Susceptibility of Plasmodium falciparum to the drugs used to treat severe malaria (quinine) and to prevent malaria (mefloquine, cycloguanil) in Comoros Union and Madagascar

Objectives. To monitor the sensitivity of Plasmodium falciparum to the drugs used to treat severe malaria and to prevent malaria in Comoros and Madagascar. Design. We used the in vitro isotopic method to test the sensitivity of P. falciparum to quinine, mefloquine and cycloguanil.Results. We tested fresh isolates of P. falciparum, collected from patients living in urban, suburban and rural areas and suffering from uncomplicated malaria in 2001, against at least one of the antimalarials cited above. In both countries all of the successfully tested isolates were sensitive to quinine (N = 243) and to cycloguanil (N = 67). The mean IC50 ranged from 85.7 to 133.7 nM for quinine. For cycloguanil, the mean IC50 ranged from 1.4 to 20.2 nM and the highest IC50 value (102.5 nM) was recorded in Comoros. Only 0.9% (1/110) of the informative isolates from Madagascar were mefloquineresistant (0/18 in Comoros). The mefloquine mean IC50s were 8.2 nM, 14.1 nM and 11.6 nM respectively in the rural, suburban and urban areas of Madagascar, and 5.9 nM in Comoros. A positive correlation was found between quinine and mefloquine IC50s (N = 127, r = 0.48, p < 10 6 ), but in vitro mefloquine was 6 -16 times more potent than quinine. No correlation was noticed between the activities of quinine and cydoguanil or between the activities of mefloquine and cycloguaniL Conclusion. We therefore advocate the use of a full-course regimen of quinine, as recommended by the World Health Organisation (WHO), to treat above all severe malaria in Madagascar and Comoros. Our results also demonstrate that the use of mefloquine- and cycloguanil-based antimalarials is still justified to prevent malaria in both countries, mainly in the case of travellers

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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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).</p> <p>Results</p> <p>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 <it>Plasmodia </it>that infect humans were also found: <it>Plasmodium falciparum</it>; <it>Plasmodium vivax</it>, <it>Plasmodium malariae </it>and <it>Plasmodium ovale</it>. 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. <it>P. falciparum </it>malaria has been predominant (98%). The high prevalence of <it>P. falciparum </it>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 <it>P. falciparum </it>per annum. Moreover, estimated incidence of <it>P. falciparum </it>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.</p> <p>Conclusion</p> <p>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.</p

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

<p>Abstract</p> <p>Background</p> <p>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).</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p

Plasmodium vivax dhfr and dhps mutations in isolates from Madagascar and therapeutic response to sulphadoxine-pyrimethamine

<p>Abstract</p> <p>Background</p> <p>Four of five <it>Plasmodium </it>species infecting humans are present in Madagascar. <it>Plasmodium vivax </it>remains the second most prevalent species, but is understudied. No data is available on its susceptibility to sulphadoxine-pyrimethamine, the drug recommended for intermittent preventive treatment during pregnancy. In this study, the prevalence of <it>P. vivax </it>infection and the polymorphisms in the <it>pvdhfr </it>and <it>pvdhps </it>genes were investigated. The correlation between these polymorphisms and clinical and parasitological responses was also investigated in <it>P. vivax</it>-infected patients.</p> <p>Methods</p> <p><it>Plasmodium vivax </it>clinical isolates were collected in eight sentinel sites from the four major epidemiological areas for malaria across Madagascar in 2006/2007. <it>Pvdhfr </it>and <it>pvdhps </it>genes were sequenced for polymorphism analysis. The therapeutic efficacy of SP in <it>P. vivax </it>infections was assessed in Tsiroanomandidy, in the foothill of the central highlands. An intention-to-treat analysis of treatment outcome was carried out.</p> <p>Results</p> <p>A total of 159 <it>P. vivax </it>samples were sequenced in the <it>pvdhfr/pvdhps </it>genes. Mutant-types in <it>pvdhfr </it>gene were found in 71% of samples, and in <it>pvdhps </it>gene in 16% of samples. Six non-synonymous mutations were identified in <it>pvdhfr</it>, including two novel mutations at codons 21 and 130. For <it>pvdhps</it>, beside the known mutation at codon 383, a new one was found at codon 422. For the two genes, different combinations were ranged from wild-type to quadruple mutant-type. Among the 16 patients enrolled in the sulphadoxine-pyrimethamine clinical trial (28 days of follow-up) and after adjustment by genotyping, 3 (19%, 95% CI: 5%–43%) of them were classified as treatment failure and were <it>pvdhfr </it>58R/117N double mutant carriers with or without the <it>pvdhps </it>383G mutation.</p> <p>Conclusion</p> <p>This study highlights (i) that genotyping in the <it>pvdhfr </it>and <it>pvdhps </it>genes remains a useful tool to monitor the emergence and the spread of <it>P. vivax </it>sulphadoxine-pyrimethamine resistant in order to improve the national antimalarial drug policy, (ii) the issue of using sulphadoxine-pyrimethamine as a monotherapy for intermittent preventive treatment of pregnant women or children.</p

