Partie III - Traitement du paludisme à Plasmodium falciparum non compliqué chez les enfants malnutris sévères en milieu hospitalier au Kivu, en République Démocratique du Congo.
Note de synthèse sur la pharmacocinétique des antipaludéens au cours de la malnutrition
Cette partie consacrée au traitement du paludisme chez les enfants malnutris sévères débute par cette note de synthèse sur la pharmacocinétique des médicaments. Dans cette note, il est fait mention des modifications physiopathologiques théoriques qui surviennent au cours des stades sévères de la malnutrition. Ces modifications sont susceptibles d’interférer avec l’efficacité des médicaments. En outre, elle passe en revue la bibliographie existante sur la pharmacocinétique de quelques antipaludéens chez le sujet malnutri. Ces aspects théoriques sont essentiels dans l’appréhension des subtilités qui pourraient être évoquées au sujet d’un traitement antipaludéen chez l’enfant en état de malnutrition.
I. Pharmacocinétique et malnutrition sévère
La malnutrition carentielle est d’une complexité telle que plusieurs déficiences peuvent apparaitre concomitamment. Ces carences conduisent souvent à de multiples changements physiopathologiques dont les manifestations cliniques sont fréquemment décrites chez le sujet malnutri (1). Ces changements physiopathologiques peuvent interférer avec la cinétique des médicaments administrés (2, 3, 4). Les principaux changements physiopathologiques sont décrits ci-dessous en fonction des quatre phases classiques de la pharmacocinétique :
[1] Absorption :
Une atrophie de la muqueuse intestinale est observée en cas de malnutrition sévère. Cette atrophie pourrait gêner l’absorption des médicaments administrés par voie orale.
La bradycardie couplée à la réduction du débit cardiaque observées chez le sujet sévèrement malnutri conduisent à une mauvaise irrigation périphérique.
En plus, le sujet malnutri sévère est caractérisé par une réduction de la masse musculaire.
La diminution de la masse musculaire peut rendre difficile une pratique répétée d’injections par la voie intramusculaire. En plus, la réduction de la masse musculaire couplée à la diminution de l’irrigation périphérique
pourraient compromettre l’absorption des médicaments administrés par voie intramusculaire ou par voie intra rectale.
[2] Distribution :
Le volume d’eau est augmenté essentiellement dans la forme œdémateuse de la malnutrition.
L’albumine plasmatique, qui est la protéine la plus impliquée dans le transport de nombreux médicaments, est diminuée. La synthèse des autres protéines impliquées dans le transport des médicaments notamment les globulines et les lipoprotéines est généralement peu affectée en cas de malnutrition.
Malgré tout, la fraction libre des médicaments à forte fixation à l’albumine, devrait théoriquement être augmentée. Ce qui, théoriquement, accroîtrait non seulement le risque de toxicité dudit médicament, mais aussi son élimination.
Théoriquement, le volume de distribution en serait aussi diminué. Ce qui pourrait éventuellement influer sur la concentration minimale pour une réponse thérapeutique adéquate.
[3] Métabolisme :
Les perturbations hépatiques font que certains systèmes enzymatiques en l’occurrence celui du cytochrome P450, largement impliqué dans le catabolisme des composés organiques, dont les médicaments, aient une activité réduite en cas de malnutrition sévère.
Cette diminution de l’activité de certains systèmes enzymatiques pourrait entrainer une diminution non seulement de l’activité des médicaments pour lesquels le principe actif est un métabolite issu du catabolisme du produit administré, mais aussi de son élimination.
[4] Elimination :
La biotransformation nécessaire pour une excrétion ou élimination biliaire est réduite du fait de la diminution de l’activité de certains systèmes enzymatiques.
La filtration glomérulaire et les fonctions tubulaires au niveau du rein sont réduites du fait de la réduction du débit cardiaque dans les situations de malnutrition sévère.
Ceci pourrait entrainer une diminution du coefficient d’épuration plasmatique des médicaments qui s’éliminent préférentiellement par les voies biliaire et / ou rénale, avec pour corollaire, un risque d’augmentation de la concentration desdits médicaments dans le plasma. Pour les médicaments qui sont administrés pendant plusieurs jours consécutifs, théoriquement, le risque d’accumulation serait accru avec comme corollaire une augmentation de la toxicité.
Les perturbations physiopathologiques influant sur l’une des phases de la cinétique des médicaments pourraient inéluctablement influencer la demi-vie des médicaments. La demi- vie d’un médicament est le temps nécessaire pour que la quantité du médicament contenue dans un système biologique soit diminuée de la moitié de sa valeur initiale.
Des études analysant la pharmacocinétique des médicaments dans les situations de malnutrition sévère ont été menées. Les résultats de deux revues sur la question ont permis de montrer (i) une absorption gastro-intestinale lente ou diminuée, (ii) une diminution des protéines fixatrices et transporteuses des médicaments, (iii) des variations dans le volume de distribution, (iv) une modification des biotransformations au niveau hépatique et (v) une élimination rénale réduite ou lente (4, 5). En plus, la biodisponibilité des médicaments est influencée par le degré de sévérité de la malnutrition (6).
