Intrigue sur le paludisme insulairede Madagascar

Milijaona Randrianarivelojosia, PhD, HDR

7ème édition du cours international “Atelier Paludisme”16 Mars 2009 – Institut Pasteur de Madagascar

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History of malaria in Madagascarlinked to the origin of Malagasy people

Source : Atlas nautique portugais (Atlas Miller) de Lopo Homem (1519)

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Malagasy people: Afro-Asian features mainly

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rHistory of malaria in Madagascar

linked to the origin of Malagasy people

Origin of the human population in the south-western part of the

Indian Ocean

On the basis of- laguage- agricultural practice- archeological data- genetic study- traditional habit

Source : Biodiversité du paludisme dans le monde

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r Maladie parasitaire, curable mais mortelle, due à Plasmodium sp

Groupes vulnérables au paludisme : femmes enceintes etenfants de moins de 5 ans

(~35% des cas de paludisme présumé à Madagascar selon lerapport officiel du Ministère de la Santé et du Planning Familial)

Paludisme

Murphy SC & Breman JG: Gaps in the childhood malaria burden in Africa: cerebral malaria, neurologicalsequelae, anemia, respiratory distress, hypoglycemia, and complications of pregnancy. Am J Trop Med Hyg2001, 64(1-2 Suppl):57-67.

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Paludisme : problème de santé dans le monde

World Malaria Report 2008, WHO/HTM/GMP/2008.1

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rMalaria, among major communicable diseases

in Madagascar

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r Geological diversity

Climate determined by geographic variables of latitude andaltitude with a contrast between

• eastern and central regions (humid climate)

• versus western and southern regions (dry climate)

Madagascar in few words

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Madagascar in few words

587,000 km2

111 districts18 ethnical groupsAfro-asianOne language (with dialects)

~19 millions inhabitants2 millions of presumed malaria cases/yearTB, AIDS, leprosy, …

1 physician per 6,000 inhabitantsGNP per capita : less than 300 USD

… a lovely country

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Malaria risk, vector, parasite species and

transmission

P. malariae P. ovale

P. falciparum P. vivax

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Malaria history in the island of Madagascar: myth, legend and reality

Oral tradition prior to the European arrival

“Hazo (trees) and tazo (fever) are the protection of thekingdom. Do not open the road” said the queen of the centralhighland.

“Man is the one who survives tazo (fever) in the costal areas”

Madagascar: known as cemetery for Europeansfever as killer in the cost areas as in XVI centuryfever as killer during the French military campaign in 1895

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1878 : first malaria outbreak on the central highland

Events:• extension of irrigated rice field• introduction of immigrant manpowerfrom mainland Africa to build churchesabove all

Plasmodium falciparum probably !!

Anopheles funestus ++

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r1895 : Second malaria outbreak

on the central highland

Eventsconstruction of railway,and population migration due to thecolonial war

Plasmodium falciparum probably

Anopheles funestus ++

Repost: use of quinine for cure andprevention mainly among French people,and extended to local population step bystep later on

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rEvolution of Malagasy population between 1900 and 2005 (X1000)

Gastineau B., Rakotoson L. (2005). Evolution de la population à Madagascar. Travaux etDocuments, n°5, Programme 4D, Institut Catholique de Madagascar et IRD, 14p., Antananarivo.

DDT and Chloroquinemassive use

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1980s : last malaria outbreak in Madagascar

(Africa Malaria Report, WHO, 2003)

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Little is known on malaria in Madagascar

Example : malaria burden

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What were mapped ?

http://www.pasteur.mg/AtlasPalu/index.html

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Malaria burden in Madagascar

Data from the official report at the Ministry of Health as in 1999 – 2000

20 – 30%

30 – 40%

>40%

Presumed malaria casesper consultant

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Malaria burden in Madagascar

Lack of malaria diagnosis tool is a

big issue

How high is malaria prevalence

in Madagascar ?

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r Area Region Type oflocality

Month Year Age Group

Examined Malariapositive

Brickaville E coast Rural 9-11 2006 <15 321 4 (1.2%)

Antananarivo IP highland Urban 1-12 2004 All 1456 21 (1.4%)

Antananarivo CS highland Urban 7 2003 All 739 11 (1.5%)

Antananarivo CS highland Urban 2 2003 All 771 15 (1.9%)

Antananarivo IP highland Urban 1-12 2003 All 1754 39 (2.2%)

Andapa E coast Rural 9-11 2006 <15 304 21 (6.9%)

Mahajanga W coast All 9-11 2003 All 107 19 (17.8%)