Geographical and environmental approaches to urban malaria in Antananarivo (Madagascar)

<p>Abstract</p> <p>Background</p> <p>Previous studies, conducted in the urban of Antananarivo, showed low rate of confirmed malaria cases. We used a geographical and environmental approach to investigate the contribution of environmental factors to urban malaria in Antananarivo.</p> <p>Methods</p> <p>Remote sensing data were used to locate rice fields, which were considered to be the principal mosquito breeding sites. We carried out supervised classification by the maximum likelihood method. Entomological study allowed vector species determination from collected larval and adult mosquitoes. Mosquito infectivity was studied, to assess the risk of transmission, and the type of mosquito breeding site was determined. Epidemiological data were collected from November 2006 to December 2007, from public health centres, to determine malaria incidence. Polymerase chain reaction was carried out on dried blood spots from patients, to detect cases of malaria. Rapid diagnostic tests were used to confirm malaria cases among febrile school children in a school survey.</p> <p>A geographical information system was constructed for data integration. Altitude, temperature, rainfall, population density and rice field surface area were analysed and the effects of these factors on the occurrence of confirmed malaria cases were studied.</p> <p>Results</p> <p>Polymerase chain reaction confirmed malaria in 5.1% of the presumed cases. Entomological studies showed <it>An. arabiensis </it>as potential vector. Rice fields remained to be the principal breeding sites. Travel report was considered as related to the occurrence of <it>P. falciparum </it>malaria cases.</p> <p>Conclusion</p> <p>Geographical and environmental factors did not show direct relationship with malaria incidence but they seem ensuring suitability of vector development. Absence of relationship may be due to a lack of statistical power. Despite the presence of <it>An. arabiensis</it>, scarce parasitic reservoir and rapid access to health care do not constitute optimal conditions to a threatening malaria transmission. However, imported malaria case is suggestive to sustain the pocket transmission in Antananarivo.</p

Effectiveness of malaria control interventions in Madagascar: a nationwide case-control survey

International audienceBACKGROUND:Madagascar, as other malaria endemic countries, depends mainly on international funding for the implementation of malaria control interventions (MCI). As these funds no longer increase, policy makers need to know whether these MCI actually provide the expected protection. This study aimed at measuring the effectiveness of MCI deployed in all transmission patterns of Madagascar in 2012-2013 against the occurrence of clinical malaria cases.METHODS:From September 2012 to August 2013, patients consulting for non-complicated malaria in 31 sentinel health centres (SHC) were asked to answer a short questionnaire about long-lasting insecticidal nets (LLIN) use, indoor residual spraying (IRS) in the household and intermittent preventive treatment of pregnant women (IPTp) intake. Controls were healthy all-ages individuals sampled from a concurrent cross-sectional survey conducted in areas surrounding the SHC. Cases and controls were retained in the database if they were resident of the same communes. The association between Plasmodium infection and exposure to MCI was calculated by multivariate multilevel models, and the protective effectiveness (PE) of an intervention was defined as 1 minus the odds ratio of this association.RESULTS:Data about 841 cases (out of 6760 cases observed in SHC) and 8284 controls was collected. The regular use of LLIN provided a significant 51 % PE (95 % CI [16-71]) in multivariate analysis, excluding in one transmission pattern where PE was -11 % (95 % CI [-251 to 65]) in univariate analysis. The PE of IRS was 51 % (95 % CI [31-65]), and the PE of exposure to both regular use of LLIN and IRS was 72 % (95 % CI [28-89]) in multivariate analyses. Vector control interventions avoided yearly over 100,000 clinical cases of malaria in Madagascar. The maternal PE of IPTp was 73 %.CONCLUSIONS:In Madagascar, LLIN and IRS had good PE against clinical malaria. These results may apply to other countries with similar transmission profiles, but such case-control surveys could be recommended to identify local failures in the effectiveness of MCI