Management of uncomplicated malaria among children under five years at public and private sector facilities in Mali.

BACKGROUND: Prompt and effective malaria diagnosis and treatment is a cornerstone of malaria control. Case management guidelines recommend confirmatory testing of suspected malaria cases, then prescription of specific drugs for uncomplicated malaria and for severe malaria. This study aims to describe case management practices for children aged 1-59 months seeking treatment with current or recent fever from public and private, rural and urban health providers in Mali. METHODS: Data were collected at sites in Sikasso Region and Bamako. Health workers recorded key information from the consultation including malaria diagnostic testing and result, their final diagnosis, and all drugs prescribed. Children with signs of severe diseases were ineligible. Consultations were not independently observed. Appropriate case management was defined as both 1) tested for malaria using rapid diagnostic test or microscopy, and 2) receiving artemisinin combination therapy (ACT) and no other antimalarials if test-positive, or receiving no antimalarials if test-negative. RESULTS: Of 1602 participating children, 23.7% were appropriately managed, ranging from 5.3% at public rural facilities to 48.4% at community health worker sites. The most common reason for 'inappropriate' management was lack of malaria diagnostic testing (50.4% of children). Among children with confirmed malaria, 50.8% received a non-ACT antimalarial (commonly artesunate injection or artemether), either alone or in combination with ACT. Of 215 test-negative children, 44.2% received an antimalarial drug, most commonly ACT. Prescription of multiple drugs was common: 21.7% of all children received more than one type of antimalarial, while 51.9% received an antibiotic and antimalarial. Inappropriate case management increased in children with increasing axillary temperatures and those seeking care over weekends. CONCLUSIONS: Multiple limitations in management of febrile children under five were identified, including inconsistent use of confirmatory testing and apparent use of severe malaria drugs for uncomplicated malaria. While we cannot confirm the reasons for these shortcomings, there is a need to address the high use of non-ACT antimalarials in this context; to minimize potential for drug resistance, reduce unnecessary expense, and preserve life-saving treatment for severe malaria cases. These findings highlight the challenge of managing febrile illness in young children in a high transmission setting.

Rapid reduction of malaria transmission following the introduction of indoor residual spraying in previously unsprayed districts: an observational analysis of Mopti Region, Mali, in 2017.

BACKGROUND: The National Malaria Control Programme (NMCP) of Mali has had recent success decreasing malaria transmission using 3rd generation indoor residual spraying (IRS) products in areas with pyrethroid resistance, primarily in Ségou and Koulikoro Regions. In 2015, national survey data showed that Mopti Region had the highest under 5-year-old (u5) malaria prevalence at 54%-nearly twice the national average-despite having high access to long-lasting insecticidal nets (LLINs) and seasonal malaria chemoprevention (SMC). Accordingly, in 2016 the NMCP and other stakeholders shifted IRS activities from Ségou to Mopti. Here, the results of a series of observational analyses utilizing routine malaria indicators to evaluate the impact of this switch are presented. METHODS: A set of retrospective, eco-observational time-series analyses were performed using monthly incidence rates of rapid diagnostic test (RDT)-confirmed malaria cases reported in the District Health Information System 2 (DHIS2) from January 2016 until February 2018. Comparisons of case incidence rates were made between health facility catchments from the same region that differed in IRS status (IRS vs. no-IRS) to describe the general impact of the 2016 and 2017 IRS campaigns, and a difference-in-differences approach comparing changes in incidence from year-to-year was used to describe the effect of suspending IRS operations in Ségou and introducing IRS operations in Mopti in 2017. RESULTS: Compared to communities with no IRS, cumulative case incidence rates in IRS communities were reduced 16% in Ségou Region during the 6 months following the 2016 campaign and 31% in Mopti Region during the 6 months following the 2017 campaign, likely averting a total of more than 22,000 cases of malaria that otherwise would have been expected during peak transmission months. Across all comparator health facilities (HFs) where there was no IRS in either year, peak malaria case incidence rates fell by an average of 22% (CI95 18-30%) from 2016 to 2017. At HFs in communities of Mopti where IRS was introduced in 2017, peak incidence fell by an average of 42% (CI95 31-63%) between these years, a significantly greater decrease (p = 0.040) almost double what was seen in the comparator HFCAs. The opposite effect was observed in Ségou Region, where peak incidence at those HFs where IRS was withdrawn after the 2016 campaign increased by an average of 106% (CI95 63-150%) from year to year, also a significant difference-in-differences compared to the comparator no-IRS HFs (p < 0.0001). CONCLUSION: Annual IRS campaigns continue to make dramatic contributions to the seasonal reduction of malaria transmission in communities across central Mali, where IRS campaigns were timed in advance of peak seasonal transmission and utilized a micro-encapsulated product with an active ingredient that was of a different class than the one found on the LLINs used throughout the region and to which local malaria vectors were shown to be susceptible. Strategies to help mitigate the resurgence of malaria cases that can be expected should be prioritized whenever the suspension of IRS activities in a particular region is considered.

