Effect of seasonal malaria chemoprevention in children between 5 and 9 years old in Kita and Bafoulabe districts, Mali.

Background: Seasonal malaria chemoprevention (SMC) has been widely expanded in Mali since its recommendation by the the World Health Organization in 2012. SMC guidelines currently target children between three months and five years of age. The SMC initiative has been largely successful. Children at least five years of age are not currently covered by current SMC guidelines but bear a considerable portion of the malaria burden. For this reason, this study sought to determine the feasibility and effectiveness for extending SMC to children aged 5-9 years. Methods: A non-randomized, pre-post study was performed with an intervention district (Kita) and a comparison district (Bafoulabe). Children aged 3-59 months received SMC in both comparison districts, and children aged 60-120 months received SMC in the intervention district. SMC was delivered as sulfadoxine-pyriméthamine plus amodiaquine (SP-AQ) at monthly intervals from July to October in 2017 and 2018 during the historical transmission seasons. Baseline and endline cross-sectional surveys were conducted in both comparison districts. A total of 200 household surveys were conducted at each of the four monthly SMC cycles to determine adherence and tolerance to SMC in the intervention district. Results: In July 2017, 633 children aged 60-120 months old were enrolled at the Kita and Bafoulabe study sites (n = 310 and n = 323, respectively). Parasitemia prevalence was similar in the intervention and comparison districts prior the SMC campaign (27.7% versus 21.7%, p = 0.07). Mild anemia was observed in 14.2% children in Kita and in 10.5% of children in Bafoulabé. At the Kita site, household surveys showed an SMC coverage rate of 89.1% with a response rate of 93.3% among child caregivers. The most common adverse event reported by parents was drowsiness (11.8%). One year following SMC implementation in the older age group in Kita, the coverage of three doses per round was 81.2%. Between the baseline and endline surveys, there was a reduction in parasitemia prevalence of 40% (OR = 0.60, CI: 0.41-0.89). Malaria molecular resistance was low in the intervention district following the intervention. A significant reduction in the prevalence of parasitemia in children 60 to 120 months was observed in the intervention district, but the prevalance of clinical malaria remained relatively constant. Conclusion: This study shows that the prospect of extending SMC coverage to children between five and nine years old is encouraging. The reduction in the parasitemia could also warrant consideration for adapting SMC policy to account for extended malaria transmission seasons.

Monitoring of the Sensitivity In Vivo of Plasmodium falciparum to Artemether-Lumefantrine in Mali.

In Mali, since 2007, artemether-lumefantrine has been the first choice against uncomplicated malaria. Despite its effectiveness, a rapid selection of markers of resistance to partner drugs has been documented. This work evaluated the treatment according to the World Health Organization's standard 28-day treatment method. The primary endpoint was the clinical and parasitological response corrected by a polymerase chain reaction. It was more than 99.9 percent, the proportion of patients with anemia significantly decrease compared to baseline (p < 0.001), and no serious events were recorded. Plasmodium falciparum remains sensitive to artemether-lumefantrine in Mali.

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.

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.

Impact evaluation of malaria control interventions on morbidity and all-cause child mortality in Mali, 2000-2012.

