Intrigue sur le paludisme insulaire de Madagascar

Intrigue sur le paludisme insulaire
de Madagascar

Milijaona Randrianarivelojosia, PhD, HDR

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

History of malaria in Madagascar
linked to the origin of Malagasy people
P aludism e à M adagascar

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

Malagasy people: Afro-Asian features mainly

History 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

Paludisme

Maladie parasitaire, curable mais mortelle, due à Plasmodium sp

Groupes vulnérables au paludisme : femmes enceintes et
enfants de moins de 5 ans

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

Murphy SC & Breman JG: Gaps in the childhood malaria burden in Africa: cerebral malaria, neurological
sequelae, anemia, respiratory distress, hypoglycemia, and complications of pregnancy. Am J Trop Med Hyg
2001, 64(1-2 Suppl):57-67.

Paludisme : problème de santé dans le monde

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

Malaria, among major communicable diseases
in Madagascar

Madagascar in few words

Geological diversity

Climate determined by geographic variables of latitude and
altitude with a contrast between

• eastern and central regions (humid climate)

• versus western and southern regions (dry climate)

Madagascar in few words
587,000 km2
111 districts

18 ethnical groups
Afro-asian
One language (with dialects)

~19 millions inhabitants
2 millions of presumed malaria cases/year
TB, AIDS, leprosy, …

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

… a lovely country

Malaria risk, vector,
parasite species and
transmission

P . falciparum P . vivax

P . m alariae P . ovale

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 the
kingdom. Do not open the road” said the queen of the central
highland.

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

Madagascar: known as cemetery for Europeans
fever as killer in the cost areas as in XVI century
fever as killer during the French military campaign in 1895

1878 : first malaria outbreak
on the central highland

Events:
• extension of irrigated rice field
• introduction of immigrant manpower
from mainland Africa to build churches
above all

Plasmodium falciparum probably !!

Anopheles funestus ++

1895 : Second malaria outbreak
on the central highland

Events

construction of railway,
and population migration due to the
colonial war
Plasmodium falciparum probably
Anopheles funestus ++

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

Evolution of Malagasy population
between 1900 and 2005 (X1000)

DDT and
Chloroquine
massive use

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

1980s : last malaria outbreak in Madagascar

(Africa Malaria Report, WHO, 2003)


Little is known on malaria in Madagascar

Example : malaria burden

What were mapped ?

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

Malaria burden in
Madagascar

Presumed malaria cases
per consultant
20 – 30%
30 – 40%

>40%

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

Malaria burden in
Madagascar

Lack of malaria How high
is malaria prevalence
diagnosis tool is a
in Madagascar ?
big issue

Malaria burden in Madagascar: unclear

Area Region Type of Month Year Age Examined Malaria

locality Group positive
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

Area Region Type of Month Year Age Examined Malaria
locality Group positive
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%)

Surveillance
clinique
des fièvres à

Madagascar,
2007-2008

Paludisme confirmé
Suspicion d’arboviroses
Syndrome grippal
Autres

mars2007 à avril2008


Paludisme confirmé
Suspicion d’arboviroses
Syndrome grippal
Mars à Avril 2007 Autres Mars à Avril 2008


Malaria control in Madagascar today

Malaria in the south-western part of the
Indian Ocean (described since ~1500)

Today situation (2009)

Endemic malaria
Comoros Union
Mayotte (France)
Madagascar
Almost eradicated
Maurice
Eradication done
La Reunion (France)
Absence of local anopheles
Seychelles

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

Drugs Bed nets Diagnosis
(treatment) (ITN) (biological)
Madagascar +++ +++ +/-
Comoros Union +++ +++ ++
Mayotte +++ +++ +++
Maurice +++ ! +++
La Reunion +++ ! +++

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

Year
1995 1999 2003
La Reunion
Imported cases 132 153 163
Local transmission - - -
Maurice
Imported cases 46 73 40
Local transmission - - -
(biologically diagnosed cases of malaria)

Key for malaria control in Madagascar

Environment

Malaria Parasite
Vector
endemicity Autochthonous or imported
Nets (ITN)
Indoor spraying Drugs (CT)
Diagnosis
Human