Combining next-generation indoor residual spraying and drug-based malaria control strategies: observational evidence of a combined effect in Mali.

BACKGROUND: Ségou Region in central Mali is an area of high malaria burden with seasonal transmission. The region reports high access to and use of long-lasting insecticidal nets (LLINs), though the principal vector, Anopheles gambiae, is resistant to pyrethroids. From 2011 until 2016, several high-burden districts of Ségou also received indoor residual spraying (IRS), though in 2014 concerns about pyrethroid resistance prompted a shift in IRS products to a micro-encapsulated formulation of the organophosphate insecticide pirimiphos-methyl. Also in 2014, the region expanded a pilot programme to provide seasonal malaria chemoprevention (SMC) to children aged 3-59 months in two districts. The timing of these decisions presented an opportunity to estimate the impact of both interventions, deployed individually and in combination, using quality-assured passive surveillance data. METHODS: A non-randomized, quasi-experimental time series approach was used to analyse monthly trends in malaria case incidence at the district level. Districts were stratified by intervention status: an SMC district, an IRS district, an IRS + SMC district, and control districts that received neither IRS nor SMC in 2014. The numbers of positive rapid diagnostic test (RDT +) results reported at community health facilities were aggregated and epidemiological curves showing the incidence of RDT-confirmed malaria cases per 10,000 person-months were plotted for the total all-ages and for the under 5 year old (u5) population. The cumulative incidence of RDT + malaria cases observed from September 2014 to February 2015 was calculated in each intervention district and compared to the cumulative incidence reported from the same period in the control districts. RESULTS: Cumulative peak-transmission all-ages incidence was lower in each of the intervention districts compared to the control districts: 16% lower in the SMC district; 28% lower in the IRS district; and 39% lower in the IRS + SMC district. The same trends were observed in the u5 population: incidence was 15% lower with SMC, 48% lower with IRS, and 53% lower with IRS + SMC. The SMC-only intervention had a more moderate effect on incidence reduction initially, which increased over time. The IRS-only intervention had a rapid, comparatively large impact initially that waned over time. The impact of the combined interventions was both rapid and longer lasting. CONCLUSION: Evaluating the impact of IRS with an organophosphate and SMC on reducing incidence rates of passive RDT-confirmed malaria cases in Ségou Region in 2014 suggests that combining the interventions had a greater effect than either intervention used individually in this high-burden region of central Mali with pyrethroid-resistant vectors and high rates of household access to LLINs.

Measuring malaria diagnosis and treatment coverage in population-based surveys: a recall validation study in Mali among caregivers of febrile children under 5 years.

BACKGROUND: Nationally-representative household surveys are the standard approach to monitor access to and treatment with artemisinin-based combination therapy (ACT) among children under 5 years (U5), however these indicators are dependent on caregivers' recall of the treatment received. METHODS: A prospective case-control study was performed in Mali to validate caregivers' recall of treatment received by U5s when seeking care for fever from rural and urban public health facilities, community health workers and urban private facilities. Clinician-recorded consultation details were the gold standard. Consenting caregivers were followed-up for interview at home within 2 weeks using standard questions from Demographic and Health Surveys and Malaria Indicator Surveys. RESULTS: Among 1602 caregivers, sensitivity of recalling that the child received a finger/heel prick was 91.5%, with specificity 85.7%. Caregivers' recall of a positive malaria test result had sensitivity 96.2% with specificity 59.7%. Irrespective of diagnostic test result, the sensitivity and specificity of caregivers' recalling a malaria diagnosis made by the health worker were 74.3% and 74.9%, respectively. Caregivers' recall of ACT being given had sensitivity of 43.2% and specificity 90.2%, while recall that any anti-malarial was given had sensitivity 59.0% and specificity 82.7%. Correcting caregivers' response of treatment received using a combination of a visual aid with photographs of common drugs for fever, prescription documents and retained packaging changed ACT recall sensitivity and specificity to 91.5% and 71.1%, respectively. CONCLUSIONS: These findings indicate that caregivers' responses during household surveys are valid when assessing if a child received a finger/heel prick during a consultation in the previous 2 weeks, and if the malaria test result was positive. Recall of ACT treatment received by U5s was poor when based on interview response only, but was substantially improved when incorporating visual aids, prescriptions and drug packaging review.