II. Pharmacocinétique des antipaludéens
Tableau III-1 : Quelques éléments sur la pharmacocinétique de certains antipaludéens
Médicament Biodisponibilité orale
Délai moyen concentration plasmatique maximale
Liaison aux protéines plasmatiques
Elimination Demi-vie d’élimination
Aminoquinoléine
Chloroquine Très rapide* 1 – 6 heures 50% Rénale 56 jours
Amodiaquine Très rapide Pas connue Pas connue Rénale lente Pas connue
Primaquine Très rapide 1 – 2 heures - Rénale 3 – 6 heures
Arylamino-alcools
Quinine Très rapide et
complète
2 – 3 heures 70%
glycoprotéine 30% albumine
Rénale inchangée 20%
Métabolite 80%
10 heures **
Méfloquine Rapide 85% 6 – 24 heures 98% 10% rénale
90% digestive
21 jours
Artémisinine Rapide 3 – 11 heures 95% Rénale et
fèces
1 heure
Artémeter Rapide 2 – 3 heures 95% - 2 heures
Artésunate Rapide 1 heure 47 – 76% - 45 minutes
Luméfantrine Lente 10% 6 – 8 heures 99,7% fécale 3 jours
Halofantrine Variable* - - fécale 1 – 2 jours
Antifoliniques Pyriméthamine + sulfadoxine
Lente 2 – 6 h pyri
4 h sulfa
80 – 90% pyri 90 – 95% sulfa
Lente rénale 4 – 9 jours sulfadoxine
Proguanil Rapide 3 – 4 heures 75% 50% fèces
50% rénale
20 heures
Antibiotiques
Doxycycline Très rapide et Excellente
2 – 4 heures 82 – 93% Rénale 40%
inchangée 60% fécale
16 – 22 heures
Tétracycline Incomplète (60%
reste dans le tube digestif)
1 – 3 heures 20 – 65% 40 – 70%
rénale Reste fèces
8 heures
Autres
Atovaquone Faible - 99% Fèces 1 – 2 jours
* Biodisponibilité augmente lorsque pris avec un repas
** S’allonge en cas d’impaludation Pyri= Pyriméthamine Sulfa= sulfadoxine
Le tableau III-1 présente un inventaire de quelques antipaludéens couramment utilisés et leur pharmacocinétique (7-10).
Cette synthèse de la pharmacocinétique prend essentiellement en compte les aspects de ces antipaludéens administrés par voie orale qui pourraient être affectés par les modifications physiopathologiques survenant au cours de la malnutrition sévère.
Dans ce tableau, la biodisponibilité orale désigne la fraction de la dose administrée par voie orale qui atteint la circulation générale. La biodisponibilité est un reflet de la vitesse d'absorption et de la quantité de médicament absorbée.
III. Pharmacocinétique des antipaludéens chez le sujet malnutri.
Alors que la malnutrition demeure toujours un problème de santé publique dans le monde, le nombre de publications axées sur la pharmacocinétique des médicaments en général et chez le sujet malnutri est en baisse depuis deux décennies (5). Dans le cas spécifique des antipaludéens, devant cette insuffisance de publications, les résultats de nombreuses études sur l’efficacité des antipaludéens auraient pu être d’une grande utilité dans l’appréhension approximative de la cinétique des médicaments antipaludiques chez l’enfant malnutri sévère. Malheureusement, dans les protocoles des études portant sur l’efficacité des antipaludéens, l’état de malnutrition sévère constitue un critère d’exclusion (11). Malgré le fait que la majorité d’enfants souffrant de carences nutritionnelles vit dans les zones d’endémie palustre (12), la pharmacocinétique des antipaludéens en cas de malnutrition sévère n’a jamais été suffisamment documentée. A notre connaissance, seules quelques publications portant sur la pharmacocinétique de quelques antipaludéens chez le sujet sévèrement malnutri sont disponibles. Chez l’enfant sévèrement malnutri, les publications existantes ne se rapportent qu’à la quinine et la chloroquine (13 -18).
[1] Chloquine et quinine
Pour la chloroquine, les études menées sur les enfants malnutris ont montré une baisse du taux d’absorption (13, 14) et une réduction de sa métabolisation (14). Ces études n’ont pris en compte ni la fixation aux protéines plasmatiques, ni la distribution du médicament dans l’organisme. Cependant Buchanan et al ont montré qu’en cas de kwashiorkor, la fixation de la chloroquine reste globalement inchangée et se fait préférentiellement à la fraction gamma globuline (15).
Les études de la pharmacocinétique de la quinine chez les enfants malnutris ont mis en évidence la baisse du taux d’absorption (16, 17), un faible pic de concentration plasmatique, une vitesse d’élimination lente (16). Enfin il a été noté que le métabolisme était accru (17), la clearance plasmatique et le volume de distribution étaient faibles (18).
Les études tant sur la chloroquine que sur la quinine ne font nullement allusion à une quelconque accumulation plasmatique du médicament, quand bien même certaines d’entre elles mentionnent un allongement du temps d’élimination (16, 18) et une réduction de la métabolisation (14). Cette accumulation des médicaments chez les enfants malnutris sévères pourrait d’autant plus être probable que, dans le traitement curatif du paludisme, la durée est souvent supérieure ou égale à trois jours pour la chloroquine et à cinq jours pour la quinine alors que les études dont il est question ci-dessus donnent des résultats après l’administration d’une dose unique du médicament. En plus, la demi-vie d’élimination est au-delà de 24 heures pour la chloroquine (tableau III-1), pour laquelle une dose quotidienne est administrée chaque jour et de 10 heures pour la quinine pour laquelle il est recommandé une administration du médicament toutes les 8 heures.
[2] Tétracycline et Doxycycline
Les études sur la pharmacocinétique de la tétracycline et de la doxycycline chez les sujets malnutris ont porté sur des personnes plus âgées et sans rapport avec l’impaludation (19 - 23). Pour ce qui est de la tétracycline, les études ont montré un faible taux de fixation aux protéines, une diminution de la distribution et une demi-vie d’élimination plus courte (19- 21), et chez des sujets présentant un œdème nutritionnel une réduction de l’élimination ainsi que du volume de distribution (22). En ce qui concerne la doxycycline, la demi-vie d’élimination et le taux de fixation aux protéines plasmatiques étaient réduits alors que l’élimination était augmentée (23).
