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Intrigue sur le paludisme insulaire de Madagascar - Conférence du 7e édition du Cours international « Atelier Paludisme » - RANDRIANARIVELOJOSIA Milijaona - Madagascar - [email protected]
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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
Pal
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à M
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Pal
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à M
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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