An observational analysis of the impact of indoor residual spraying with non-pyrethroid insecticides on the incidence of malaria in Ségou Region, Mali: 2012-2015.

BACKGROUND: Ségou Region in Central Mali is an area of high malaria burden with seasonal transmission, high access to and use of long-lasting insecticidal nets (LLINs), and resistance to pyrethroids and DDT well documented in Anopheles gambiae s.l. (the principal vector of malaria in Mali). Ségou has recently received indoor residual spraying (IRS) supported by Mali's collaboration with the US President's Malaria Initiative/Africa Indoor Residual Spraying programme. From 2012 to 2015, two different non-pyrethroid insecticides: bendiocarb in 2012 and 2013 and pirimiphos-methyl in 2014 and 2015, were used for IRS in two districts. This report summarizes the results of observational analyses carried out to assess the impact of these IRS campaigns on malaria incidence rates reported through local and district health systems before and after spraying. METHODS: A series of retrospective time series analyses were performed on 1,382,202 rapid diagnostic test-confirmed cases of malaria reported by district routine health systems in Ségou Region from January 2012 to January 2016. Malaria testing, treatment, surveillance and reporting activities remained consistent across districts and years during the study period, as did LLIN access and use estimates as well as An. gambiae s.l. insecticide resistance patterns. Districts were stratified by IRS implementation status and all-age monthly incidence rates were calculated and compared across strata from 2012 to 2014. In 2015 a regional but variable scale-up of seasonal malaria chemoprevention complicated the region-wide analysis; however IRS operations were suspended in Bla District that year so a difference in differences approach was used to compare 2014 to 2015 changes in malaria incidence at the health facility level in children under 5-years-old from Bla relative to changes observed in Barouéli, where IRS operations were consistent. RESULTS: During 2012-2014, rapid reductions in malaria incidence were observed during the 6 months following each IRS campaign, though most of the reduction in cases (70% of the total) was concentrated in the first 2 months after each campaign was completed. Compared to non-IRS districts, in which normal seasonal patterns of malaria incidence were observed, an estimated 286,745 total fewer cases of all-age malaria were observed in IRS districts. The total cost of IRS in Ségou was around 9.68 million USD, or roughly 33.75 USD per case averted. Further analysis suggests that the timing of the 2012-2014 IRS campaigns (spraying in July and August) was well positioned to maximize public health impact. Suspension of IRS in Bla District after the 2014 campaign resulted in a 70% increase in under-5-years-old malaria incidence rates from 2014 to 2015, significantly greater (p = 0.0003) than the change reported from Barouéli District, where incidence rates remained the same. CONCLUSIONS: From 2012 to 2015, the annual IRS campaigns in Ségou are associated with several hundred thousand fewer cases of malaria. This work supports the growing evidence that shows that IRS with non-pyrethroid insecticides is a wise public health investment in areas with documented pyrethroid resistance, high rates of LLIN coverage, and where house structures and population densities are appropriate. Additionally, this work highlights the utility of quality-assured and validated routine surveillance and well defined observational analyses to rapidly assess the impact of malaria control interventions in operational settings, helping to empower evidence-based decision making and to further grow the evidence base needed to better understand when and where to utilize new vector control tools as they become available.

Do the venous blood samples replicate malaria parasite densities found in capillary blood? A field study performed in naturally-infected asymptomatic children in Cameroon.

BACKGROUND: The measure of new drug- or vaccine-based approaches for malaria control is based on direct membrane feeding assays (DMFAs) where gametocyte-infected blood samples are offered to mosquitoes through an artificial feeder system. Gametocyte donors are identified by the microscopic detection and quantification of malaria blood stages on blood films prepared using either capillary or venous blood. However, parasites are known to sequester in the microvasculature and this phenomenon may alter accurate detection of parasites in blood films. The blood source may then impact the success of mosquito feeding experiments and investigations are needed for the implementation of DMFAs under natural conditions. METHODS: Thick blood smears were prepared from blood obtained from asymptomatic children attending primary schools in the vicinity of Mfou (Cameroon) over four transmission seasons. Parasite densities were determined microscopically from capillary and venous blood for 137 naturally-infected gametocyte carriers. The effect of the blood source on gametocyte and asexual stage densities was then assessed by fitting cumulative link mixed models (CLMM). DMFAs were performed to compare the infectiousness of gametocytes from the different blood sources to mosquitoes. RESULTS: Prevalence of Plasmodium falciparum asexual stages among asymptomatic children aged from 4 to 15 years was 51.8% (2116/4087). The overall prevalence of P. falciparum gametocyte carriage was 8.9% and varied from one school to another. No difference in the density of gametocyte and asexual stages was found between capillary and venous blood. Attempts to perform DMFAs with capillary blood failed. CONCLUSIONS: Plasmodium falciparum malaria parasite densities do not differ between capillary and venous blood in asymptomatic subjects for both gametocyte and trophozoite stages. This finding suggests that the blood source should not interfere with transmission efficiency in DMFAs.