[3] Combinaisons Thérapeutiques à base d’Artémisinine et autres antipaludéens
L’OMS a recommandé l’utilisation des Combinaisons Thérapeutiques à base d’Artémisinine (CTA) pour le traitement du paludisme non compliqué en vue de faire face à l’émergence d’une résistance croissante du Plasmodium falciparum aux antipaludéens (24). En application de cette recommandation de l’OMS, plusieurs pays avaient progressivement adopté différentes CTA pour le traitement de première ligne du paludisme non compliqué (25). Malgré l’adoption massive des CTA pour le traitement du paludisme, les études sur la pharmacocinétique de l’artémisinine et celle de ses dérivés chez l’enfant sévèrement malnutri ne sont malheureusement pas encore disponibles dans la littérature.
Il n’existe pas non plus d’étude de pharmacocinétique chez l’enfant malnutri portant sur la sulfadoxine-pyriméthamine et l’amodiaquine, autres médicaments couramment utilisés dans le traitement du paludisme.
Malgré la carence d’études publiées sur les autres antipaludéens, on pourrait déduire que leur biodisponibilité ne saurait largement s’écarter de la synthèse globale décrite ci-dessus sur la pharmacocinétique des médicaments chez l’enfant malnutri.
Bibliographie
1. Critian Carip. Physiopathologie. Bases physiopathologiques de la diététique, 2ème Edition. Edition Tec & Doc Lavoisier, 2004, 522 p.
2. Kazeem A Oshikoya and Idowu O Senbanjo. Pathophysiological changes that affect drug disposition in protein-energy malnourished children. Nutr Metab (Lond) 2009 Dec 1 ; 6:50.
3. OMS/RBM. Directives pour le traitement du paludisme. Deuxième édition. Genève, Organisation mondiale de la Santé, 2011 : 81 – 117.
4. Krishnaswamy K. Drug metabolism and pharmacokinetics in malnourished children. Clin Pharmacokinet 1989; 17 Suppl 1:68-88.
5. Oshikoya KA, Sammons HM, Choonara I. A systematic review of pharmacokinetics studies in children with protein-energy malnutrition. Eur J Clin Pharmacol 2010 Oct; 66(10):1025- 35.
6. Raghuram TC, Krishnaswamy K. Pharmacokinetics of tetracycline in nutritional edema.
Chemotherapy. 1982; 28(6):428-33.
7. Serge Paul Eholié, Emmanuel Bissagnéné, Pierre-Marie Girard. Memento thérapeutique du paludisme en Afrique. Doin éditions 2008, 139 p.
8. OMS. Progrès en chimiothérapie du paludisme. Rapport d’un groupe scientifique de l’OMS. Genève : Organisation Mondiale de la Santé 1984 : 99 – 143.
9. Martindale: The Complete Drug Reference, 35th edition 2006. Pharmaceutical Press, 3335 p.
10. Vidal 2010. Le Dictionnaire. Vidal 86ème édition, 2981 p.
11. OMS (2004) Evaluation et surveillance de l’efficacité des antipaludiques à plasmodium falciparum non compliqué. Organisation mondiale de la Santé.
WHO/HTM/RBM/2003.50.
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1970 Sep; 16(3):130-2.
14. Walker O, Dawodu AH, Salako LA, Alván G, Johnson AO. Single dose disposition of chloroquine in kwashiorkor and normal children--evidence for decreased absorption in kwashiorkor. Br J Clin Pharmacol. 1987 Apr; 23(4):467-72.
15. Buchanan N, Van der Walt LA. The binding of chloroquine to normal and kwashiorkor serum. Am J Trop Med Hyg 1977; 26:1025-27.
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17. Tréluyer JM, Roux A, Mugnier C, Flouvat B, Lagardère B. Metabolism of quinine in children with global malnutrition. Pediatr Res. 1996 Oct; 40(4):558-63.
18. Pussard E, Barennes H, Daouda H et al. Quinine disposition in globally malnourished children with cerebral malaria. Clin Pharmacol Ther 1999 May; 65(5):500-10.
19. Shastri RA, Krishnaswamy K. Undernutrition and tetracycline half life. Clin Chim Acta.
1976 Jan 16; 66(2):157-64.
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21. Santosh KK, Raghuram TC, Krishnaswamy K. Bioavailability of different brands of tetracycline in undernourished subjects. Int J Clin Pharmacol Ther Toxicol. 1992 Jan;
30(1):13-7.
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24. World Health Organisation: Antimalarial drug combination therapy: report of a technical consultation. Geneva: WHO 2001.
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564-73.
Introduction au traitement du paludisme chez l’enfant malnutri sévère
L’analyse de l’étude réalisée en communauté sur une cohorte d’enfants suivis pendant un an a permis de montrer que, d’une part le paludisme était devenu de niveau hypoendémique après un large programme de distribution de MII dans la région, et que d’autre part le risque d’une densité parasitaire ≥ 5000 formes asexuées par microlitre de sang était plus bas chez les enfants en état de malnutrition chronique sévère que chez ceux en bon état nutritionnel.
Cette observation qui est en faveur de l’hypothèse I de ce travail, est cohérente avec les résultats obtenus au cours de l’exploration rétrospective des données recueillies en milieu hospitalier qui montraient que l’enfant atteint de malnutrition sévère était protégé contre l’impaludation.
Les résultats de cette première partie consacrée à la description de la relation entre l’impaludation et la malnutrition, tant en milieu hospitalier qu’en communauté, nécessitent une vérification sous contrôle.