Politique nationale de traitement antipaludique
à Madagascar

• Accès palustre simple

Dans le passé
Chloroquine en 1ère ligne (1945 – 2005)
Sulfadoxine-pyrimethamine en 2nde ligne
Depuis Décembre 2005
Artesunate + amodiaquine en 1ère ligne
Artemether + luméfantrine en 2nde ligne

• Accès palustre grave : Quinine
• TPI (femmes enceintes) : sulfadoxine-pyrimethamine

Traitement de 3 jours par ASAQ

Co-blister AS+AQ
Combinaison fixe ASAQ Artesunate-amodiaquine
Artesunate-amodiaquine

AS: 50 mg; AQ 153 mg
Infants (4.5-8 kg)
AS: 25 mg
AQ: 67.5 mg

Young Children (8-17 kg)
AS: 50 mg
AQ: 135 mg

Children (17-35 kg)

AS: 100 mg
AQ: 270 mg

Adults (≥36 kg)
AS: 100 mg
AQ: 270 mg

Recommendations versus reality
introduction of ACT in Madagascar

ACT efficacy confirmed

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

Recommendation versus reality:
therapeutic itinerary in Madagascar

Weakness of the health system

Long distance between villages and
health facilities

Lack of health personnel

Local population leans sometimes on
traditional medicine usage and drugs
sold at groceries within the village

Recommendations versus reality:
therapeutic error

Fever is not malaria (it may be due

to viruses, bacterial infection, …)

Self medication

Usage of « traditional remedies »
while their efficacies are not
demonstrated

Therapeutic anarchy
(such as systematic quinine use at
the health centre and some
hospital) (?)


Susceptibility of P. falciparum to drugs
in Madagascar today

Surveillance of antimalarial drug resistance
(RER created in 1999)

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

Surveillance of antimalarial drug resistance

Chemosusceptibility

of parasites in vitro

Blood
In vitro tests
samples

Genotyping
of genetic
resistance markers

In vivo test
(WHO protocols)

Sainte Marie island, in the eastern coast of
Madagascar
Ambatouro

Sainte Marie

Toamasina
Antananarivo Loukintsy Sahasifotra
Maromandia

Ambodifotatra
Ambodiforaha
Ambodivoampeno
Vohilava

Chloroquine efficacy to treat falciparum malaria
in Sainte Marie (Madagascar)

Therapeutic responses in children <5 years
ETF LCF LPF ACPR Total

CQ (25 mg/kg) 1 (2%) 3 (5%) 17 (30%) 36 (63%) 57
CQ prepackaged 0 2 (8%) 4 (16%) 19 (76%) 25

Total 1 (1%) 5 (6%) 21 (26%) 55 (67%) 82

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

Chloroquine efficacy to treat falciparum malaria
in Sainte Marie (Madagascar)
55.000
50.000
45.000
Parasites/µl blood

40.000
35.000
30.000 RCPA (n = 35)
EPT (n = 17)
25.000 ECT (n = 3)
20.000
14 day follow-up
15.000
10.000
5.000
0
J0 J3 J7 J14
Day of follow-up
CQ 25 mg/kg

Study in the eastern foothill area: Saharevo

Variation of the Anopheles density in Saharevo

Anopheles density

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

Malaria incidence in Saharevo
(%)
0.5

0.4

0.3

0.2

0.1

0
9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8
1999 2000 2001
Months

Malaria infection in Saharevo

6%

30% clone no.:1
clone no.:2
clone no.:3
64%

(Courtesy of Razaiarimanga)

Chloroquine 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 11 20 31 (68.9%)
and Clinical Response
Total 19 26 45

OMS protocol, 14 day follow up, 2004
But no pfcrt K76T mutant Plasm odium falciparum

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

Therapeutic responses
Drug ACPR ETF LCF LPF Total

Amodiaquine 68 0 0 0 68
(100%)
SP 92 0 0 0 92
(100%)