A comparison of Plasmodium falciparum circumsporozoite protein-based slot blot and ELISA immuno-assays for oocyst detection in mosquito homogenates.

BACKGROUND: The infectivity of Plasmodium gametocytes is typically determined by microscopically examining the midguts of mosquitoes that have taken a blood meal containing potentially infectious parasites. Such assessments are required for the development and evaluation of transmission-reducing interventions (TRI), but are limited by subjectivity, technical complexity and throughput. The detection of circumsporozoite protein (CSP) by enzyme-linked immunosorbent assay (ELISA) and enhanced chemiluminescent slot-blot (ECL-SB) may be used as objective, scalable alternatives to microscopy for the determination of infection prevalence. METHODS: To compare the performance of the CSP ELISA and ECL-SB for the detection of mosquito infection, four groups of Anopheles stephensi mosquitoes were infected with cultured Plasmodium falciparum gametocytes. At day-8 post-infection (PI), parasite status was determined by microscopy for a sample of mosquitoes from each group. At days 8 and 10 PI, the parasite status of separate mosquito samples was analysed by both CSP ELISA and ECL-SB. RESULTS: When mosquito samples were analysed 8 days PI, the ECL-SB determined similar infection prevalence to microscopy; CSP ELISA lacked the sensitivity to detect CSP in all infected mosquitoes at this early time point. When mosquitoes were analysed 48 h later (10 days PI) both assays performed as well as microscopy for infection detection. CONCLUSIONS: Whilst microscopical examination of mosquito guts is of great value when quantification of parasite burden is required, ECL-SB and CSP ELISA are suitable alternatives at day 10 PI when infection prevalence is the desired endpoint, although CSP ELISA is not suitable at day 8 PI. These results are important to groups considering large-scale implementation of TRI.

Seasonality in malaria transmission: implications for case-management with long-acting artemisinin combination therapy in sub-Saharan Africa.

BACKGROUND: Long-acting artemisinin-based combination therapy (LACT) offers the potential to prevent recurrent malaria attacks in highly exposed children. However, it is not clear where this advantage will be most important, and deployment of these drugs is not rationalized on this basis. METHODS: To understand where post-treatment prophylaxis would be most beneficial, the relationship between seasonality, transmission intensity and the interval between malaria episodes was explored using data from six cohort studies in West Africa and an individual-based malaria transmission model. The total number of recurrent malaria cases per 1000 child-years at risk, and the fraction of the total annual burden that this represents were estimated for sub-Saharan Africa. RESULTS: In settings where prevalence is less than 10 %, repeat malaria episodes constitute a small fraction of the total burden, and few repeat episodes occur within the window of protection provided by currently available drugs. However, in higher transmission settings, and particularly in high transmission settings with highly seasonal transmission, repeat malaria becomes increasingly important, with up to 20 % of the total clinical burden in children estimated to be due to repeat episodes within 4 weeks of a prior attack. CONCLUSION: At a given level of transmission intensity and annual incidence, the concentration of repeat malaria episodes in time, and consequently the protection from LACT is highest in the most seasonal areas. As a result, the degree of seasonality, in addition to the overall intensity of transmission, should be considered by policy makers when deciding between ACT that differ in their duration of post-treatment prophylaxis.

Applications and limitations of Centers for Disease Control and Prevention miniature light traps for measuring biting densities of African malaria vector populations: a pooled-analysis of 13 comparisons with human landing catches.

