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Scandinavian Journal of Infectious Diseases, 2010; 42: 22–32 REVIEW ARTICLE History and current status of Plasmodium falciparum antimalarial drug resistance in Madagascar VALÉRIE ANDRIANTSOANIRINA 1, DIDIER MÉNARD1, LUCIANO TUSEO2 & RÉMY DURAND3 From the 1Malaria Research Unit, Institut Pasteur de Madagascar, Antananarivo, Madagascar, 2World Health Organization Offi ce of Madagascar and La Réunion, Antananarivo, Madagascar, and 3Laboratoire de Parasitologie-Mycologie, Hôpital Avicenne, AP-HP, Bobigny, France Abstract Malaria remains a major health problem in Madagascar. Over past decades, the burden of malarial disease has fl uctuated over time, partly in line with the successes and failures of antimalarial policy. In the 1950s and 1960s, a sharp decline in malaria transmission was observed in the central highlands due to indoor spraying with DDT and to the massive use of chloroquine by the population. Following this, the discontinuation of the ‘nivaquinization’ policy was followed by devastat- ing outbreaks in the central highlands in the 1980s. Currently, the rate of in vitro chloroquine-resistant Plasmodium falci- parum isolates does not exceed 5%. This fi gure appears disconnected from the high level of clinical treatment failure (near 40%). pfcrt mutant isolates are found in less than 1% of isolates on the Island. Conversely, pfmdr1 mutant isolates are found in more than 60% of isolates and may be responsible for the bulk of resistance to chloroquine in Madagascar. Other anti- malarials remain generally effective in Madagascar. Recent clinical and in vitro data support the complete effi cacy of the combination artesunate–amodiaquine in Madagascar. As such, this artemisinin combination therapy should play a central role in the control and possible elimination of P. falciparum malaria in Madagascar. For personal use only. Introduction chloroquine as the fi rst-line treatment, whereas the sulfadoxine–pyrimethamine combination (SP) is given Malaria remains a major health problem in Mada- intermittently as preventive treatment in pregnant gascar [ 1,2]. Together with indoor spraying of DDT women. Following the global trend, the Malagasy (and the use of long lasting impregnated bed nets), government claims as its objective the elimination of the use of antimalarial drugs is central to the control malaria as a public health problem [10]. The aim of of malaria [ 3]. Malaria morbidity and mortality have this review is to present the history and current fl uctuated over time, partly in line with the successes status of P. falciparum antimalarial drug resistance Scand J Infect Dis Downloaded from informahealthcare.com by Institut Pasteur on 09/11/12 and failures of antimalarial policy. In the 1950s and in Madagascar and to consider its impact on malaria 1960s, a sharp decline in malaria transmission was control programmes. observed, mostly in the central highlands, due to indoor spraying with dichlorodiphenyltrichloroethane (DDT) and to the massive use of chloroquine by the population Context and malaria situation in Madagascar [4,5]. These results were obtained because of the well-organized healthcare system, which in particular Madagascar appears as an isolated fragment of the allowed the implementation of parasitological diag- ancient continent ‘Gondwana’, which was separated nosis. Subsequently, the discontinuation of the ‘niva- from Africa 65–100 million y ago [ 11]. Human set- quinization’ policy was followed by devastating tlement in Madagascar occurred relatively recently, outbreaks in the central highland areas in the 1980s with the population originating from overseas. The [6–8]. Meanwhile, Plasmodium falciparum clinical fi rst arrivals are thought to have settled during the resistance emerged and spread [ 9]. Today, artemisinin- fi rst centuries of the Christian era, reaching the central based combination therapy (ACT) has replaced highlands only in the 5 th–7th centuries. Parasites and Correspondence: R. Durand, Laboratoire de Parasitologie-Mycologie, AP-HP, Hôpital Avicenne, 125 rue de Stalingrad, 93009 Bobigny Cedex, France. E-mail: [email protected] (Received 25 June 2009; accepted 24 August 2009) ISSN 0036-5548 print/ISSN 1651-1980 online © 2009 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS) DOI: 10.3109/00365540903289670 Antimalarial drug resistance in Madagascar 23 2500000 12 10 2000000 8 1500000 6 1000000 4 500000 2 0 0 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 number of reported malaria cases incidence (%) Figure 1. Malaria incidence and number of cases in the y 1999–2008 in Madagascar. For personal use only. vectors were probably introduced to the Malagasy reported 1.01 million cases in 2006 [15]. Reported coasts by the Indonesian, Bantou and Arab migrations cases since 1999 are presented in Figure 1 . More than of the 1 st to 14 th centuries [ 12]. Hence, all human 90% of malaria cases are due to P. falciparum. The malaria species except Plasmodium knowlesi (P. fal- prevalence of P. vivax has been estimated to be 