WHO protocol, 14 day follow-up, in 2005

First evidence of pfcrt Comoros

mutant P . falciparum in
Madagascar Sambava
Antsohihy

Andapa
Mahajanga
Ste Marie

mutant pfcrt detected Tsiroanomandidy Saharevo
Antananarivo
No mutant pfcrt detected yet

Where is IPM

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

First evidence of pfcrt mutant P . falciparum in
Madagascar
183 isolates
of P. falciparum

(PCR/RFLP)

Absence of pfcrt K76T Presence of pfcrt K76T
mutation: 177 mutation : 6

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

(n = 12) Haplotypes
Haplotype CVMNK CVIET (n = 4)
CVIDT (n = 2)

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

Massive uses of chloroquine in Madagascar

?

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 the
malaria outbreak (CQ dispatched by 37,480
dispensers throughout the country)

Massive uses of chloroquine in Madagascar today

Marketing social
(0.025 USD)

Free of charge

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

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

Résultats des examens parasitologiques à J3 à
Madagascar

Sans
Coarsucam-1 Coarsucam-2 Coartem Total
parasites
OUI 59 59 60 178
(100.0%) (100.0%) (100.0%) (100.0%)

NON 0 0 0 0

Absent 0 1 0 1

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

Réponses Coarsucam-1 Coarsucam-2 Coartem Total
thérapeutiques N=59 N=58 N=60 N=177

ECP 0 0 0 0

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

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

58 58 59 175
RCPA (98.3%) (100.0%) (98.3%) (98.9%)

Avis personnel : artésunate + amodiaquine pour
Madagascar
Co-blister AS+AQ
Combinaison fixe ASAQ Artesunate-amodiaquine
Artesunate-amodiaquine

AS: 50 mg; AQ 153 mg
Infants (4.5-8 kg)
AS: 25 mg
AQ: 67.5 mg

Young Children (8-17 kg)
AS: 50 mg
AQ: 135 mg

Children (17-35 kg)

AS: 100 mg
AQ: 270 mg

Adults (≥36 kg)
AS: 100 mg
AQ: 270 mg


What is malaria for the population ?

And how to deal and live with ?

Nouvelle vision à Madagascar : « Elimination du
paludisme »

Missions :

Moustiquaire imprégnée d’insecticide

Aspersion intra-domiciliaire d’insecticide

Artesunate + amodiaquine

TPI par SP (femmes enceintes)

PECADOM

…

Plan stratégique de lutte antipaludique à
Madagascar de 2008 – 2012

Malaria known as well known by Malagasy

(page 73)

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

Recommendations versus reality
introduction of ACT in Madagascar

First line treatment:

Artesunate + amodiaquine (Dec 2005)

ACT efficacy confirmed

Questions : artemisinin
Are they used ? Are they accepted ?

Results from Manja, south-western region

Remote area

13,430 km²

62,606 inhabitants
Manja
6 communes

Moderate to high malaria transmission

150 mothers/caregivers interviewed

April 2006 (courtesy of Ralemary)

Child caregiver’s knowledge on malaria in Manja

Clinical signs of malaria
Fever 147 (98%)

Chill 78 (52%)
Loss of appetite 19 (13%)
Muscle pain 4 (2%)
Malaria treatment for children
Chloroquine 136 (91%)
Paracetamol 135 (90%)
Aspirin 63 (42%)
Cotrim 52 (35%)
Tetracycline 35 (23%)
PaluStop (prepacked chloroquine) 26 (17%)
Ody Tazomoka (prepacked chloroquine) 27 (18%)
Plante 3 (2%)
Source : Nicolas Ralemary, IMATEP 2006

Enquête CAP chez les
femmes enceintes vues N

en CPN à Antananarivo
en 2007

a : CSB2 Isotry Central
b : CSB2 Tsaralalàna (CSMI)
c : CSB2 Ambohipo
d : CSB2 Andoharanofotsy

Source : Jemima RAVELONARIVO. Femmes
enceintes face au paludisme : connaissances et
pratiques. Thèse de Médecine. 20 Décembre 2007

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

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

Total : 57,9% (IC95% : 52,9 – 62,8%)