BACKGROUND: Measurement of densities of host-seeking malaria vectors is important for estimating levels of disease transmission, for appropriately allocating interventions, and for quantifying their impact. The gold standard for estimating mosquito-human contact rates is the human landing catch (HLC), where human volunteers catch mosquitoes that land on their exposed body parts. This approach necessitates exposure to potentially infectious mosquitoes, and is very labour intensive. There are several safer and less labour-intensive methods, with Centers for Disease Control light traps (LT) placed indoors near occupied bed nets being the most widely used. METHODS: This paper presents analyses of 13 studies with paired mosquito collections of LT and HLC to evaluate these methods for their consistency in sampling indoor-feeding mosquitoes belonging to the two major taxa of malaria vectors across Africa, the Anopheles gambiae sensu lato complex and the Anopheles funestus s.l. group. Both overall and study-specific sampling efficiencies of LT compared with HLC were computed, and regression methods that allow for the substantial variations in mosquito counts made by either method were used to test whether the sampling efficacy varies with mosquito density. RESULTS: Generally, LT were able to collect similar numbers of mosquitoes to the HLC indoors, although the relative sampling efficacy, measured by the ratio of LT:HLC varied considerably between studies. The overall best estimate for An. gambiae s.l. was 1.06 (95% credible interval: 0.68-1.64) and for An. funestus s.l. was 1.37 (0.70-2.68). Local calibration exercises are not reproducible, since only in a few studies did LT sample proportionally to HLC, and there was no geographical pattern or consistent trend with average density in the tendency for LT to either under- or over-sample. CONCLUSIONS: LT are a crude tool at best, but are relatively easy to deploy on a large scale. Spatial and temporal variation in mosquito densities and human malaria transmission exposure span several orders of magnitude, compared to which the inconsistencies of LT are relatively small. LT, therefore, remain an invaluable and safe alternative to HLC for measuring indoor malaria transmission exposure in Africa.

Analysis of Preventive Interventions for Malaria: Exploring Partial and Complete Protection and Total and Primary Intervention Effects.

Event dependence, the phenomenon in which future risk depends on past disease history, is not commonly accounted for in the statistical models used by malaria researchers. However, recently developed methods for the analysis of repeated events allow this to be done, while also accounting for heterogeneity in risk and nonsusceptible subgroups. Accounting for event dependence allows separation of the primary effect of an intervention from its total effect, which is composed of its primary effect on risk of disease and its secondary effect mediated by event dependence. To illustrate these methods and show the insights they can provide, we have reanalyzed 2 trials of seasonal malaria chemoprevention (SMC) in Boussé, Burkina Faso, and Kati, Mali, in 2008-2009, as well as a trial of intermittent preventive treatment of malaria in infants in Navrongo, Ghana, in 2000-2004. SMC completely protects a large fraction of recipients, while intermittent preventive treatment in infants provides modest partial protection, consistent with the rationale of these 2 different chemopreventive approaches. SMC has a primary effect that is substantially greater than the total effect previously estimated by trials, with the lower total effect mediated by negative event dependence. These methods contribute to an understanding of the mechanisms of protection from these interventions and could improve understanding of other tools to control malaria, including vaccines.

Development of a transmission-blocking malaria vaccine: progress, challenges, and the path forward.

New interventions are needed to reduce morbidity and mortality associated with malaria, as well as to accelerate elimination and eventual eradication. Interventions that can break the cycle of parasite transmission, and prevent its reintroduction, will be of particular importance in achieving the eradication goal. In this regard, vaccines that interrupt malaria transmission (VIMT) have been highlighted as an important intervention, including transmission-blocking vaccines that prevent human-to-mosquito transmission by targeting the sexual, sporogonic, or mosquito stages of the parasite (SSM-VIMT). While the significant potential of this vaccine approach has been appreciated for decades, the development and licensure pathways for vaccines that target transmission and the incidence of infection, as opposed to prevention of clinical malaria disease, remain ill-defined. This article describes the progress made in critical areas since 2010, highlights key challenges that remain, and outlines important next steps to maximize the potential for SSM-VIMTs to contribute to the broader malaria elimination and eradication objectives.

The INDEPTH standard population for low- and middle-income countries, 2013.

Crude rates such as the crude death rate are functions of both the age-specific rates and the age composition of a population. However, differences in the age structure between two populations or two time periods can result in specious differences in the corresponding crude rates making direct comparisons between populations or across time inappropriate. Therefore, when comparing crude rates between populations, it is desirable to eliminate or minimize the influence of age composition. This task is accomplished by using a standard age structure yielding an age-standardized rate. This paper proposes an updated International Network for the Demographic Evaluation of Populations and Their Health (INDEPTH) standard for use in low- and middle-income countries (LMICs) based on newly available data from the health and demographic surveillance system site members of the INDEPTH network located throughout Africa and southern Asia. The updated INDEPTH standard should better reflect the age structure of LMICs and result in more accurate health indicators and demographic rates. We demonstrate use of the new INDEPTH standard along with several existing 'world' standards and show how resulting age-standardized crude deaths rates differ when using the various standard age compositions.

Consistently high estimates for the proportion of human exposure to malaria vector populations occurring indoors in rural Africa.

