAM. This could be associated with poorer exposure to the antimalarials as documented by a lower lumefantrine concentration on day 7. (Continued on next page) * Correspondence: 1 Epicentre, Paris, France Full list of author information is available at the end of the article The Author(s) Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Denoeud-Ndam et al. BMC Medicine (2016) 14:167 Page 2 of 14 (Continued from previous page) Trial registration: ClinicalTrials.gov: NCT , registration date: October 7, Keywords: Plasmodium falciparum malaria, Severe acute malnutrition, Artemether-lumefantrine, Treatment outcome, Pharmacokinetics, Niger, Mali Background Malnutrition and Plasmodium falciparum malaria frequently coexist in Sahelian countries and account for a large part of under-five morbidity and mortality during their concomitant peak seasons [1, 2]. Malnutrition is associated with a higher risk of infection and infectious episodes contribute to the deterioration of nutritional status [3]. The question of the impact of child malnutrition on malaria susceptibility is still debated, with conflicting results in the literature. However, it is established that children with either acute or chronic malnutrition are at higher risk to develop severe malaria [4], and to die from it [3, 5]. Reciprocally, malaria could favortheoccurrenceofsevere acute malnutrition (SAM), and implementation of malaria preventive strategies have improved the nutritional status of targeted populations [6]. SAM is defined by the anthropometric indicators of weight-for-height z-score ( 3), mid-upper arm circumference (MUAC; 115 mm), or presence of nutritional edema [7]. SAM may be complicated by the presence of comorbidities which necessitate inpatient treatment. The current recommended World Health Organization standard protocol for assessing antimalarial efficacy excludes children with SAM from the eligible population [8]. Consequently, few studies have assessed the efficacy of antimalarials in SAM children, and were only conducted with the previous generation of antimalarials, i.e., quinine, chloroquine and sulfadoxine-pyrimethamine [9, 10]. Overall, efficacy of these treatments appeared to be reduced, attributed to lower immunity and for quinine and chloroquine to altered pharmacokinetic properties resulting in lower drug concentrations [11, 12]. Although SAM has been associated with increased volume of distribution and intestinal malabsorption of drugs [13, 14], research on the pharmacokinetics and pharmacodynamics of artemisinin-combination therapies (ACTs) in SAM children is currently lacking [15]. Among published efficacy studies, none have measured drug concentrations and more generally, to our knowledge, the pharmacokinetic (PK) properties of ACTs havenotbeenassessedinchildrenwithsam[16,17]. A recent meta-analysis conducted by the Worldwide Antimalarial Resistance Network (WWARN) indicated that the risk of treatment failure with artemether-lumefantrine (AL) was greatest in children suffering from global malnutrition; however, it did not include SAM children nor did it measure drug concentration [18]. Here, we aim to assess whether the efficacy of AL, the most commonly used ACT, is altered in children with uncomplicated SAM compared to non-sam children, and to what extent this can be attributed to inadequate drug exposures as reflected by low lumefantrine concentrations. SAM children received ready-to-use therapeutic food (RUTF) concomitantly with their malaria treatment in this intervention study. Methods Study design and participants We performed an open comparative intervention study to assess the efficacy of AL and the capillary blood concentrations of lumefantrine in uncomplicated SAM and non-sam children. The study protocol and procedures have been described elsewhere [19]. The study was conducted in Oulessebougou district hospital, region of Koulikoro, Mali, and the primary healthcare center of Andoume, Maradi city, Niger. In these areas, malaria transmission is hyperendemic with seasonal peaks during the rainy season (between July and November [19]) and AL is recommended as first-line malaria treatment. Each year, during the hunger gap period (generally from June to October), acute malnutrition increases among young children [20, 21]. According to the 2012 Demographic and Health Surveys, the prevalence of global acute malnutrition in the Koulikoro region of Mali (Aug Sep 2012) and Maradi region of Niger (Jun Aug 2012) were 8.6 % (95 % confidence interval (CI), ) and 16.2 % ( ), respectively, while those of SAM were 1.8 % ( ) and 2.5 % ( ), respectively. Children aged between 6 and 59 months with uncomplicated P. falciparum malaria were eligible if they fulfilled criteria listed in Box 1. After their parent or guardian provided written informed consent, children with weightfor-height z-score 3 or MUAC 115 mm were enrolled in the SAM group, then two children without SAM were subsequently enrolled in the non-sam group. Children with kwashiorkor or complications requiring hospitalization were excluded as were children with severe stunting (height-for-age z-score 3). Denoeud-Ndam et al. BMC Medicine (2016) 14:167 Page 3 of 14 Box 1. Eligibility criteria Inclusion criteria: Age between 6 and 59 months Weight 5kg Axillary temperature 37.5 C or history of fever during the previous 24 hours as reported by the parent/guardian P. falciparum monoinfection confirmed on blood film Parasitic density between 1000 and 200,000 asexual forms/ μl of blood High probability of compliance with follow-up visits (no near-term travel plans) Written consent of a