Le retour en milieu hospitalier va permettre d’analyser l’impaludation en fonction de l’état nutritionnel de manière contrôlée. Ce qui permettra de vérifier les hypothèses de protection de l’enfant malnutri sévère contre l’impaludation et de réactivation de l’impaludation au cours de la réhabilitation nutritionnelle, jusque là observées dans les résultats présentés dans les trois chapitres précédents.
Cette troisième partie du travail est constituée de 3 chapitres portant chacun sur une analyse. Les analyses des chapitres 5 et 6 ont été faites sur les données d’une même étude qui avait porté sur l’efficacité du traitement antipaludéen chez l’enfant malnutri alors que l’analyse du chapitre 7 découle d’une étude à part ayant porté sur l’efficacité d’une stratégie de traitement antipaludéen systématique au cours de la réhabilitation nutritionnelle.
Le chapitre 5 va présenter les résultats de la réponse au traitement antipaludéen chez l’enfant en fonction de l’état nutritionnel. Ils permettront de vérifier l’hypotnèse II de ce travail. Ces résultats vont permettre de s’assurer que l’état de dépression immunitaire souvent décrit dans les situations de carences nutritionnelles, ne peut pas être un obstacle pour une élimination rapide des parasites de paludisme au cours du traitement antipaludéen. Cet obstacle à une élimination rapide des parasites se manifesterait par une grande proportion d’échec au traitement ou échec thérapeutique. Si cette dépression immunitaire constituait un véritable obstacle à l’élimination rapide du plasmodium, malgré
l’observation faite selon laquelle l’état de malnutrition sévère protège contre l’impaludation, une stratégie de traitement antipaludéen systématique au cours de la réhabilitation nutritionnelle serait inefficace.
De l’exploration des données individuelles des enfants inclus dans cette étude portant sur la réponse au traitement antipaludéen, une analyse sur le portage des gamétocytes a été initiée. Au départ, cette analyse n’était pas planifiée. La nécessité de sa réalisation est apparue en cours d’analyse des données sur l’efficacité du traitement antipaludéen chez l’enfant malnutri sévère. Les résultats de cette analyse sur le portage et la production des gamétocytes de Plasmodium falciparum au cours d’un traitement antipaludéen chez l’enfant en fonction de l’état nutritionnel sont présentés au chapitre 6. La discussion des résultats de cette étude aborde des mécanismes physiopathologiques qui pourraient figurer parmi les facteurs explicatifs éventuels de la relation entre l’impaludation et la malnutrition sévère.
La dernière étude a permis de tester l’efficacité d’une stratégie d’administration d’un traitement antipaludéen systématique au cours de la réhabilitation nutritionnelle.
C’est une étude randomisée en double aveugle qui inclut les enfants de 6 à 59 mois malnutris, admis dans le programme de thérapeutique nutritionnelle à l’hôpital général de référence de la zone de santé de Kirotshe (Photo III-1), dans la province du Nord Kivu. Le premier groupe a reçu le traitement antipaludéen fait de la combinaison Artésunate- Amodiaquine (AS+AQ) (médicament de première ligne recommandé pour le traitement du paludisme non compliqué en RDC) et le second groupe a reçu un placebo. Tous les enfants étaient
Photo III-2 : Enfants malnutris sévères à Kirotshe
Photo III-1 : hôpital général de référence de Kirotshe : vue partielle de derrière
malnutris (photo III-2) et ont été suivis pendant 28 jours. Le cours de cette étude offre une occasion d’observation et de description de l’impaludation chez l’enfant malnutri au cours de la réhabilitation nutritionnelle. Les analyses des données issues de cette étude qui font l’objet du chapitre 7, vont ainsi permettre de vérifier notre hypothèse III libellée comme suit : « la réhabilitation nutritionnelle apporte des nutriments qui seraient nécessaires à la croissance rapide du Plasmodium spp. Cette croissance rapide du Plasmodium spp augmenterait le risque d’attaque clinique de paludisme chez le sujet malnutri en cours de réhabilitation. Un traitement antipaludéen systématique au cours de cette réhabilitation nutritionnelle diminuerait ce risque d’attaque clinique de paludisme ».
Chapitre 5 - Efficacy of artesunate plus amodiaquine for treatment of
uncomplicated clinical falciparum malaria in severely malnourished children aged 6–59 months, Democratic Republic of Congo.
Mitangala Ndeba P., U. D’Alessandro, P. Hennart, P. Donnen, D. Porignon, G. Bisimwa Balaluka, A. Bisimwa Nkemba, N Cobohwa Mbiribindi et M. Dramaix Wilmet (Article sous presse dans J Clin Exp Pathol S3:005. doi:10.4172/2161-0681).
Abstract
Background: Recent published studies on efficacy and safety of antimalarial treatment in children with Severe Acute Malnutrition (SAM) suffering from uncomplicated malaria are not available.
Methods: Between March 2007 and December 2010 the efficacy of AS+AQ in treating uncomplicated malaria children under five with SAM was carried out in Lwiro (Eastern Republic Democratic of Congo) according to the WHO standard protocol. Among the 445 children included, 69 had SAM. AS+AQ was given according to national protocol. Analysis was done using per protocol method. Odds ratio (OR) and their 95% confidence interval (95% CI) were computed.
Results: The treatment failure rate was 24.4% of 414 infections included in the analysis.
After adjustment for malaria parasitemia, ACPR in children without SAM were 73.0% when it was 91.4% among those with SAM (OR 3.15 95%CI 1.19 – 8.30). Malaria parasitemia median at admission was statistically low among children who had subsequently Adequate Clinical and Parasitological Response (ACPR).
Conclusion: AS+AQ has a good efficacy among children with both uncomplicated falciparum malaria and malnutrition including severe acute form. AS+AQ dosing national strategy unmodified can be used, to treat under five children with malnutrition including severe acute form suffering from uncomplicated malaria.
