Longitudinal survey of malaria morbidity over 10 years in Saharevo (Madagascar): further lessons for strengthening malaria control.

BACKGROUND: Madagascar has been known for having bio-geo-ecological diversity which is reflected by a complex malaria epidemiology ranging from hyperendemic to malaria-free areas. Malaria-related attacks and infection are frequently recorded both in children and adults living in areas of low malaria transmission. To integrate this variability in the national malaria control policy, extensive epidemiological studies are required to up-date previous records and adjust strategies. METHODS: A longitudinal malaria survey was conducted from July 1996 to June 2005 among an average cohort of 214 villagers in Saharevo, located at 900 m above the sea. Saharevo is a typical eastern foothill site at the junction between a costal wet tropical area (equatorial malaria pattern) and a drier high-altitude area (low malaria transmission). RESULTS: Passive and active malaria detection revealed that malaria transmission in Saharevo follows an abrupt seasonal variation. Interestingly, malaria was confirmed in 45% (1,271/2,794) of malaria-presumed fevers seen at the health centre. All four Plasmodia that infect humans were also found: Plasmodium falciparum; Plasmodium vivax, Plasmodium malariae and Plasmodium ovale. Half of the malaria-presumed fevers could be confirmed over the season with the highest malaria transmission level, although less than a quarter in lower transmission time, highlighting the importance of diagnosis prior to treatment intake. P. falciparum malaria has been predominant (98%). The high prevalence of P. falciparum malaria affects more particularly under 10 years old children in both symptomatic and asymptomatic contexts. Children between two and four years of age experienced an average of 2.6 malaria attacks with P. falciparum per annum. Moreover, estimated incidence of P. falciparum malaria tends to show that half of the attacks (15 attacks) risk to occur during the first 10 years of life for a 60-year-old adult who would have experienced 32 malaria attacks. CONCLUSION: The incidence of malaria decreased slightly with age but remained important among children and adults in Saharevo. These results support that a premunition against malaria is slowly acquired until adolescence. However, this claims for a weak premunition among villagers in Saharevo and by extension in the whole eastern foothill area of Madagascar. While the Malagasy government turns towards malaria elimination plans nowadays, choices and expectations to up-date and adapt malaria control strategies in the foothill areas are discussed in this paper.

Lessons learnt from the six decades of chloroquine use (1945-2005) to control malaria in Madagascar.

On the island of Madagascar, malaria was nearly eradicated in the highland areas and malaria transmission was significantly decreased in the coastal areas between the 1940s and 1960s. The success of the control programme was primarily achieved by chloroquine (CQ) use at the community level. CQ was administered to children weekly on a routine basis for malaria prevention in the period 1949-1971. Then, the Malagasy Government was unable to financially support the malaria control programme. The malarial situation worsened in the 1980s, partly due to the shortage of CQ. A malaria epidemic occurred. To deal with this epidemic, massive CQ use was urgently adopted. CQ has remained the first-line drug since 1945, but the prevalence of Plasmodium falciparum carrying the pfcrt mutation associated with CQ resistance remains low (<3%). However, late CQ treatment failure has been reported and the prevalence may be as high as 35% during 14-day follow-up since 1982. In an effort to eliminate malaria as a public health problem, a shift from CQ to artemisinin-based combination therapy has been advocated by a new policy since December 2005. A change of this kind is complex and the lessons learnt from the six decades of CQ use are of the utmost importance to achieve malaria control.

Assessment of the efficacy of antimalarial drugs recommended by the National Malaria Control Programme in Madagascar: up-dated baseline data from randomized and multi-site clinical trials.

BACKGROUND: In order to improve the monitoring of the antimalarial drug resistance in Madagascar, a new national network based on eight sentinel sites was set up. In 2006/2007, a multi-site randomized clinical trial was designed to assess the therapeutic efficacy of chloroquine (CQ), sulphadoxine-pyrimethamine (SP), amodiaquine (AQ) and artesunate plus amodiaquine combination (ASAQ), the antimalarial therapies recommended by the National Malaria Control Programme (NMCP). METHODS: Children between six months and 15 years of age, with uncomplicated falciparum malaria, were enrolled. Primary endpoints were the day-14 and day-28 risks of parasitological failure, either unadjusted or adjusted by genotyping. Risks of clinical and parasitological treatment failure after adjustment by genotyping were estimated using Kaplan-Meier survival analysis. Secondary outcomes included fever clearance, parasite clearance, change in haemoglobin levels between Day 0 and the last day of follow-up, and the incidence of adverse events. RESULTS: A total of 1,347 of 1,434 patients (93.9%) completed treatment and follow-up to day 28. All treatment regimens, except for the chloroquine (CQ) treatment group, resulted in clinical cure rates above 97.6% by day-14 and 96.7% by day-28 (adjusted by genotyping). Parasite and fever clearance was more rapid with artesunate plus amodiaquine, but the extent of haematological recovery on day-28 did not differ significantly between the four groups. No severe side-effects were observed during the follow-up period. CONCLUSION: These findings (i) constitute an up-dated baseline data on the efficacy of antimalarial drugs recommended by the NMCP, (ii) show that antimalarial drug resistance remains low in Madagascar, except for CQ, compared to the bordering countries in the Indian Ocean region such as the Comoros Archipelago and (iii) support the current policy of ASAQ as the first-line treatment in uncomplicated falciparum malaria.