Attitudes et pratiques des femmes enceintes à
Antananarivo
 Médicaments les plus utilisés pour traiter le

paludisme avec ou sans prescription médicale :

- Antipaludiques
Chloroquine 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 le

paludisme avec ou sans prescription médicale :

- Antipaludiques
Chloroquine 76,9% (IC95% : 72,5 – 80,9%)
ACT = 0%
Quinine injectable 25,7% (IC95% : 21,6 – 30,3%)
- Antipyrétiques : Paracetamol 60,6%
- Antibiotiques : Cotrimoxazole 10,6%
- Médecine traditionnelle : 2,9%

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

Médicaments antipaludiques prescrits : quinine (49,4%), artéméther-

luméfantrine (21,5%), sulfadoxine-pyriméthamine (12,7%), artésunate-
amodiaquine (11,4%), chloroquine (5,1%)

Prescripteurs Prescripteurs p
privés (%) publics (%)
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)

66


View point :

Is malaria elimination doable in Madagascar ?

Sainte Marie island, in the eastern coast of
Madagascar
Ambatouro

Sainte Marie

Toamasina
Antananarivo Loukintsy Sahasifotra
Maromandia

Ambodifotatra
Ambodiforaha
Ambodivoampeno
Vohilava

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

French Malagasy WHO
Governement Government (MoH) office in Madagascar

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

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-helminth
Treatment of acute and chronic filariasis
Coordinated actions (with extra manpower for the project)

Résultats de lutte antipaludique mitigés à Ste
Marie en 2009
Moustiquaires distribuées > nombre de population

Prévalence du paludisme chez les écoliers
Mars – Mai 2004 = ~50%
Janvier – Février 2009 = ~23%
Moustiquaire pour la pêche, clôture de pépinière, …


Concluding remarks

Paludisme dans le monde (1900 – 2002)

Malaria in the future in Madagascar

Unpredictable !

"Our current events will someday
become ancient history indispensable
to those who are our successors."

Main problem in
Madagascar: poverty and
corruption


To combat malaria
and infectious diseases related to poverty in general

Research has the first words

Intervention has the last words

People naturally live with malaria in Madagascar

Prevention

Traditional method: burn aromatic plant
Modern method: bed nets, drugs, repellent, indoor
spraying of insecticide, modern house

Treatment
Traditional medicine: plants, exorcism, prayers
Modern drug in : self medication at home, recommended
in-home management of fever, mass treatment, health
facilities, intermittent preventive treatments, …

Concluding remarks on combat against parasites

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 resistance
surveillance in Madagascar

Concluding remarks on combat against parasites

The pfcrt K76T mutation which is critical for resistance to
chloroquine was detected in few samples within the mutant
haplotypes CVIET and CVIDT

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

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 »

Will chloroquine withdrawal be enough to bring back

chloroquine-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?

In which way the ACTs use will affect the Plasm odium

sp population structures and the malaria transmission
in Madagascar ?
cf. the malaria transmission levels in Madagascar

Madagascar an island can house the first trial at large
scale to “eliminate malaria” by use of combined
therapy (ACT or non-ACT) and insecticide
cf. the successful malaria control in Madagascar by use of CQ and DDT in
the 1950s

Acknowledgements

Villagers and patients IP Madagascar
PNLP, Comoros
from different study sites Lucie Raharimalala Union
Laurence Randrianasolo

Rahamatou Silai
SLP Madagascar Arthur Randriamantena
Said Ahmed Bedja
Louise H. Ranaivo Arsène Ratsimbasoa
Ahmed Ouledi
Josée Sahondra-Harisoa Léon Rabarijaona …
Désiré Rakotoson Ronan Jambou Oversea collaborations
Andrianirina Raveloson Frédéric Ariey Frédéric Ariey
Arthur Rakotonjanabelo Marie Ange Rason Odile Puijalon
Virginio Pietra … David Fidock
… Christophe Rogier
Peripheral health facilities …

Financial supports
Ministry of Health and Family Planning, Madagascar French Government
World Bank (Cresan-2) FSP/RAI
Raf 6025, IAEA Pal+, France
WHO Académies des Sciences, France
European Union Institut Pasteur

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