5.1 Introduction
In Sub-Saharan Africa, malaria and malnutrition often co-exist and represent an important public health burden [1,2]. Prompt treatment with an effective antimalarial treatment is one of the cornerstones of malaria control [3]. Because of unacceptable resistance, chloroquine (CQ), The most affordable and widely available antimalarial treatment in the past, has been replaced, according to the World Health Organization recommendations, by artemisinin-
based combination treatments (ACT) [4,5]. This was followed by a strong advocating of the use of the ACT [6].
In Eastern Democratic Republic of Congo (DRC), resistance of Plasmodium falciparum to CQ has been documented since 1983 and was estimated at 80% in 2001 [7]. This prompted the National Malaria Control Program (NMCP) to change in 2005 the national antimalarial treatment policy and the first line treatment, from CQ to amodiaquine plus artesunate (AS+AQ). Nevertheless, since its implementation, few studies on AS+AQ efficacy have been carried out [8-10], and none of them took into account the patients’ nutritional state.
Nevertheless it has been often reported that both malnutrition and malaria affect antimalarial disposition [11,12].
Malaria is endemic in areas where malnutrition is common. Among children suffering from uncomplicated malaria to treat using antimalarial for which efficacy tests are achieved, a good many of them are malnourished. Yet severely malnourished children are usually excluded from antimalarial efficacy studies. Consequently, to our knowledge, there are no recent published studies on efficacy and safety of antimalarial treatment in severely malnourished children with uncomplicated malaria. Therefore there is a need to further study the efficacy and the safety of artemisinin-based combination for uncomplicated malaria treatment in malnourished children although its efficacy and safety have been reported for use in children in Africa.
We compared the efficacy and safety of AS+AQ dosing DRC national strategy in malnourished vs non malnourished children aged 6–59 months with uncomplicated clinical falciparum malaria.
5.2 Methodology
The study was carried out between March 2007 and December 2010 in Lwiro pediatric hospital (LPH), in South Kivu province, Katana health district, at the eastern border of DRC.
LPH is a unit of the nutrition department of Lwiro CRSN (“Centre de Recherche en Sciences Naturelles”), the oldest research center in the Kivu region for the last 60 years.
Patient recruitment
Children with suspected uncomplicated malaria attending LPH or its satellite nearest health centre were screened and enrolled in the study if they met the following inclusion criteria:
age 6 -59 months old, fever (axillary temperature ≥37.5°C) or a history of fever in the previous 24 hours, Plasmodium falciparum mono-infection with density between 1,000 and 200,000/μl. Exclusion criteria were the following: cause for fever other than malaria; dangers signs (unable to sit or stand up, unable to drink or breastfeed, lethargy or unconsciousness, recent history of convulsions, persistent vomiting) or signs of severe malaria [13].
The aim and the procedures of the study were explained to the parent/guardian and an individual informed consent was obtained.
Treatment
Enrolled children were treated with AS+AQ (Falcimon®, Cipla ltd, Mumbai Central, Mumbai 400008, India) at the dose of 4 mg/kg for AS and 10 mg/kg for AQ given over 3 days (dosing DRC national strategy). AS+AQ was procured by Asrames (“Association régionale d’Aprovisionnement en Médicaments Essentiels”), the drug’s regional central distribution located in Goma, North Kivu province. Treatment was administered over 3 days (day 0-2) under the supervision of a nurse who kept the children at the clinic for about 1 hour post- treatment to check for possible vomiting. Treatment failures were given a full course of quinine according to the NMCP guidelines. Children with severe acute malnutrition were included in a nutritional rehabilitation program and managed according to the national nutritional therapeutic protocol.
Follow-up
After completion of the treatment, scheduled visits were at days 3, 7, 14 and 28. Between visits parents were encouraged to attend LPH whenever their child was sick. Community health workers did regular home visits to remind parents/guardians the next scheduled meeting.
Laboratory tests
Each visit, a blood sample was collected by finger prick for thick and thin smears that were stained, with 3% Giemsa for 30 min (thin smears were first fixed with methanol). Parasite density was estimated by counting the number of asexual parasites against 200 White Blood Cells (WBC), assuming a WBC count of 8000/ μL. Serum albumin was measured using the bromocresol green assay on spectrophometer.
Anthropometric and clinical measurements
Weight, height and the middle upper arm circumference (MUAC) were collected at each follow-up visit by a skilled nurse from the HPL according to international recommendations [14]. Axillary temperature was measured with a digital thermometer.
Outcome measure
Outcomes were assessed after 28 days and were classified into four categories of therapeutic responses, i.e. Early Treatment Failure (ETF), Late Clinical Failure (LCF), Late Parasitological Failure (LPF), Adequate Clinical and Parasitological Response (ACPR) [13].
Statistical analysis
Children were not included in the analysis if (1) the parents/ guardians had administered another antimalarial during follow – up; (2) they withdrew consent; (3) the child had a concomitant disease that would interfere with the treatment outcome; (4) children were lost to follow up after two successive
missing visits.
The z scores (ZS) height for age (HAZ), weight for age (WAZ) and weight for height (WHZ) were computed with the software WHO Anthro V2.0.4 using the reference population as defined by WHO in 2006 [15].
The HAZ, WHZ, WAZ, MUAC, albumin and the presence of edemas were used to quantify the degree of under nutrition. The cut offs were 115 and 125 mm for the MUAC and -3 and -2 for HAZ, WHZ and WAZ ([16,17]).
