partie iii - traitement du paludisme à falciparum non

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.

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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)


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



Total Failure (TF) 15.8 (6) 25.3 (95) 0.78 (0.30 – 2.01)


HAZ < -2 (n=290) >= -2 (n=124) 0.78



Total Failure (TF) 24.5 (71) 24.2 (30) 1.11 (0.67 – 1.82)


* 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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partie iii - traitement du paludisme à falciparum non

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