Malaria burden in Madagascar: unclear

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Area Region Type oflocality

Month Year Age Group

Examined Malariapositive

Ambohibary foothill Rural 3-6 2005 <5 60 24 (40%)

Tsiroanomandidy foothill All 3-7 2006 All 1656 731 (44.1%)

Lakato foothill Rural 3-6 2005 <5 147 70 (47.6%)

Ambodifotatra E. coast Rural 3-5 2004 <5 164 90 (54.9%)

Malaria burden in Madagascar: unclear

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Surveillance clinique des fièvres à Madagascar, 2007-2008

Paludisme confirméSuspicion d’arbovirosesSyndrome grippalAutres

mars2007 à avril2008

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Paludisme confirméSuspicion d’arbovirosesSyndrome grippalAutresMars à Avril 2007 Mars à Avril 2008

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Malaria control in Madagascar today

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rMalaria in the south-western part of the

Indian Ocean (described since ~1500)

Today situation (2009)

Endemic malariaComoros UnionMayotte (France)Madagascar

Almost eradicatedMaurice

Eradication doneLa Reunion (France)

Absence of local anophelesSeychelles

Drugs(treatment)

Bed nets(ITN)

Diagnosis(biological)

Madagascar +++ +++ +/-

Comoros Union +++ +++ ++

Mayotte +++ +++ +++Maurice +++ ! +++La Reunion +++ ! +++

What are used for malaria control in the south-western part of the Indian Ocean ?

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Year

1995 1999 2003

La ReunionImported casesLocal transmission

132-

153-

163-

MauriceImported casesLocal transmission

46-

73-

40-

(biologically diagnosed cases of malaria)

Malaria cases in the south-western part of the Indian Ocean (source : OMS)

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Key for malaria control in Madagascar

Environment

Malaria endemicity

Vector

Human

ParasiteAutochthonous or imported

Drugs (CT)Diagnosis

Nets (ITN)Indoor spraying

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rPolitique nationale de traitement antipaludique

à Madagascar

• Accès palustre simpleDans le passéChloroquine en 1ère ligne (1945 – 2005)Sulfadoxine-pyrimethamine en 2nde ligne

Depuis Décembre 2005Artesunate + amodiaquine en 1ère ligneArtemether + luméfantrine en 2nde ligne

• Accès palustre grave : Quinine

• TPI (femmes enceintes) : sulfadoxine-pyrimethamine

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Co-blister AS+AQArtesunate-amodiaquine

AS: 50 mg; AQ 153 mg

AS: 100 mgAQ: 270 mg

AS: 100 mgAQ: 270 mg

AS: 50 mgAQ: 135 mg

AS: 25 mgAQ: 67.5 mg

Combinaison fixe ASAQArtesunate-amodiaquine

Adults (≥36 kg)

Children (17-35 kg)

Young Children (8-17 kg)

Infants (4.5-8 kg)

Traitement de 3 jours par ASAQ

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artemisinin

ACT efficacy confirmed

Questions:Availability of ACT ?Funding for ACT : for how long ?

Recommendations versus realityintroduction of ACT in Madagascar

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rRecommendation versus reality:

therapeutic itinerary in Madagascar

Weakness of the health system

Long distance between villages andhealth facilities

Lack of health personnel

Local population leans sometimes ontraditional medicine usage and drugssold at groceries within the village

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r Fever is not malaria (it may be dueto viruses, bacterial infection, …)

Self medication

Usage of « traditional remedies »while their efficacies are notdemonstrated

Therapeutic anarchy(such as systematic quinine use atthe health centre and somehospital)

Recommendations versus reality:therapeutic error

(?)

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Susceptibility of P. falciparum to drugsin Madagascar today

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rSurveillance of antimalarial drug resistance

(RER created in 1999)

Randrianarivelojosia et al., Parassitologia 2002, 44: 141-147

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Surveillance of antimalarial drug resistance

In vivo test(WHO protocols)

Blood samples

In vitro tests

Chemosusceptibilityof parasites in vitro

Genotyping of genetic

resistance markers

Toamasina

Antananarivo

Sainte Marie

Ambatouro

SahasifotraLoukintsy

Maromandia

Ambodifotatra

Ambodiforaha

VohilavaAmbodivoampeno

Sainte Marie island, in the eastern coast of Madagascar

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8255 (67%)21 (26%)5 (6%)1 (1%)Total

2519 (76%)4 (16%)2 (8%)0CQ prepackaged

5736 (63%)17 (30%)3 (5%)1 (2%)CQ (25 mg/kg)

TotalACPRLPFLCFETF

Therapeutic responses in children <5 years

Chloroquine efficacy to treat falciparum malariain Sainte Marie (Madagascar)