parent or guardian who is at least 18 years of age According to the group: in SAM children, weight-for-height z-score 3 SD or MUAC 115 mm and/or bilateral edema, and in non-sam children, weight-for-height z-score 3 SD, and MUAC 115 mm Exclusion criteria: General danger signs or signs of severe malaria as defined by the World Health Organization Mixed or mono-infection with another Plasmodium species detected by microscopy Severe anemia (hemoglobin 5 g/dl) Known underlying chronic or severe disease (e.g., HIV/ AIDS, TB, cardiac, renal or hepatic disease, sickle cell) Presence of febrile conditions due to diseases other than malaria which could alter the outcome of the study Known history of hypersensitivity or contra-indication to any of the study medications: artemether, lumefantrine (firstline medications), or artesunate, amodiaquine (rescue medications). History of a full treatment course with artemetherlumefantrine in the past 14 days Height-for-age 3 z-score (severe chronic malnutrition) Severe complications of malnutrition requiring hospitalization in intensive care or stabilization, including kwashiorkor Procedures Children were treated with a fixed dose combination of non-dispersible artemether 20 mg-lumefantrine 120 mg (Coartem Novartis) following the manufacturer weightbased dose recommendation (one tablet per intake for bodyweights 15 kg; two tablets for those weighing 15 kg), twice daily for 3 days. The drug was administered under direct observation with a fat intake consisting of milk (one glass, approximately 15 ml), or RUTF (Plumpy Nut, one bag of 92 g) in case of SAM. If vomiting occurred within 30 minutes after intake, a second dose was administered. Children vomiting the second dose were given rescue medication (Additional file 1: Table S1) and excluded. Children were given an insecticide-treated bed net at enrolment. Other treatments included iron and folic acid supplementation, deworming, and for SAM children, RUTF, amoxicillin and others as recommended in national nutritional protocols (Additional file 1: Table S1). Children were followed for 42 days. Any clinical or laboratory adverse event was reported by the investigator as described elsewhere [19]. Serious adverse events were reviewed by a Data Safety and Monitoring Board. Laboratory methods Only capillary blood was collected from finger pricks. SD Bioline HRP2 RDT (Gyeonggi-do, Republic of Korea) was used for screening of malaria parasitemia. Thick and thin blood films were performed at baseline, at 6, 12, 24, 36, 48, and 72, hours, and at day 7, and then weekly until day 42, or in case of malaria signs. All blood films were read by two microscopists blinded to the other reading, and a third reading was performed in case of discrepancy. Films were read using a 100 objective and considered negative after 200 microscopic fields were assessed. P. falciparum asexual forms were counted on the thick film against at least 200 leukocytes [22]. Parasite density was calculated assuming a leukocyte density of 8000/μL. The presence of gametocytes was assessed. Hemoglobin concentration was determined using HemoCue HB 301 -Hemoglobin brand device (Ängelholm, Sweden) on days 0 and 28. Anemia was defined as a hemoglobin concentration 10 g/dl and severe anemia as a concentration 7 g/dl. PCR genotyping of malaria parasites collected from filter papers at enrolment and at the day of treatment failure were performed in MRTC laboratory in Bamako by amplification of the merozoite surface protein 2 (MSP-2) gene [23] and the microsatellites CA1 and TA87 [24]. Outcomes were defined as recrudescent if at least one shared allele was found with all three markers tested and as reinfection if day 0 and day of failure alleles were different in any of the three markers tested [25]. Pharmacokinetics A population-based sparse sampling approach was used to limit the number of PK samples required per child and concerned 150 SAM and 150 non-sam children [26]. For each child, five capillary blood samples (50 μl spotted on filter paper) were collected; first, at 6, 12, 24, 36, or 48 hours (randomly allocated), second at 60 hours, Denoeud-Ndam et al. BMC Medicine (2016) 14:167 Page 4 of 14 third at 72 hours, fourth at day 7, and fifth at day 14 or day 21 (randomly allocated) post treatment initiation. Lumefantrine concentrations were measured at the Division of Clinical Pharmacology, University of Cape Town, using liquid chromatography tandem mass spectrometry as described previously [19]. Outcomes The primary outcome was the proportion of patients having an adequate clinical and parasitological response (ACPR) on day 28, after PCR correction. Secondary outcomes were the proportions of PCRcorrected ACPR on day 42, non PCR-corrected ACPR, early therapeutic failure, late clinical failure, late parasitological failure on days 28 and 42 [8], proportion of reinfection and recrudescence, gametocyte carriage, hematological recovery as witnessed by hemoglobin change between baseline and day 28, and parasite clearance slope half-life. The main PK outcome was lumefantrine concentration on day 7 since it is strongly correlated with the overall drug exposure in the terminal phase and therefore considered a good predictor of therapeutic response [27]. Secondary PK outcomes were measured lumefantrine concentrations at 60 and 72 hours post treatment initiation. Population-based PK modelling will be reported elsewhere. Statistical analysis Unbalanced groups with the non-sam/sam ratio set to two was chosen both for ethical and practical reasons, because, for a fixed number of SAM children, twice the