Acute malnutrition was defined as a WHZ ≤ -2 while chronic malnutrition as a ZS for HAZ ≤ -2 [16]. Severe acute malnutrition (SAM) was defined by a
WHZ < -3 and/or the presence of nutritional edema [17]. According to the previous
1237 well nourish children screned for malaria
77 malnourish children with malaria parasitemia
= 1000/µL
376 without SAM and with malaria parasitemia = 1000/µL
69 received ACT 376 received ACT
Refusal cooperate 4 Move 3
Protocol violation 3 Hospitalization 3 47 with malaria parasitaemia < 1000 49 mixed infection 773 negative for malaria 368 well nourish children with malaria parasitemia = 1000/µL
1327 malnourish children screned for malaria
38 with malaria parasitaemia < 1000 29 mixed infection 1183 negative for malaria
445 children recruited
69 children with SAM and malaria parasitemia = 1000/µL
Death 1 Protocol violation 3
58 children with SAM and falciparum malaria included into per protocol analysis
Plasmodium malariae 6 Plasmodium ovale 1 PLasmodium
malariae 7
356 children without SAM and with falciparum malaria included into per protocol analysis
Fig 5 – 1: Trial profile
experience on the prognostic indices for mortality in LPH, thresholds for albumin were 16 and 23 mg/L.
Analysis of treatment outcome was per protocol. Either the χ² or the Fisher exact tests were used for proportions comparison, Mantel— Haenszel for adjustment and non parametric Kruskal-Wallis test for continuous variables with skewed distribution. Odds ratio (OR) for failure was computed with 95% confidence intervals (95%CI). All reported p-values were two-sided, considered statistically significant if less than 0.05.
Ethical considerations
The protocol was submitted to and approved by the Lwiro CRSN ethical committee. The procedure for obtaining consent was according to international guidelines and local habits for research on human subjects. Parents/guardians were informed they could withdraw at any time without compromising access to health care.
5.3 Results
The figure 5-1 gives the trial profile. Baseline characteristics are reported in Table 5-1.
The median age was 26.5 months (range: 6.0 – 57.9). SAM was found in 14.4% (62/431) children. Median age was 30.2 months (range: 7.3 – 56.9) in children with SAM vs 25.5 months (range: 6.0 – 57.97) in those without SAM (p=0.005). The risk for SAM increased with age, i.e. compared to <12 months old, odds ratio (OR): 1.66 (95% CI: 0.55 -5.01) in 12-23 months old, 3.59 (95%CI: 1.30 – 9.96) in 24 – 35 months old and 3.16 (1.14 – 8.74) in 36 – 59 months old. Nutritional status did not differ by gender.
Median parasite density was 26,600/μl (range: 1,000 – 198,000) and significantly lower in older children (Table 5-2) and in the undernourished one (Table 5-2). The body temperature was significantly lower in children suffering from SAM (n=62) [mean (standard deviation) 37.0°C (0.9)] compared to those without SAM (n=369) [mean (standard deviation) 38.3°C (1.3)] (p < 0.001).
Table 5 - 1: Baseline characteristics under five children with uncomplicated malaria treated with AS+AQ in eastern DRC, from march 2007 to December 2010 (n=431).
% (number) fever % (number) Age (in months)
< 12 16.2 (70) 72.9 (51)
12 - < 24 26.9 (116) 55.2 (64)
24 - < 36 26.0 (112) 71.4 (80)
36 - 59 30.9 (133) 57.1 (76)
Gender
Female 48.7 (210) 63.8 (134)
Edema
Yes 13.0 (56) 25.0 (14)
WHZ
< -3 3.9 (17) 17.6 (3)
-3 - < -2 7.0 (30) 43.3 (13)
>= -2 89.1 (384) 66.4 (255)
HAZ
< -3 42.5 (183) 50.3 (92)
-3 - < -2 27.1 (117) 70.9 (83)
>= -2 30.4 (131) 73.3 (96)
MUAC (in mm)
< 115 7.4 (32) 31.3 (10)
115 - < 125 10.4 (45) 53.3 (24)
>= 125 82.1 (354) 66.9 (237)
Serum albumin (g/L)
< 16 2.8* (12) 8.3 (1)
16 - < 23 6.5* (28) 35.7 (10)
>= 23 90.7* (390) 66.7 (260)
* n=430
Table 5 - 2 : Malaria parasitemia by several features among under five children with uncomplicated malaria treated with AS+AQ in eastern DRC, from march 2007 to December 2010.
n Median per µL (range) p
Age (in months) 0.033
< 12 70 39 100 (1600 - 163420)
12 - < 24 116 24 570 (1200 - 193600)
24 - < 36 111 26 800 (1120 - 198000)
36 - 59 133 19 280 (1000 - 170820)
Gender 0.76
Female 210 26 480 (1000 - 181000)
Male 220 26 900 (1040 - 198000)
SAM < 0.001
Yes 61 7 600 (1040 - 162280)
No 369 31 000 (1000 - 198000)
MUAC (mm) 0.008
< 115 32 10 550 (1460 - 110660)
115 - < 125 45 19 840 (1120 - 198000)
≥ 125 353 29 880 (1000 - 193600)
Albumin (g/dL) < 0.001
< 16 12 2 330 (1040 - 32240)
16 - <
23 28 10 040 (1680 - 88660)
≥ 23 390 29 940 (1000 - 198000)
HAZ 0.016
< -2 299 24 390 (1000 - 198000)
≥ -2 131 34 120 (1040 - 181000)
Overall, by day 28, the ACPR was 75.6% (313/414) and the total treatment failure was significantly lower in malnourished children after adjustment for malaria parasitemia (Table 5-3). Median parasitemia at admission was significant lower in children whose outcome was ACPR (21, 560/μL; range: 1,000 – 198,000) than in those with LCF (46,920/μL; range: 1,120 – 193,600) (n=69) and LPF (41,560/μL (2,020 – 140,000) (n=32) (p < 0.001).