OMS protocol, 14 day follow up, March-June 2004

05.000

10.00015.00020.00025.00030.00035.00040.00045.00050.00055.000

J0 J3 J7 J14

Para

site

s/µl

blo

od

Day of follow-upCQ 25 mg/kg

RCPA (n = 35)EPT (n = 17)ECT (n = 3)

14 day follow-up

Chloroquine efficacy to treat falciparum malariain Sainte Marie (Madagascar)

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rStudy in the eastern foothill area: Saharevo

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Variation of the Anopheles density in SaharevoAn

ophe

les

dens

ity

Months (1996 – 2000)1 2 3 4 5 6 7 8 9 10 11 12

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Malaria incidence in Saharevo

Months

(%)

0

0.1

0.2

0.3

0.4

0.5

9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 81999 2000 2001

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64%

30%

6%

clone no.:1clone no.:2clone no.:3

Malaria infection in Saharevo

(Courtesy of Razaiarimanga)

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rChloroquine efficacy in children with P. falciparum

malaria in Saharevo in 2004 (14 day follow-up)

Age (year)

Therapeutic responses <5 5-15 Total

Early Treatment Failure 0 0 0

Late Clinical Failure 5 1 6 (13.3%)

Late Parasitological Failure 3 5 8 (17.8%)

Accurate Parasitological and Clinical Response

11 20 31 (68.9%)

Total 19 26 45

But no pfcrt K76T mutant Plasmodium falciparum

OMS protocol, 14 day follow up, 2004

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Therapeutic responses

Drug ACPR ETF LCF LPF Total

Amodiaquine 68 (100%)

0 0 0 68

SP 92 (100%)

0 0 0 92

WHO protocol, 14 day follow-up, in 2005

Efficacy of monotherapy amodiaquine or SP in Saharevo (Madagascar) in children <10 years

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mutant pfcrt detected

No mutant pfcrt detected yet

Where is IPM

Comoros

Madagascar

TsiroanomandidyAntananarivo

Saharevo

Ste Marie

Andapa

SambavaAntsohihy

Mahajanga

First evidence of pfcrtmutant P. falciparum in

Madagascar

Randrianarivelojosia M et al. Trans R Soc Trop Med Hyg. 2006

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183 isolates of P. falciparum

(PCR/RFLP)

Absence of pfcrt K76Tmutation: 177

Presence of pfcrt K76Tmutation : 6

(Analysis of the pfcrt gene segment, spanning codons 72-76)

(n = 12)Haplotype CVMNK

HaplotypesCVIET (n = 4)CVIDT (n = 2)

First evidence of pfcrt mutant P. falciparum in Madagascar

Randrianarivelojosia M et al. Trans R Soc Trop Med Hyg. 2006

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?Since 1945 : chloroquine, first line drug to treat malaria

1952 – 1971 : chemoprophylaxis (children at the Red Cross Centers and at the primary schools)

1971 – 1975/78 : irregular chemoprophylaxis (MOH)

1985 – 1988 : in-home treatment of fever to control themalaria outbreak (CQ dispatched by 37,480dispensers throughout the country)

Massive uses of chloroquine in Madagascar

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Marketing social(0.025 USD)

Free of charge

Massive uses of chloroquine in Madagascar today

The current massive distribution of chloroquine for in-homemanagement of fever in children will promote the disseminationof these mutant, chloroquine-resistant parasites.

• 179 patients inclus (dont 58 enfants < 5 ans)

• Aucun patient perdu de vue

• Un seul patient s’est retiré de l’étude

• Les patients ne se présentant le jour prévu de la visite étaient immédiatement contactés

Aucun événement indésirable grave

Etude clinique phase III avec la combinaison fixe artésunate + amodiaquine en 2006 à Madagascar

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Résultats des examens parasitologiques à J3 à Madagascar

Sans parasites Coarsucam-1 Coarsucam-2 Coartem Total

OUI

NON

Absent

59 (100.0%)

0

0

59(100.0%)

0

1

60(100.0%)

0

0

178(100.0%)

0

1

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Efficacité thérapeutique de Coarsucam® à J28 à Madagascar après la correction par PCR (PP

population)

Réponsesthérapeutiques

Coarsucam-1N=59

Coarsucam-2N=58

CoartemN=60

TotalN=177

ECP 0 0 0 0

ECT 0 0 1 (1.7%) 1 (0.6%)

EPT 1 (1.7%) 0 0 1 (0.6%)

RCPA58

(98.3%) 58

(100.0%) 59

(98.3%) 175

(98.9%)

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Co-blister AS+AQArtesunate-amodiaquine

AS: 50 mg; AQ 153 mg

AS: 100 mgAQ: 270 mg

AS: 100 mgAQ: 270 mg

AS: 50 mgAQ: 135 mg

AS: 25 mgAQ: 67.5 mg

Combinaison fixe ASAQArtesunate-amodiaquine

Adults (≥36 kg)

Children (17-35 kg)

Young Children (8-17 kg)

Infants (4.5-8 kg)

Avis personnel : artésunate + amodiaquine pour Madagascar

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What is malaria for the population ?