number of non-sam allowed obtaining a higher power than a balanced design. A total of 540 children (180 SAM and 360 non-sam) allowed detection of a minimum difference of 8 % (87 % ACPR in SAM vs. 95 % in non-sam children), with a power of 80 %, two-sided significance level of 5 %, and taking into account up to 15 % dropouts. We planned to enroll two thirds of the sample in Mali during the 2013 and 2014 malaria seasons, and one third in Niger during the 2014 malaria season. Study data were double entered using REDCap electronic data capture tools hosted at Epicentre [28], and analysis was performed with STATA 13, StataCorp, College Station, TX, USA. Analyses of treatment response were performed on two different populations: (1) modified intention-to-treat (mitt) population that included all enrolled patients with parasitological confirmation of mono-infection with P. falciparum with density 1000/μL at screening, who took at least one dose of study drug; and (2) per protocol population including all patients who were part of the mitt and who completed the 3-day treatment course, did not experience major deviation, nor premature discontinuation before day 28 for other reason than failure. Safety analysis was performed in all patients who had received at least one dose of the study drug. Comparisons of the main treatment outcomes (PCRuncorrected and corrected ACPR, reinfection) were performed using two analysis methods: Kaplan Meier analysis comparing the cumulative success rates and allowing to account for censored data, and simple comparison of proportions. The 95 % CIs were estimated using either Wald CI (for Kaplan Meier estimators) or binomial exact CI (for proportions). Log-rank test for equality of survivor functions was used for comparison of survival curves. Comparisons of proportions were done using a χ 2 or Fisher exact test. For other outcomes (hematological recovery, gametocyte carriage, parasite clearance slope half-life), comparisons were performed between the SAM and non-sam groups using a Student or Wilcoxon test for continuous variables and a χ 2 or Fisher exact test for categorical variables. To calculate the parasite clearance slope half-life, the log-transformed parasite counts over time were modelled using the Parasite Clearance Estimator Tool developed by the WWARN [29]. Cox multivariable modelling investigated the effect of SAM and other cofactors (study site, baseline parasite density, child s age, and all covariates with a statistically significant difference at baseline between the SAM and non-sam groups) on malaria-free survival. Finally, we compared lumefantrine concentration at 60 and 72 hours and at day 7 between groups using Wilcoxon rank-sum test, and we investigated if a lower day 7 lumefantrine concentration was associated with the risk of malaria infection using Cox modelling as described above. Each adverse event was coded to a Preferred Term using the Medical Dictionary for Regulatory Activities, version 11 [30]. Then, the number and percentage of patients with at least one adverse event of the following categories were provided: those leading to treatment discontinuation, serious adverse events, and most common adverse events ( 5 %, regardless of the treatment group). All analyses described above were also conducted after adjusting for study site, and site by site where the sample size allowed. Results Patient disposition and baseline characteristics Overall, 871 children were assessed for eligibility, and 399 were included in the study. Respectively, 360 were enrolled in Mali (Nov 2013 to Jan 2014 then June to Dec 2014) and 39 children in Niger (Oct 2014 to Jan 2015), making a total of 399. Recruitment in Niger did not reach the targeted 120 children due to external constraints in the study site that have delayed the start of the inclusions. Following a Data Safety and Monitoring Denoeud-Ndam et al. BMC Medicine (2016) 14:167 Page 5 of 14 Board meeting held in February 2015, i.e., at the end of the planned recruitment period, the study was terminated before completion of the 540 inclusions, because efficacy results already obtained for the 218 first recruited children did not show any difference between groups or lack of efficacy (these interim results were in line with the final results which will be developed hereunder). Among the 133 and 266 children included in the SAM and non-sam groups131 (98.5 %) and 266 (100 %), respectively, were part of the mitt population. After exclusion of patients with premature discontinuation or protocol deviations, 118 SAM (88.7 %) and 244 non-sam (91.7 %) patients were included in the per protocol population (Fig. 1). Apart from the anthropometric characteristics, which were de facto different between groups, SAM children were significantly younger than non-sam (mean 17 vs. 28 months, P ; Table 1), with only 10 % of SAM being older than 26 months in comparison to 50 % in the non-sam group. Clinical presentation also differed with more frequent fatigue, anorexia, and diarrhea at onset in SAM children. Baseline characteristics by study site are shown in Additional file 2: Table S2. Season at inclusion, type of habitat (rural vs. urban) baseline parasitemia, baseline hemoglobin, and mosquito net use were significantly different between sites. Treatment administration Due to lower weight in children with SAM, the mean dose-weight received in the SAM group was significantly Fig. 1 Study profile. SAM, severe acute malnutrition, mitt, modified intent-to-treat, PP, per protocol, PK, pharmacokinetics Deno
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