Randomized Trial of Piperaquine with Sulfadoxine-Pyrimethamine or Dihydroartemisinin for Malaria Intermittent Preventive Treatment in Children

BACKGROUND: The long terminal half life of piperaquine makes it suitable for intermittent preventive treatment for malaria but no studies of its use for prevention have been done in Africa. We did a cluster randomized trial to determine whether piperaquine in combination with either dihydroartemisin (DHA) or sulfadoxine-pyrimethamine (SP) is as effective, and better tolerated, than SP plus amodiaquine (AQ), when used for intermittent preventive treatment in children delivered by community health workers in a rural area of Senegal. METHODS: Treatments were delivered to children 3-59 months of age in their homes once per month during the transmission season by community health workers. 33 health workers, each covering about 60 children, were randomized to deliver either SP+AQ, DHA+PQ or SP+PQ. Primary endpoints were the incidence of attacks of clinical malaria, and the incidence of adverse events. RESULTS: 1893 children were enrolled. Coverage of monthly rounds and compliance with daily doses was similar in all groups; 90% of children received at least 2 monthly doses. Piperaquine combinations were better tolerated than SP+AQ with a significantly lower risk of common, mild adverse events. 103 episodes of clinical malaria were recorded during the course of the trial. 68 children had malaria with parasitaemia >3000/microL, 29/671 (4.3%) in the SP+AQ group, compared with 22/604 (3.6%) in the DHA+PQ group (risk difference 0.47%, 95%CI -2.3%,+3.3%), and 17/618 (2.8%) in the SP+PQ group (risk difference 1.2%, 95%CI -1.3%,+3.6%). Prevalences of parasitaemia and the proportion of children carrying Pfdhfr and Pfdhps mutations associated with resistance to SP were very low in all groups at the end of the transmission season. CONCLUSIONS: Seasonal IPT with SP+PQ in children is highly effective and well tolerated; the combination of two long-acting drugs is likely to impede the emergence of resistant parasites. TRIAL REGISTRATION: ClinicalTrials.gov NCT00529620

Methods to collect Anopheles mosquitoes and evaluate malaria transmission: A comparative study in two villages in Senegal

<p>Abstract</p> <p>Background</p> <p>Various methods have been studied as replacement of human landing catches (HLC) for mosquito sampling in entomological studies on malaria transmission. Conflicting results have been obtained in comparing relative efficiency of alternative methods, according to the area, the species present and their density. The aim of this study was to compare the number and characteristics of mosquitoes sampled in two areas of Senegal by three different methods: HLC, light traps adjacent to an occupied bed net (LT/N), pyrethrum spray catches (PSC).</p> <p>Methods</p> <p>Collections were performed in two villages: Dielmo (Soudan savanna) and Bandafassi (Soudan Guinean savanna), two or three nights per month for a 4-5 months period during the maximal transmission season in 2001-2002. Species were identified and <it>Plasmodium </it>infection determined by ELISA. The specific composition, circumsporozoite protein rate and entomological inoculation rate were calculated.</p> <p>Results</p> <p>The diversity of mosquito species captured was maximal with LT/N, minimal with PSC. The mean number of anopheles captures each night was significantly different according to the method used and the species. PSC displayed a significantly lower anopheles density. HLC was the most efficient sampling method when <it>Anopheles gambiae </it>was the main vector (in Bandafassi); LT/N when it was <it>Anopheles funestus </it>(in Dielmo). A significant correlation was found between HLC and LT/M but correlation parameters were different according to the species. Circumsporozoite protein rates were not significantly different between methods or species. The entomological inoculation rate varied along with vector density and thus with methods and species.</p> <p>Conclusions</p> <p>The choice of sampling method influenced entomological data recorded. Therefore, the sampling technique has to be chosen according to the vector studied and the aim of the study. Only HLC must be considered as the reference method, but in some conditions LT/N can be used as an alternative method.</p

Resistance to DDT and Pyrethroids and Increased kdr Mutation Frequency in An. gambiae after the Implementation of Permethrin-Treated Nets in Senegal

Introduction: The aim of this study was to evaluate the susceptibility to insecticides of An. gambiae mosquitoes sampled in Dielmo (Senegal), in 2010, 2 years after the implementation of Long Lasting Insecticide-treated Nets (LLINs) and to report the evolution of kdr mutation frequency from 2006 to 2010. Methods: WHO bioassay susceptibility tests to 6 insecticides were performed on adults F0, issuing from immature stages of An. gambiae s.l., sampled in August 2010. Species and molecular forms as well as the presence of L1014F and L1014S kd

Effectiveness of Seasonal Malaria Chemoprevention in Children under Ten Years of Age in Senegal: A Stepped-Wedge Cluster-Randomised Trial.