[Rapid diagnostic test for malaria: preliminary study in Madagascar in 2003]. / Utilisation du test de diagnostic rapide du paludisme à Madagascar: étude préliminaire en 2003.

This study was conducted in 2003 as part of the training of laboratory technicians in the use of rapid diagnostic tests (RDTs) for malaria and to evaluate these tests in Madagascar in field conditions for the first time. Two types of RDT were used separately. The dipstick (Optimal-I) that detects circulating pLDH was tested in 168 patients with clinically suspected malaria (fever or recent history of fever) at primary health centers. Microscopy confirmed malaria in 93/168 (55.4%) cases. Monoparasitic P. falciparum infection was identified in 86/93, P. malariae in 3/93, P. vivax in 3/93 and P. ovale in 1/93. A positive Optimal-I test was a highly sensitive indicator of P. falciparum infection with parasitemia exceeding 500 trophozoites/mul (sensitivity of 97.2%; with a specificity of 100%); it also confirmed 6/7 cases of non-P. falciparum malaria. A community malaria survey used the Malaria Hexagon dipstick (detecting P. falciparum-specific HRP2) for 273 patients: 17 (6.2%) RDT tests were positive, and 16 (5.9%) microscopic tests. Although this dipstick did not detect the only case of infection with P. vivax, its specificity was 100% for detection of P. falciparum infection. Installing microscopes and qualified microscopists in the health centers of the one hundred and eleven districts in Madagascar would be extremely difficult, but our results show that RDT is an effective alternative diagnostic tool for daily use as well as for sporadic malaria epidemics. The revised antimalarial treatment policy, involving a drug ten to twenty times more expensive than chloroquine, demonstrates the need to improve malaria diagnosis: presumptive treatment has become prohibitively expensive. RDT can be used to improve malaria case management at the primary heath centers in Madagascar. We discuss the choice of RDTs.

[A network RER rooted on in vitro readout assays of Plasmodium falciparum sensitivity to chloroquine in the Indian Ocean Region]. / Evaluation in vitro de la sensibilité de Plasmodium falciparum à la chloroquine dans la région de l'océan Indien dans le cadre du réseau d'étude de la résistance (RER).

Chloroquine has been used as a first line drug to treat uncomplicated malaria cases during the last five decades in Madagascar and in the Comoros Union. The four plasmodial species known to infect humans occur on Madagascar Island. Chloroquine-resistant malaria cases, sometimes only suspected from presumptive malaria cases, have been reported in both countries. Thus, to redefine a strategy and a policy to cure malaria, there is a need to get relevant and updated data. In December 1999, the Madagascan Ministry of Health and the Institut Pasteur de Madagascar formed a network named RER for malaria resistance surveillance. In 2000 and 2001, 18 study sites (17 throughout Madagascar and 1 in Comoros) joined this network. Health-care workers were trained mainly for malaria diagnosis through the use of blood smear examination and for malaria case management. To alleviate the lack of competent medical teams within the health centres, and for technical and logistic reasons, as part of the network activities, it was decided to start with in vitro tests to assess the sensitivity of P.falciparum isolates to chloroquine by means of the isotopic method. Parasitized blood samples were collected from consenting patients. P.falciparum isolates were more predominant (989/1,036). Out of the 564 tests done, 432 (76.6%) could be assessed. Results demonstrated that 94.3% (381/404) of the Madagascan P.falciparum isolates were susceptible to chloroquine. In contrast, chloroquine-resistant isolates were prevalent in Comoros (8/28). The network set-up is presented. The usefulness of the in vivo approach and of the in vitro investigations (chemosusceptibility test and screening of mutations accounting for resistance to chloroquine) to monitor the emergence and the dissemination of chloroquine-resistant parasites is discussed.

Current absence of pyrimethamine resistance of Plasmodium falciparum in Madagascar.

Reported are (i) the in vitro sensitivities to pyrimethamine of 58 primary Plasmodium falciparum isolates collected from the foothill and coastal areas in Madagascar, and (ii) the results of the amplification of the dhfr gene followed by restriction enzyme digestion of codon 108. Testing took place between March 1999 and February 2000 and all the isolates were sensitive to pyrimethamine. The 50% inhibitory concentration (IC50) ranged from 0.1 nM to 242.9 nM (mean IC50 = 30.5 nM, median IC50 = 4.8 nM, 95% confidence interval 17.6-43.4 nM). None of the 58 isolates yielded digestion products after polymerase chain reaction product treatment with BsrI or ScrFI. The results indicate the absence of the dhfr encoding Asn108 and Thr108 among tested clinical isolates. The sensitivity of P. falciparum to pyrimethamine-based antimalarial drugs in Madagascar is discussed.