6.3% ciparum, Plasmodium vivax, Plasmodium ovale, and and of P. malariae to be 1.1% [ 16,17]. The estimated Plasmodium malariae) are found in Madagascar. population of the whole island soared from 2.5 million Currently, the main vectors (Anopheles gambiae, in 1900 to 5.5 million in 1961, 9 million in 1980 and Anopheles funestus and Anopheles arabiensis) are 18 million in 2008 [ 10]. Children aged very similar to those of the African continent. The 5 y make up 16.7% of the population and half of Scand J Infect Dis Downloaded from informahealthcare.com by Institut Pasteur on 09/11/12 symptoms of ‘tazomoka’ (mosquito-borne fever), the the population is aged 20 y. The Republic of Mada- Malagasy word for malaria, were known by the local gascar is one of the poorest countries in the world. inhabitants who treated them with traditional herbal Malaria is the second most important cause of mor- remedies. Europeans brought with them their anti- bidity (after acute respiratory infections) and mortal- malarial medication in the form of Cinchona bark ity (after diarrhoea). Malaria is responsible for powder (from which quinine was isolated in 1820). more than 30% of outpatient attendance at health At the end of the 19 th century, French colonizers, centres [ 10]. lead by Gallieni, brought large quantities of quinine The 587,000 km 2 of Madagascar can be divided to Madagascar [ 10]. Chloroquine (CQ), the fi rst into 5 geographical regions: the east coast, the Tsar- synthetic antimalarial compound, was introduced in atanana Massif, the central highlands, the west coast, 1945. Resistance to CQ (CQR) in Madagascar was and the southwest. For epidemiological studies and suspected in 1975 [ 13] and confi rmed in 1981–1983 malaria control purposes, the country has been strat- [9,14]. However the level of CQR remained low for ifi ed into 4 distinct zones (as there is no transmission many years and even today CQ is still used, though in the Tsaratanana Massif): equatorial in the east, it should be replaced by other antimalarials. austral in the central highlands, tropical in the west, Half of the population of Madagascar is at high risk and semi-arid in the south ( Figure 2 ) [ 18]. In the east of malaria. The National Malaria Control Programme and in the west, transmission is stable – perennial in 24 V. Andriantsoanirina et al. For personal use only. Figure 2. Map of Madagascar based on malarious epidemiological strata and 1982–2002 collection sites of isolates used in the in vitro studies. EIR: entomological inoculation rate. Scand J Infect Dis Downloaded from informahealthcare.com by Institut Pasteur on 09/11/12 the east and more seasonal on the west coast, with a travel and migration may also contribute to the emer- decrease in transmission in July and August. In both gence of epidemics. Madagascar is located between regions, immunity amongst adults is reported to be Asia and Africa, both of which are known to have a high and most of the severe cases affect children aged high prevalence of antimalarial resistance. Interna- 10 y and pregnant women. In the central highlands, tional travel and trade between Madagascar and malaria is stable up to 1000 m in altitude, unstable these 2 continents has resulted in an increase in imported with seasonal transmission from November to May malaria cases. A high prevalence of antimalarial resis- between 1000 and 1500 m, and rare above 1500 m. In tance is also present in the Comoros Islands, which the semi-desert of the south, malaria is unstable and are not far from Madagascar [ 20]. hypoendemic, with a short seasonal transmission. In both the central highlands and in the south, immunity is limited and all age groups are vulnerable to periodic History of antimalarial use in Madagascar epidemics, which are often associated with high levels of morbidity and mortality. Human activity such as the CQ was the fi rst 4-aminoquinoline introduced to the cultivating of rice fi elds is of paramount importance Island. In 1949, the Ministry of Health launched an for the proliferation of the vectors [ 19]. Transportation, ambitious campaign for malaria prevention in children, Antimalarial drug resistance in Madagascar 25 on the basis of a weekly administration of CQ [ 4,5]. First detection of antimalarial resistance A sharp decline in malaria prevalence was observed In 1975, Goasguen et al. reported 2 cases of suspected at the end of the 1950s in the central highlands and CQR in Madagascar [ 13]. The fi rst case was a on its fringes. The weekly administration of CQ was prophylactic failure and a treatment failure in a maintained at all primary schools and at the Red Britannic traveller. The second case was a treatment Cross centres on the Island until 1970. In addition, failure in a Malagasy woman. Parasitological diagnosis CQ was readily available in many groceries. A short- was performed and both cases were cured with SP, age in CQ supply then occurred, together with the however isolates were not sent to a reference centre end of indoor residual spraying with DDT.

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