BACKGROUND: Seasonal Malaria Chemoprevention (SMC) with sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ), given each month during the transmission season, is recommended for children living in areas of the Sahel where malaria transmission is highly seasonal. The recommendation for SMC is currently limited to children under five years of age, but, in many areas of seasonal transmission, the burden in older children may justify extending this age limit. This study was done to determine the effectiveness of SMC in Senegalese children up to ten years of age. METHODS AND FINDINGS: SMC was introduced into three districts over three years in central Senegal using a stepped-wedge cluster-randomised design. A census of the population was undertaken and a surveillance system was established to record all deaths and to record all cases of malaria seen at health facilities. A pharmacovigilance system was put in place to detect adverse drug reactions. Fifty-four health posts were randomised. Nine started implementation of SMC in 2008, 18 in 2009, and a further 18 in 2010, with 9 remaining as controls. In the first year of implementation, SMC was delivered to children aged 3-59 months; the age range was then extended for the latter two years of the study to include children up to 10 years of age. Cluster sample surveys at the end of each transmission season were done to measure coverage of SMC and the prevalence of parasitaemia and anaemia, to monitor molecular markers of drug resistance, and to measure insecticide-treated net (ITN) use. Entomological monitoring and assessment of costs of delivery in each health post and of community attitudes to SMC were also undertaken. About 780,000 treatments were administered over three years. Coverage exceeded 80% each month. Mortality, the primary endpoint, was similar in SMC and control areas (4.6 and 4.5 per 1000 respectively in children under 5 years and 1.3 and 1.2 per 1000 in children 5-9 years of age; the overall mortality rate ratio [SMC: no SMC] was 0.90, 95% CI 0.68-1.2, p = 0.496). A reduction of 60% (95% CI 54%-64%, p < 0.001) in the incidence of malaria cases confirmed by a rapid diagnostic test (RDT) and a reduction of 69% (95% CI 65%-72%, p < 0.001) in the number of treatments for malaria (confirmed and unconfirmed) was observed in children. In areas where SMC was implemented, incidence of confirmed malaria in adults and in children too old to receive SMC was reduced by 26% (95% CI 18%-33%, p < 0.001) and the total number of treatments for malaria (confirmed and unconfirmed) in these older age groups was reduced by 29% (95% CI 21%-35%, p < 0.001). One hundred and twenty-three children were admitted to hospital with a diagnosis of severe malaria, with 64 in control areas and 59 in SMC areas, showing a reduction in the incidence rate of severe disease of 45% (95% CI 5%-68%, p = 0.031). Estimates of the reduction in the prevalence of parasitaemia at the end of the transmission season in SMC areas were 68% (95% CI 35%-85%) p = 0.002 in 2008, 84% (95% CI 58%-94%, p < 0.001) in 2009, and 30% (95% CI -130%-79%, p = 0.56) in 2010. SMC was well tolerated with no serious adverse reactions attributable to SMC drugs. Vomiting was the most commonly reported mild adverse event but was reported in less than 1% of treatments. The average cost of delivery was US$0.50 per child per month, but varied widely depending on the size of the health post. Limitations included the low rate of mortality, which limited our ability to detect an effect on this endpoint. CONCLUSIONS: SMC substantially reduced the incidence of outpatient cases of malaria and of severe malaria in children, but no difference in all-cause mortality was observed. Introduction of SMC was associated with an overall reduction in malaria incidence in untreated age groups. In many areas of Africa with seasonal malaria, there is a substantial burden in older children that could be prevented by SMC. SMC in older children is well tolerated and effective and can contribute to reducing malaria transmission. TRIAL REGISTRATION: ClinicalTrials.gov NCT00712374

Genetic Determination and Linkage Mapping of Plasmodium falciparum Malaria Related Traits in Senegal

Plasmodium falciparum malaria episodes may vary considerably in their severity and clinical manifestations. There is good evidence that host genetic factors contribute to this variability. To date, most genetic studies aiming at the identification of these genes have used a case/control study design for severe malaria, exploring specific candidate genes. Here, we performed a family-based genetic study of falciparum malaria related phenotypes in two independent longitudinal survey cohorts, as a first step towards the identification of genes and mechanisms involved in the outcome of infection. We studied two Senegalese villages, Dielmo and Ndiop that differ in ethnicity, malaria transmission and endemicity. We performed genome-scan linkage analysis of several malaria-related phenotypes both during clinical attacks and asymptomatic infection. We show evidence for a strong genetic contribution to both the number of clinical falciparum malaria attacks and the asymptomatic parasite density. The asymptomatic parasite density showed linkage to chromosome 5q31 (LOD = 2.26, empirical p = 0.0014, Dielmo), confirming previous findings in other studies. Suggestive linkage values were also obtained at three additional chromosome regions: the number of clinical malaria attacks on chromosome 5p15 (LOD = 2.57, empirical p = 0.001, Dielmo) and 13q13 (LOD = 2.37, empirical p = 0.0014 Dielmo), and the maximum parasite density during asymptomatic infection on chromosome 12q21 (LOD = 3.1, empirical p<10−4, Ndiop). While regions of linkage show little overlap with genes known to be involved in severe malaria, the four regions appear to overlap with regions linked to asthma or atopy related traits, suggesting that common immune related pathways may be involved