BACKGROUND: Insecticide-treated nets (ITNs) and indoor residual spraying (IRS) are highly effective tools for controlling malaria transmission in Africa because the most important vectors, from the Anopheles gambiae complex and the A. funestus group, usually prefer biting humans indoors at night. METHODS: Matched surveys of mosquito and human behaviour from six rural sites in Burkina Faso, Tanzania, Zambia, and Kenya, with ITN use ranging from 0.2% to 82.5%, were used to calculate the proportion of human exposure to An. gambiae sensu lato and An. funestus s.l. that occurs indoors (πi), as an indicator of the upper limit of personal protection that indoor vector control measures can provide. This quantity was also estimated through use of a simplified binary analysis (π(i)(B)) so that the proportions of mosquitoes caught indoors (Pi), and between the first and last hours at which most people are indoors (Pfl) could also be calculated as underlying indicators of feeding by mosquitoes indoors or at night, respectively. RESULTS: The vast majority of human exposure to Anopheles bites occurred indoors (π(i)(B)= 0.79-1.00). Neither An. gambiae s.l. nor An. funestus s.l. strongly preferred feeding indoors (P(i) = 0.40-0.63 and 0.22-0.69, respectively), but they overwhelmingly preferred feeding at times when most humans were indoors (P(fl) = 0.78-1.00 and 0.86-1.00, respectively). CONCLUSIONS: These quantitative summaries of behavioural interactions between humans and mosquitoes constitute a remarkably consistent benchmark with which future observations of vector behaviour can be compared. Longitudinal monitoring of these quantities is vital to evaluate the effectiveness of ITNs and IRS and the need for complementary measures that target vectors outdoors.

Effect of the Affordable Medicines Facility--malaria (AMFm) on the availability, price, and market share of quality-assured artemisinin-based combination therapies in seven countries: a before-and-after analysis of outlet survey data.

BACKGROUND: Malaria is one of the greatest causes of mortality worldwide. Use of the most effective treatments for malaria remains inadequate for those in need, and there is concern over the emergence of resistance to these treatments. In 2010, the Global Fund launched the Affordable Medicines Facility--malaria (AMFm), a series of national-scale pilot programmes designed to increase the access and use of quality-assured artemisinin based combination therapies (QAACTs) and reduce that of artemisinin monotherapies for treatment of malaria. AMFm involves manufacturer price negotiations, subsidies on the manufacturer price of each treatment purchased, and supporting interventions such as communications campaigns. We present findings on the effect of AMFm on QAACT price, availability, and market share, 6-15 months after the delivery of subsidised ACTs in Ghana, Kenya, Madagascar, Niger, Nigeria, Uganda, and Tanzania (including Zanzibar). METHODS: We did nationally representative baseline and endpoint surveys of public and private sector outlets that stock antimalarial treatments. QAACTs were identified on the basis of the Global Fund's quality assurance policy. Changes in availability, price, and market share were assessed against specified success benchmarks for 1 year of AMFm implementation. Key informant interviews and document reviews recorded contextual factors and the implementation process. FINDINGS: In all pilots except Niger and Madagascar, there were large increases in QAACT availability (25·8-51·9 percentage points), and market share (15·9-40·3 percentage points), driven mainly by changes in the private for-profit sector. Large falls in median price for QAACTs per adult equivalent dose were seen in the private for-profit sector in six pilots, ranging from US$1·28 to $4·82. The market share of oral artemisinin monotherapies decreased in Nigeria and Zanzibar, the two pilots where it was more than 5% at baseline. INTERPRETATION: Subsidies combined with supporting interventions can be effective in rapidly improving availability, price, and market share of QAACTs, particularly in the private for-profit sector. Decisions about the future of AMFm should also consider the effect on use in vulnerable populations, access to malaria diagnostics, and cost-effectiveness. FUNDING: The Global Fund to Fight AIDS, Tuberculosis and Malaria, and the Bill & Melinda Gates Foundation.

Estimating the potential public health impact of seasonal malaria chemoprevention in African children.

Seasonal malaria chemoprevention, previously known as intermittent preventive treatment in children, is highly effective in areas with a short malaria transmission season. Here we assess seasonality in malaria incidence data and define a predictor of seasonality based on rainfall. We then use spatial rainfall, malaria endemicity and population data to identify areas likely to have highly seasonal malaria incidence, and estimate the population at risk and malaria burden in areas where seasonal malaria chemoprevention would be appropriate. We estimate that in areas suitable for seasonal malaria chemoprevention, there are 39 million children under 5 years of age, who experience 33.7 million malaria episodes and 152,000 childhood deaths from malaria each year. The majority of this burden occurs in the Sahelian or sub-Sahelian regions of Africa. Our data suggest that seasonal malaria chemoprevention has the potential to avert several million malaria cases and tens of thousands of childhood deaths each year if successfully delivered to the populations at risk.