And how to deal and live with ?

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Missions :

Moustiquaire imprégnée d’insecticide

Aspersion intra-domiciliaire d’insecticide

Artesunate + amodiaquine

TPI par SP (femmes enceintes)

PECADOM

…

Nouvelle vision à Madagascar : « Elimination du paludisme »

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rPlan stratégique de lutte antipaludique à

Madagascar de 2008 – 2012

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Malaria known as well known by Malagasy

(page 73)

Tazo (fever, chill, headache, fatigue …) is not only malaria

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artemisinin

First line treatment:Artesunate + amodiaquine (Dec 2005)

ACT efficacy confirmed

Questions :Are they used ? Are they accepted ?

Recommendations versus realityintroduction of ACT in Madagascar

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Manja

Results from Manja, south-western region

Remote area

13,430 km²

62,606 inhabitants

6 communes

Moderate to high malaria transmission

150 mothers/caregivers interviewed

April 2006 (courtesy of Ralemary)

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Child caregiver’s knowledge on malaria in Manja

Clinical signs of malariaFeverChill Loss of appetite Muscle pain

147 (98%)78 (52%)19 (13%)4 (2%)

Malaria treatment for childrenChloroquineParacetamol AspirinCotrimTetracyclinePaluStop (prepacked chloroquine)Ody Tazomoka (prepacked chloroquine)Plante

136 (91%)135 (90%)63 (42%)52 (35%)35 (23%)26 (17%)27 (18%)3 (2%)

Source : Nicolas Ralemary, IMATEP 2006

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rEnquête CAP chez les

femmes enceintes vues en CPN à Antananarivo

en 2007

a : CSB2 Isotry Centralb : CSB2 Tsaralalàna (CSMI) c : CSB2 Ambohipod : CSB2 Andoharanofotsy

N

Source : Jemima RAVELONARIVO. Femmesenceintes face au paludisme : connaissances etpratiques. Thèse de Médecine. 20 Décembre 2007

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Association de la fièvre au diagnostic du paludismeCSB2 d’Ambohipo : 69,6%CSB2 d’Andoharanofotsy : 56,2%CSB2 d’Isotry Central : 45,8%CSB2 de Tsaralalàna : 68,7%

Évaluation de l’état de connaissances des femmes enceintes à Antananarivo (N = 404)

Total : 57,9% (IC95% : 52,9 – 62,8%)

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- AntipaludiquesChloroquine 76,9% (IC95% : 72,5 – 80,9%)Quinine injectable 25,7% (IC95% : 21,6 – 30,3%)

- Antipyrétiques : Paracetamol 60,6%

- Antibiotiques : Cotrimoxazole 10,6%

- Médecine traditionnelle : 2,9%

Attitudes et pratiques des femmes enceintes à Antananarivo

Médicaments les plus utilisés pour traiter lepaludisme avec ou sans prescription médicale :

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- AntipaludiquesChloroquine 76,9% (IC95% : 72,5 – 80,9%)Quinine injectable 25,7% (IC95% : 21,6 – 30,3%)

- Antipyrétiques : Paracetamol 60,6%

- Antibiotiques : Cotrimoxazole 10,6%

- Médecine traditionnelle : 2,9%

Attitudes et pratiques des femmes enceintes à Antananarivo

Médicaments les plus utilisés pour traiter lepaludisme avec ou sans prescription médicale :

ACT = 0%

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66

Médicaments antipaludiques prescrits : quinine (49,4%), artéméther-luméfantrine (21,5%), sulfadoxine-pyriméthamine (12,7%), artésunate-amodiaquine (11,4%), chloroquine (5,1%)

Prescripteurs privés (%)

Prescripteurs publics (%)

p

ACT 18 (50) 7 (17,9) < 10-3

Quinine 8 (22,2) 29 (74,4)

Chloroquine ou SP 10 (27,8) 3 (7,8)

Total 36 (100) 39 (100)

Etude de la prescription d’antipaludiques à Moramanga (marge est) en 2008

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View point :

Is malaria elimination doable in Madagascar ?