Table 5 - 3: Therapeutic responses to AS+AQ by nutritional indicators status in under five children with uncomplicated falciparum malaria in eastern DRC, between march 2007 to December 2010.
Nutritional indicator % (Number) % (Number) OR* (95% IC)* p
Severe Acute malnutrition (SAM) Yes (n=58) NO (n=356) 0.002
Late Clinical Failure (LCF) 5.2 (3) 18.5 (66) 0.30 (0.09 – 0.1.01)
Late Parasitological Failure (LPF) 3.4 (2) 8.4 (30) 0.47 (0.11 – 2.08)
Total Failure (TF) 8.6 (5) 27.9 (96) 0.32 (0.12 – 0.84)
Adequate Clinical and Parasitological Response (ACPR) 91.4 (53) 73.0 (260) 3.15 (1.19– 8.30)
MUAC < 125 mm (n=74) ≥ 125 mm (n=340) 0.033
Late Clinical Failure (LCF) 6.8 (5) 18.8 (64) 0.35 (0.13 – 0.91)
Late Parasitological Failure (LPF) 6.8 (5) 7.9 (27) 0.94 (0.35 – 2.55)
Total Failure (TF) 13.5 (10) 26.8 (91) 0.48 (0.23 – 0.98)
Adequate Clinical and Parasitological Response (ACPR) 86.5 (64) 73.2 (249) 2.10 (1.02 – 4.34)
Serum albumin <23 g/L (n=38) ≥ 23 g/L (n=375) 0.22
Late Clinical Failure (LCF) 10.5 (4) 17.3 (65) 0.78 (0.26 – 2.37)
Late Parasitological Failure (LPF) 5.3 (2) 8.0 (30) 0.84 (0.19 – 3.76)
Total Failure (TF) 15.8 (6) 25.3 (95) 0.78 (0.30 – 2.01)
Adequate Clinical and Parasitological Response (ACPR) 84.2 (32) 74.7 (280) 1.29 (0.50 – 3.31)
HAZ < -2 (n=290) >= -2 (n=124) 0.78
Late Clinical Failure (LCF) 17.2 (50) 15.3 (19) 1.25 (0.70 – 2.24)
Late Parasitological Failure (LPF) 7.2 (21) 8.9 (11) 0.85 (0.40 – 1.83)
Total Failure (TF) 24.5 (71) 24.2 (30) 1.11 (0.67 – 1.82)
Adequate Clinical and Parasitological Response (ACPR) 75.5 (219) 75.8 (94) 0.90 (0.55 – 1.49)
* Ajust for malaria parasitemia with 26 600/µL as threshold.
Table 5 - 4 : Adverse events* by nutritional status among under five children with
uncomplicated malaria treated with AS+AQ in eastern DRC, from march 2007 to December 2010.
Severe acute malnutrition
Yes (n= 62) No (n= 369)
Adverse events
Anorexia 2 8
Asthenia 2 1
Diarrhoea 0 4
Vomiting 2 5
Nausea 0 4
Cough 0 2
Grade
Mild 4 20
Moderate 0 4
Severe 2 0
*The only one predominant adverse events for the same children was considered
No child developed severe malaria after enrolment. One child with severe acute malnutrition died at day 2. The Table 5-4 summarizes the adverse events (AEs) by nutritional status.
Nutritional status did not have any effect on the occurrence of AEs.
At least one adverse event concomitant with drug administration occurred in 9.7% (6/62) children with SAM as compared to 6.5% (24/369) without SAM (p=0.52). There were two severe adverse events among SAM children, both of them asthenia as the parent/guardian reported that the child could not participate to habitual activities.
5.4 Discussion
After adjustment for malaria parasitemaia, more than a quarter of children (27.9%) without SAM experienced a treatment failure while this proportion was 8.6% among those with SAM.
Children with SAM or MUAC < 125 mm had ACPR OR > 1 compared to those without SAM or with MUAC ≥ 125 mm. This can suggest that AS+AQ has a good efficacy among children with both uncomplicated falciparum malaria and malnutrition including a severe acute form in spite of their multiple deficiencies.
These results indicate also that the tolerance of AS+AQ dosing national strategy was globally good among children including those with SAM.
Overall, these results suggest that AS+AQ dosing national strategy unmodified can be used, to treat under five children with malnutrition including SAM suffering from uncomplicated falciparum malaria. Even if this study had not aimed to monitor AS+AQ efficacy, the total failure rates observed could be an alert suggesting that it could be indicated for DRC to think about possible actions for its malaria drug policy.
However, this study has important limitations requiring to be mentioned.
First, the study took place when malaria was hypo endemic all over Katana district. A large program of insecticide-treated bed nets (ITNs) distribution began when the study was carried out. A former study conducted in 1983 in the same region had shown plasmodia index variation between 25 and 44 percent indicating a mesoendemic malaria level [18].
When recruiting, it was difficult to include children suffering from malnutrition and uncomplicated malaria with parasitemia ≥ 1000 trophozoites/μL, one of major criteria inclusion in the study. The decrease of malaria endemicity during the study time add to the difficult to get malnourished children meeting inclusion criteria led to extend the recruitment period. During this period, Plasmodium species could change their sensitivity pattern to anti-malarial drugs.
Secondary, in this study we did not measure AS+AQ blood levels to demonstrate drug and metabolite concentration or its disposition in malnourished children. This may have led either to overestimations or to underestimation of total failure rates. Nevertheless, most of anti-malarial efficacy studies don’t include confirmation of drug metabolism; demonstration of the persistence of parasites in a patient receiving directly observed therapy is quite often considered sufficient.