Intermittent preventive treatment of malaria in children: a qualitative study of community perceptions and recommendations in Burkina Faso and Mali.

BACKGROUND: Intermittent preventive treatment of malaria in children (IPTc) is a highly efficacious method of malaria control where malaria transmission is highly seasonal. However, no studies published to date have examined community perceptions of IPTc. METHODS: A qualitative study was undertaken in parallel with a double-blind, placebo-controlled, randomized trial of IPTc conducted in Mali and Burkina Faso in 2008-2009 to assess community perceptions of and recommendations for IPTc. Caregivers and community health workers (CHWs) were purposively sampled. Seventy-two in-depth individual interviews and 23 focus group discussions were conducted. FINDINGS: Widespread perceptions of health benefits for children led to enthusiasm for the trial and for IPTc specifically. Trust in and respect for those providing the tablets and a sense of obligation to the community to participate in sanctioned activities favoured initial adoption. IPTc fits in well with existing understandings of childhood illness. Participants did not express concerns about the specific drugs used for IPTc or about providing tablets to children without symptoms of malaria. There was no evidence that IPTc was perceived as a substitute for bed net usage, nor did it inhibit care seeking. Participants recommended that distribution be "closer to the population", but expressed concern over caregivers' ability to administer tablets at home. CONCLUSIONS: The trial context mediated perceptions of IPTc. Nonetheless, the results indicate that community perceptions of IPTc in the settings studied were largely favourable and that the delivery strategy rather than the tablets themselves presented the main areas of concern for caregivers and CHWs. The study identifies a number of key questions to consider in planning an IPTc distribution strategy. Single-dose formulations could increase the success of IPTc implementation, as could integration of IPTc within a package of activities, such as bed net distribution and free curative care, for which demand is already high.

Morbidity from malaria in children in the year after they had received intermittent preventive treatment of malaria: a randomised trial.

BACKGROUND: Interventions that reduce exposure to malaria infection may lead to delayed malaria morbidity and mortality. We investigated whether intermittent preventive treatment of malaria in children (IPTc) was associated with an increase in the incidence of malaria after cessation of the intervention. METHODS: An individually randomised, trial of IPTc, comparing three courses of sulphadoxine pyrimethamine (SP) plus amodiaquine (AQ) with placebos was implemented in children aged 3-59 months during the 2008 malaria transmission season in Burkina Faso. All children in the trial were given a long lasting insecticide treated net; 1509 children received SP+AQ and 1505 received placebos. Passive surveillance for malaria was maintained until the end of the subsequent malaria transmission season in 2009, and active surveillance for malaria infection, anaemia and malnutrition was conducted. RESULTS: On thousand, four hundred and sixteen children (93.8%) and 1399 children (93.0%) initially enrolled in the intervention and control arms of the trial respectively were followed during the 2009 malaria transmission season. During the period July 2009 to November 2009, incidence rates of clinical malaria were 3.84 (95%CI; 3.67-4.02) and 3.45 (95%CI; 3.29-3.62) episodes per child during the follow up period in children who had previously received IPT or placebos, indicating a small increase in risk for children in the former intervention arm (IRR = 1.12; 95%CI 1.04-1.20) (P = 0.003). Children who had received SP+AQ had a lower prevalence of malaria infection (adjusted PR: 0.88 95%CI: 0.79-0.98) (P = 0.04) but they had a higher parasite density (P = 0.001) if they were infected. There was no evidence that the risks of moderately severe anaemia (Hb<8 g/dL), wasting, stunting, or of being underweight in children differed between treatment arms. CONCLUSION: IPT with SP+AQ was associated with a small increase in the incidence of clinical malaria in the subsequent malaria transmission season. TRIAL REGISTRATION: ClinicalTrials.gov NCT00738946.

Malaria morbidity in children in the year after they had received intermittent preventive treatment of malaria in Mali: a randomized control trial.