Low and seasonal malaria transmission in the middle Senegal River basin: identification and characteristics of Anopheles vectors

<p>Abstract</p> <p>Background</p> <p>During the last decades two dams were constructed along the Senegal River. These intensified the practice of agriculture along the river valley basin. We conducted a study to assess malaria vector diversity, dynamics and malaria transmission in the area.</p> <p>Methods</p> <p>A cross-sectional entomological study was performed in September 2008 in 20 villages of the middle Senegal River valley to evaluate the variations of <it>Anopheles </it>density according to local environment. A longitudinal study was performed, from October 2008 to January 2010, in 5 selected villages, to study seasonal variations of malaria transmission.</p> <p>Results</p> <p>Among malaria vectors, 72.34% of specimens collected were <it>An. arabiensis</it>, 5.28% <it>An. gambiae </it>of the S molecular form, 3.26% M form, 12.90% <it>An. pharoensis</it>, 4.70% <it>An. ziemanni</it>, 1.48% <it>An. funestus </it>and 0.04% <it>An. wellcomei</it>. <it>Anopheles </it>density varied according to village location. It ranged from 0 to 21.4 <it>Anopheles</it>/room/day and was significantly correlated with the distance to the nearest ditch water but not to the river.</p> <p>Seasonal variations of <it>Anopheles </it>density and variety were observed with higher human biting rates during the rainy season (8.28 and 7.55 <it>Anopheles </it>bite/man/night in October 2008 and 2009 respectively). Transmission was low and limited to the rainy season (0.05 and 0.06 infected bite/man/night in October 2008 and 2009 respectively). During the rainy season, the endophagous rate was lower, the anthropophagic rate higher and L1014F kdr frequency higher.</p> <p>Conclusions</p> <p>Malaria vectors are present at low-moderate density in the middle Senegal River basin with <it>An. arabiensis </it>as the predominant species. Other potential vectors are <it>An. gambiae </it>M and S form and <it>An. funestus</it>. Nonetheless, malaria transmission was extremely low and seasonal.</p

Rapid reappearance of Plasmodium falciparum after drug treatment among Senegalese adults exposed to moderate seasonal transmission

To investigate the relationship between the entomologic inoculation rate (EIR) and time to reappearance of malaria parasites after radical treatment under moderate seasonal transmission conditions, a study was undertaken in a mesoendemic area of Senegal where malaria transmission is concentrated over an annual three-month period and averages 12 infective bites per person per year. A three-day course of quinine was administered to 48 asymptomatic adults between 19 and 66 years of age. Malaria transmission and parasitemia were monitored every week for two months and cases of fever or symptoms were investigated as part of a daily clinical surveillance. The proportion of persons reinfected at Days 28, 35, and 56 was 25%, 38%, and 54%, respectively. Adults less than 40 years of age had a shorter time to reinfection. In this age group, the median Plasmodium falciparum reappearance time was 28 days, and it was estimated that only one infected mosquito bite was able to induce a patent infection among half of the subjects. Only 8% (2 of 26) of the reinfections caused a clinical attack. These data are discussed in the light of previous studies conducted among adults naturally exposed to intense perennial transmission or among naive volunteers receiving artificial challenges. Rapid reinfection occurs at very low EIRs and dramatic differences in actual and cumulated exposure to infected mosquito bites poorly affect the median time to reappearance of malaria parasites in endemic populations

Rapid reappearance of Plasmodium falciparum after drug treatment among Senegalese adults exposed to moderate seasonal transmission

To investigate the relationship between the entomologic inoculation rate (EIR) and time to reappearance of malaria parasites after radical treatment under moderate seasonal transmission conditions, a study was undertaken in a mesoendemic area of Senegal where malaria transmission is concentrated over an annual three-month period and averages 12 infective bites per person per year. A three-day course of quinine was administered to 48 asymptomatic adults between 19 and 66 years of age. Malaria transmission and parasitemia were monitored every week for two months and cases of fever or symptoms were investigated as part of a daily clinical surveillance. The proportion of persons reinfected at Days 28, 35, and 56 was 25%, 38%, and 54%, respectively. Adults less than 40 years of age had a shorter time to reinfection. In this age group, the median Plasmodium falciparum reappearance time was 28 days, and it was estimated that only one infected mosquito bite was able to induce a patent infection among half of the subjects. Only 8% (2 of 26) of the reinfections caused a clinical attack. These data are discussed in the light of previous studies conducted among adults naturally exposed to intense perennial transmission or among naive volunteers receiving artificial challenges. Rapid reinfection occurs at very low EIRs and dramatic differences in actual and cumulated exposure to infected mosquito bites poorly affect the median time to reappearance of malaria parasites in endemic populations