Thirdly, in this study neither PCR (polymerase chain reaction) for confirmation of failure has been performed. This may also have led overestimations of failure instead of the re – infection. But the study has been carried out while a larger program of ITNs took place in the region. This could suggest that re-infection level could be low.
Lastly, these results may not be representative of the whole country. DRC is a huge country with multifaceted environmental factors including nutritional and malaria transmission patterns which may lead to regional variability in anti-malarial efficacy treatments.
In spite of these above limitations, this study has a public health strategy goal as a tool for uncomplicated malaria treatment in malnourished under five children using AS+AQ DRC national dosing.
Anti-malarial efficacy studies are scares in DRC although malaria is endemic in this huge country. More, there is no study which evaluated in the past anti-malaria efficacy in malnourished children in spite of malnutrition prevalence.
Since 2000, ACT has been recommended by WHO for the treatment of uncomplicated malaria [5]. By this way ACT has been adopted as a first-line treatment for uncomplicated malaria in several sub-Saharan countries among them the DRC. Unfortunately there are very limited pharmacokinetic studies of artemisinin, the main drug recommended for combination and derivate in African children in which chronically malnutrition is prevalent;
therefore the relationship between plasma drug concentration and efficacy in these patients is unknown [19].
However, in a recent study, Verret and al. [12] concluded to an efficacy of artemisinin-based combination therapies in chronically malnourished children for repeated episodes of malaria in Ugandan children.
Looking at the way of malaria prevention in malnourished children, Danquah et al. [20]
observed that the protective efficacies of intermittent preventive treatment with sulfadoxine-pyrimethamine in malnourished children in northern Ghana were roughly half or even less of those observed in non-malnourished children.
Our results by which children without SAM experienced a poor response to AS+AQ treatment than SAM children can be consistent with those done in studies aiming to identify pre-treatment risk factors of uncomplicated malaria treatment failure with CQ [21-23]. In those studies younger age, higher baseline temperature and higher initial parasitaemia were predictors of malaria treatment failure [21-23]. In our study, SAM children were significantly younger, had low body temperature and less malaria parasitemia density compared to those without SAM. Warsame et al. [24] observed also that patients who experienced clinical failure had significantly higher initial parasitaemia than those in whom there was an adequate clinical response.
Independently of the above mentioned factors predicting poor response to uncomplicated clinical malaria treatment, it was established that physiological changes in children with malnutrition were associated with abnormal disposition of drugs which could necessitate drug dosage modifications [25].
In human, Pussard and al observed that malaria and malnutrition increased plasma concentrations of quinine and reduced both the volume of distribution and the total plasma clearance [26]. Measuring the response to an acute uncomplicated Plasmodium falciparum malaria treatment with CQ, Olanrewaju WI and Johnson AW [27] observed that the proportion of children with persistence or recrudescence of parasitemia on days 4-7 and no significant reduction of parasitemia was higher among malnourished children compared to children with satisfactory nutritional status.
Because of the lack of sufficient published topical studies, the mechanism by which malnutrition can enhance or decrease anti-malarial efficacy is unknown.
In a former study in an animal model, vitamin E deficiency enhanced the antimalarial action of qinghaosu against Plasmodium yoelii in young female mice, both in terms of decreased parasitemia and improved survival, but Selenium deficiency did not [28].
Not withstanding malnutrition, our results related to anti-malarial efficacy could be consistent with studies carried out after AS+AQ implementation in DRC for uncomplicated malaria treatment. In 2004, a study conducted in the south of the South Kivu province presented a day 28 PCR genotyping-adjusted failure rates of 6.7% using AQ+AS [8]. Between 2003 to 2004, in Boende in north-west, the unadjusted total failures on day 28 was 41.0%; it was 8.8% in Kabalo in southeastern of DRC [29]. These total rates failures were observed before the PNLP had introduced AQ + AS as the first-line regimen for uncomplicated malaria treatment through the whole country in 2005. More than five years later it can be understandable that the total failure rates could raise. By using, usually the drug efficacy steadily declined. In Rwanda, in the neighborhood of South Kivu province, using the combination amodiaquine + sulfadoxine/ pyrimethamine (AQ + SP), the total rates failures at day 28 was estimated as 17% in 2003 [24]. Two years after its adoption as the first-line antimalarial the total rates failures at day 28 raised up 25% [30]. Lastly, the most common adverse events observed were anorexia, vomiting, nausea and diarrhoea. These events observed are consistent with those in Rwanda using AS+AQ [31]. Given that drug retention explained by the pathophysiological changes occurring in malnutrition which could result in adverse events which may be masked by a constellation of signs malnutrition, in our study, the drug tolerance was globally good among children including those with SAM despite their weakness. All children with SAM received were admitted in an intensive phase of the nutritional rehabilitation program. This can suggest that administration of AS+AQ among children with respecting a regular rhythm of the daily diet can decrease the drug adverse events. However, this study had not aimed to monitor AS+AQ efficacy, although these results cannot be representative for the whole huge country, they should alert the DRC national program to monitor the efficacy of its first-line anti-malarial for uncomplicated malaria treatment according to WHO malaria reports [32]. Actions including countrywide as ascertainment of treatment failure, assessment of other options available, and their cost and distribution, and reaching final consensus on the need to change should be carried out [3].
5.5 Conclusion
In Area where malaria and malnutrition co-exist, AS+AQ dosing recommended unmodified is an effective and safe drug which can be used to treat under five children with malnutrition including severe acute form suffering from uncomplicated falciparum malaria.
But the total failure rates observed in this study are an alert which could suggest that it could be indicated for DRC sanitary authorities to think about the possible actions of the malaria drug policy, even if this study had not aimed to monitor AS+AQ efficacy.
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