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The island of Mayotte in the Comorian Islands in the Indian Ocean is in an unusual situation because from an epidemiologic and sociologic point of view, it is an African-like setting, yet it benefits from the French health system with diagnosis and treatment facilities that are of much higher standards than those in Africa. However, the population of Mayotte is of east African origin and lives in modest housing, including huts along rare roads in a forested landscape. In contrast, since 1975 when Mayotte decided to remain a French territory, a sophisticated health system has been implemented. This includes a modern, well-equipped central hospital, and numerous dispensaries run by doctors who deliver free medical care. This, along with other factors, has contributed to massive immigration from other Comorian islands.
Malaria has always been prevalent in this region and has not been decreased by vector control. Until 2001, treatment relied on classic schemes, i.e., chloroquine for acute uncomplicated cases and parenteral quinine together with adequate nursing for complicated cases. The increasing number of malaria fatalities, particularly among cases properly handled in the central hospital, led us to initiate a drug sensitivity survey to determine why many could still die of malaria in France in 2001, even though this is a remote territory of France. The results showed an unexpectedly high prevalence of resistance to many available antimalarial drugs.
The study was conducted from May 2000 to February 2001 among the patients from the different health centers of the island and those admitted to Mamoudzou Hospital. It was reviewed and approved by the health regional authority, and samples were obtained from patients after informed consent was provided. All patients had a Plasmodium falciparum -positive histidine-rich protein 2 (Cape Biotech Malaria Rapid Test; Abbott Diagnostic, Rungis, France) or parasite lactate dehydrogenase (LDH) test (Optimal; Diamed, Paris, France) result, which was verified by microscopic examination of thin and thick blood smears. A venous blood sample was taken either at the hospital or in dispensaries and kept at 4°C for a maximum of four hours before performing an in vitro culture. Drug sensitivity assays were determined for chloroquine sulfate, quinine hydrochloride, amodiaquine hydrochloride, mefloquine hydrochloride, pyrimethamine, and artemisinin. The conditions for in vitro culture of isolates in 96-well plates are the same as those previously described.1 Antimalarial drugs solutions were prepared for each assay. Drug sensitivity was determined using the colorimetric double-site enzyme-linked LDH immunodetection (DELI) test.2 The correspondence between results obtained with the DELI assay and the classic isotopic microtest has been previously established using laboratory-adapted strains2 and field isolates in Senegal,3 Burkina Faso,4 and Asia (Brasseur P, Druilhe P, unpublished data). Two strains of P. falciparum (3D7 and Palo Alto) were used as internal controls.
The in vitro drug sensitivities of 132 isolates that were successfully cultured are shown in Figure 1
. We observed an extremely high prevalence (88%) and an extremely high degree of resistance to chloroquine, which is consistent with the clinical failures reported by rural dispensaries and the increase in the number of cases referred to the hospital. The results also showed a substantial number (17%) of isolates resistant to quinine with high IC50 values (> 500 nM), which may explain the fatality rate recently observed in the hospital despite rapid infusions of quinine and adequate intensive care. Most likely as a consequence of quinine resistance, 9% of the isolates were found resistant to mefloquine, despite the rare use of this drug. This finding is consistent with previous observations of cross-resistance between quinine and mefloquine.5
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Finally, as in many other areas where artemisinin derivatives have not yet been used, a number of isolates showed IC50 values greater than the threshold of 10 nM and 20% showed values of 5–10 nM. Although resistance to artemisinin derivatives remains debatable, it is known that even seven-day treatments have failure rates of 5–7%. This is consistent with in vitro findings. No significant difference in susceptibility was found between patients from rural areas, who constituted the majority (82%) of the study population, and those from urban areas. In addition, resistance to pyrimethamine was investigated in 40 additional parasite isolates with a nested polymerase chain reaction and restriction fragment length polymorphism as reported by Eldin de Pecoulas and others.7 This showed a point mutation in codon 108 (Ser (AGC) to Asn (AAC)) in the dihydrofolate reductase gene in 62% of the isolates (other mutations were not investigated).
Our results are puzzling and in marked contrast with those obtained in neighboring areas such as Madagascar, where results over the past 10 years have showed a moderate but stable prevalence of resistance to chloroquine, together with a low prevalence of resistance to other drugs.8 Less numerous data are available from the neighboring islands of Anjouan and other Comorian islands. The last survey conducted in 1992 showed a chloroquine resistance level of 22.2% in seven-day in vivo assays.9 This situation suggests that the improved availability in Mayotte, compared with Africa, of antimalarials and other drugs through a free and well-organized health system, has contributed to the emergence of multidrug-resistant P. falciparum malaria.
Given this state of affairs, it is somewhat puzzling that it took so many years of treatment failures to initiate a preliminary evaluation of the actual status of susceptibility. Our results should have at least triggered further in vitro and in vivo investigations, which are known to be complementary. It is shocking that given the degree of health care in Mayotte new and more adequate regimens have not yet been implemented. Indeed, the current recommendation for treatment is a combination of chloroquine with sulfadoxine-pyrimethamine, which in view of our observations, would constitute the worst possible option. In addition, this combination therapy has not been the object of rigorous in vivo investigations to determine its efficacy. It has unfortunately remained mandatory despite reports of treatment failures and communication of the present data in January 2001 to the health authorities in Mayotte, as well as to the Direction Generale de la Sante in Paris, and repeated recommendations to use artemisinin-based combinations.
In view of the data in this report, therapeutic options are scarce and few alternatives are currently available, other than drug combinations such as quinine-tetracycline or artesunate-mefloquine. However, the former combination has shown insufficient compliance during ambulatory treatment in dispensaries. In our opinion, this suggests that the three-day artesunate-mefloquine combination promoted by investigators in Thailand10 is mandatory.
One could argue that eradication through vector control might be achievable in Mayotte, as on other small islands such as la Réunion, Martinique, and Guadeloupe. However, several years of vector control in Mayotte has failed to prevent the present increase in endemicity and many breeding sites are hardly accessible in the relatively large, wild, forested areas of Mayotte. In this regard, it is worth mentioning that the increased use of artemisinin derivatives in Southeast Asia indicates that they also exert a gametocytocidal effect,11 in contrast to sulfadoxine-pyrimethamine, which tend to increase transmission. Therefore, in the case of Mayotte, artemisinin may not only be the most efficient therapeutic option, but would moreover constitute an outstanding opportunity to investigate its ability to control transmission and potentially eradicate malaria in a small, well-delineated territory, i.e., without borders with other endemic countries.
Received September 4, 2003. Accepted for publication December 18, 2003.
Authors’ addresses: François Pettinelli, Marie-Edith Pettinelli, Julie Millet, and Delphine Michel, Centre Hospitalier de Mayotte, 97600 Mamoudzou, Mayotte. Philippe Eldin de Pécoulas and Philippe Brasseur, Faculté de Médecine, 22, Boulevard Gambetta, 76183 Rouen, France. Pierre Druilhe, Unité de Parasitologie Bio-Médicale, Institut Pasteur, 75015 Paris, France.
Reprint requests: Pierre Druilhe, Unité de Parasitologie BioMédicale, Institut Pasteur, 25 Rue du Dr Roux, 75015 Paris, France, Telephone: 33-1-45-68-85-78, Fax: 33-1-45-68-86-40, E-mail: druilhe{at}pasteur.fr.
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