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Toamasina

Antananarivo

Sainte Marie

Ambatouro

SahasifotraLoukintsy

Maromandia

Ambodifotatra

Ambodiforaha

VohilavaAmbodivoampeno

Sainte Marie island, in the eastern coast of Madagascar

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rHealth project support for the district of Ste Marie

to combat malaria, worm, filariasis

French Malagasy WHOGovernement Government (MoH) office in Madagascar

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Since 2006

Malaria diagnosis by RDT and use of ACT at the health facilities

IPT by SP in pregnant women

ITN for malaria prevention (almost one net per inhabitant)

Passive and active detection of malaria

+

Mass drug administration of anti-helminthTreatment of acute and chronic filariasisCoordinated actions (with extra manpower for the project)

Health project support for the district of Ste Marieto combat malaria, worm, filariasis

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Résultats de lutte antipaludique mitigés à Ste Marie en 2009

Moustiquaires distribuées > nombre de population

Prévalence du paludisme chez les écoliersMars – Mai 2004 = ~50%Janvier – Février 2009 = ~23%

Moustiquaire pour la pêche, clôture de pépinière, …

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Concluding remarks

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Paludisme dans le monde (1900 – 2002)

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Unpredictable !

"Our current events will someday become ancient history indispensable

to those who are our successors."

Malaria in the future in Madagascar

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Main problem in Madagascar: poverty and

corruption

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To combat malaria and infectious diseases related to poverty in general

Research has the first words

Intervention has the last words

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People naturally live with malaria in Madagascar

PreventionTraditional method: burn aromatic plantModern method: bed nets, drugs, repellent, indoorspraying of insecticide, modern house

TreatmentTraditional medicine: plants, exorcism, prayersModern drug in : self medication at home, recommendedin-home management of fever, mass treatment, healthfacilities, intermittent preventive treatments, …

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The revised policy recommendations:- Shift from chloroquine to ACT as first line treatment(artesunate + amodiaquine)- Use of SP for IPT in pregnant women

Genotyping of pfcrt, pfdhfr, pfdhps, and of any “meaningful”resistance markers is a useful tool for drug resistancesurveillance in Madagascar

Concluding remarks on combat against parasites

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The pfcrt K76T mutation which is critical for resistance tochloroquine was detected in few samples within the mutanthaplotypes CVIET and CVIDT

In this context, the genotyping of pfcrt remains a useful tool forchloroquine resistance surveillance as the prevalence of pfcrtmutations is far from saturation in Madagascar

Concluding remarks on combat against parasites

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r Ma conviction :

« Améliorer le contrôle du paludisme entraînera une

amélioration du contrôle des autres maladies dont

les premiers symptômes se traduisent par de la

fièvre »

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r Will chloroquine withdrawal be enough to bring backchloroquine-sensitive P. falciparum in Madagascar ?

cf. Malawi experiences; and the malaria transmission levels in Madagascar

How to maintain the use of ACT? (funding issue;distribution matter; )

How to bring ACT to the communities?

How to assess properly malaria burden?

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r In which way the ACTs use will affect the Plasmodiumsp population structures and the malaria transmissionin Madagascar ?

cf. the malaria transmission levels in Madagascar

Madagascar an island can house the first trial at largescale to “eliminate malaria” by use of combinedtherapy (ACT or non-ACT) and insecticide

cf. the successful malaria control in Madagascar by use of CQ and DDT inthe 1950s

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SLP MadagascarLouise H. RanaivoJosée Sahondra-HarisoaDésiré Rakotoson Andrianirina RavelosonArthur RakotonjanabeloVirginio Pietra…

Financial supportsMinistry of Health and Family Planning, Madagascar French GovernmentWorld Bank (Cresan-2) FSP/RAIRaf 6025, IAEA Pal+, FranceWHO Académies des Sciences, France European Union Institut Pasteur

IP MadagascarLucie RaharimalalaLaurence RandrianasoloArthur RandriamantenaArsène RatsimbasoaLéon RabarijaonaRonan JambouFrédéric ArieyMarie Ange Rason…

Villagers and patients from different study sites

Acknowledgements

Peripheral health facilities

PNLP, Comoros UnionRahamatou SilaiSaid Ahmed BedjaAhmed Ouledi…

Oversea collaborationsFrédéric ArieyOdile PuijalonDavid FidockChristophe Rogier…

Intrigue sur le paludisme insulairede Madagascar

Milijaona Randrianarivelojosia, PhD, HDR

7ème édition du cours international “Atelier Paludisme”16 Mars 2009 – Institut Pasteur de Madagascar