BACKGROUND: Intermittent preventive treatment of malaria in children (IPTc) is a promising strategy for malaria control. A study conducted in Mali in 2008 showed that administration of three courses of IPTc with sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ) at monthly intervals reduced clinical malaria, severe malaria and malaria infection by >80% in children under 5 years of age. Here we report the results of a follow-on study undertaken to establish whether children who had received IPTc would be at increased risk of malaria during the subsequent malaria transmission season. METHODS: Morbidity from malaria and the prevalence of malaria parasitaemia and anaemia were measured in children who had previously received IPTc with SP and AQ using similar surveillance methods to those employed during the previous intervention period. RESULTS: 1396 of 1508 children (93%) who had previously received IPTc and 1406 of 1508 children (93%) who had previously received placebos were followed up during the high malaria transmission season of the year following the intervention. Incidence rates of clinical malaria during the post-intervention transmission season (July-November 2009) were 1.87 (95% CI 1.76-1.99) and 1.73 (95% CI; 1.62-1.85) episodes per child year in the previous intervention and placebo groups respectively; incidence rate ratio (IRR) 1.09 (95% CI 0.99-1.21) (P = 0.08). The prevalence of malaria infection was similar in the two groups, 7.4% versus 7.5%, prevalence ratio (PR) of 0.99 (95% CI 0.73-1.33) (P = 0.95). At the end of post-intervention malaria transmission season, the prevalence of anaemia, defined as a haemoglobin concentration<11g/dL, was similar in the two groups (56.2% versus 55.6%; PR = 1.01 [95% CI 0.91-1.12]) (P = 0.84). CONCLUSION: IPTc with SP+AQ was not associated with an increase in incidence of malaria episodes, prevalence of malaria infection or anaemia in the subsequent malaria transmission season. TRIAL REGISTRATION: ClinicalTrials.gov NCT00738946.

Intermittent preventive treatment of malaria provides substantial protection against malaria in children already protected by an insecticide-treated bednet in Mali: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Previous studies have shown that in areas of seasonal malaria transmission, intermittent preventive treatment of malaria in children (IPTc), targeting the transmission season, reduces the incidence of clinical malaria. However, these studies were conducted in communities with low coverage with insecticide-treated nets (ITNs). Whether IPTc provides additional protection to children sleeping under an ITN has not been established. METHODS AND FINDINGS: To assess whether IPTc provides additional protection to children sleeping under an ITN, we conducted a randomised, double-blind, placebo-controlled trial of IPTc with sulphadoxine pyrimethamine (SP) plus amodiaquine (AQ) in three localities in Kati, Mali. After screening, eligible children aged 3-59 mo were given a long-lasting insecticide-treated net (LLIN) and randomised to receive three rounds of active drugs or placebos. Treatments were administered under observation at monthly intervals during the high malaria transmission season in August, September, and October 2008. Adverse events were monitored immediately after the administration of each course of IPTc and throughout the follow-up period. The primary endpoint was clinical episodes of malaria recorded through passive surveillance by study clinicians available at all times during the follow-up. Cross-sectional surveys were conducted in 150 randomly selected children weekly and in all children at the end of the malaria transmission season to assess usage of ITNs and the impact of IPTc on the prevalence of malaria, anaemia, and malnutrition. Cox regression was used to compare incidence rates between intervention and control arms. The effects of IPTc on the prevalence of malaria infection and anaemia were estimated using logistic regression. 3,065 children were screened and 3,017 (1,508 in the control and 1,509 in the intervention arm) were enrolled in the study. 1,485 children (98.5%) in the control arm and 1,481 (98.1%) in the intervention arm completed follow-up. During the intervention period, the proportion of children reported to have slept under an ITN was 99.7% in the control and 99.3% in intervention arm (p = 0.45). A total of 672 episodes of clinical malaria defined as fever or a history of fever and the presence of at least 5,000 asexual forms of Plasmodium falciparum per microlitre (incidence rate of 1.90; 95% confidence interval [CI] 1.76-2.05 episodes per person year) were observed in the control arm versus 126 (incidence rate of 0.34; 95% CI 0.29-0.41 episodes per person year) in the intervention arm, indicating a protective effect (PE) of 82% (95% CI 78%-85%) (p<0.001) on the primary endpoint. There were 15 episodes of severe malaria in children in the control arm compared to two in children in the intervention group giving a PE of 87% (95% CI 42%-99%) (p = 0.001). IPTc reduced the prevalence of malaria infection by 85% (95% CI 73%-92%) (p<0.001) during the intervention period and by 46% (95% CI 31%-68%) (p<0.001) at the end of the intervention period. The prevalence of moderate anaemia (haemoglobin [Hb] <8 g/dl) was reduced by 47% (95% CI 15%-67%) (p<0.007) at the end of intervention period. The frequencies of adverse events were similar between the two arms. There was no drug-related serious adverse event. CONCLUSIONS: IPTc given during the malaria transmission season provided substantial protection against clinical episodes of malaria, malaria infection, and anaemia in children using an LLIN. SP+AQ was safe and well tolerated. These findings indicate that IPTc could make a valuable contribution to malaria control in areas of seasonal malaria transmission alongside other interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT00738946. Please see later in the article for the Editors' Summary.