BACKGROUND: Major investments have been made since 2001, with intensification of malaria control interventions after 2006. Interventions included free distribution of insecticide-treated nets (ITN) to pregnant women and children under 5 years old, the introduction of artemisinin combination therapy (ACT) for malaria treatment, and indoor residual spraying of insecticides. Funders include the Government of Mali, the Global Fund to Fight AIDS, Tuberculosis and Malaria, and the US President's Malaria Initiative. METHODS: Data from nationally representative household surveys conducted from 2000 to 2015 was used to performed the trend analysis for malaria intervention coverage, prevalence of morbidities among children under 5 years old [parasitemia and severe anaemia (< 8 g/dl)], and all-cause mortality of children under 5 (ACCM). Prevalence of contextual factors likely to contribute to ACCM were also assessed. The impact of these interventions was assessed on malaria morbidity and mortality using a plausibility argument. With the assumption that malaria contributes significantly to under-five mortality in settings with high malaria transmission, associations between malaria control interventions and all-cause under-five mortality (ACCM) were assessed taking into account other contextual factors related to child survival. RESULTS: Intervention coverage improved significantly from 2006 to 2012. Household ownership of ITN increased from 49% in 2006 to 84% in 2012. ITN use also increased over the same period, from 26% in 2006 to 69% in 2012 among children under 5 and from 28% in 2006 to 73% in 2012 among pregnant women. The coverage of intermittent preventive treatment in pregnancy (IPTp) using two or more doses of SP increased from 10% in 2006 to 29% in 2012. In 2010, 23% of febrile children under 5 received ACT, as opposed to 19% in 2012. The prevalence of Plasmodium falciparum infection increased from 2010 (38.6%) to 2012 (51.6%), followed by a decrease in 2015 (35.8%). The prevalence of severe anaemia decreased from 2010 (26.3%) to 2012 (20.6%) and continued to decline in 2015 (19.9%). An impressive decline in ACCM was observed, from 225 in 1997-2001 to 192 in 2002-2006 and 95 in 2008-2012. Changes in contextual factors such as climate, socio-economic, nutrition, and coverage of maternal and child health interventions over the evaluation period did not favour reductions in ACCM, and are therefore unlikely to explain the observed results. CONCLUSIONS: Taken as a whole, the evidence supports the conclusion that malaria control interventions substantially contributed to the observed decline in ACCM in Mali from 2000 to 2012, even in the context of continued high prevalence of parasitaemia explained by contextual factors such as climate change and political instability.

Proactive community case management and child survival in periurban Mali.

The majority of the world's population lives in urban areas, and regions with the highest under-five mortality rates are urbanising rapidly. This 7-year interrupted time series study measured early access to care and under-five mortality over the course of a proactive community case management (ProCCM) intervention in periurban Mali. Using a cluster-based, population-weighted sampling methodology, we conducted independent cross-sectional household surveys at baseline and at 12, 24, 36, 48, 60, 72 and 84 months later in the intervention area. The ProCCM intervention had five key components: (1) active case detection by community health workers (CHWs), (2) CHW doorstep care, (3) monthly dedicated supervision for CHWs, (4) removal of user fees and (5) primary care infrastructure improvements and staff capacity building. Under-five mortality rate was calculated using a Cox proportional hazard survival regression. We measured the percentage of children initiating effective antimalarial treatment within 24 hours of symptom onset and the percentage of children reported to be febrile within the previous 2 weeks. During the intervention, the rate of early effective antimalarial treatment of children 0-59 months more than doubled, from 14.7% in 2008 to 35.3% in 2015 (OR 3.198, P<0.0001). The prevalence of febrile illness among children under 5 years declined after 7 years of the intervention from 39.7% at baseline to 22.6% in 2015 (OR 0.448, P<0.0001). Communities where ProCCM was implemented have achieved an under-five mortality rate at or below 28/1000 for the past 6 years. In 2015, under-five mortality was 7/1000 (HR 0.039, P<0.0001). Further research is needed to elucidate the mechanisms of action and generalizability of ProCCM.

Optimal mode for delivery of seasonal malaria chemoprevention in Ouelessebougou, Mali: A cluster randomized trial.

BACKGROUND: Seasonal malaria chemoprevention (SMC), the administration of complete therapeutic courses of antimalarials to children aged 3-59 months during the malaria transmission season, is a new strategy recommended by the World Health Organization (WHO) for malaria control in Sahelian countries such as Mali with seasonal transmission. The strategy is a highly cost-effective approach to reduce malaria burden in these areas. Despite the substantial benefits of SMC on malaria infection and disease, the optimal approach to deliver SMC remains to be determined. While fixed-point delivery (FPD) and non-directly observed treatment (NDOT) by community health workers are logistically attractive, these need to be evaluated and compared to other modes of delivery for maximal coverage. METHODS: To determine the optimal mode fixed-point (FPD) vs door-to-door delivery (DDD); directly observed treatment (DOT) vs. non- directly observed treatment (NDOT)), 31 villages in four health sub-districts were randomized to receive three rounds of SMC with Sulfadoxine-pyrimethamine plus Amodiaquine (SP+AQ) at monthly intervals using one of the following methods: FPD+DOT; FPD+NDOT; DDD+DOT; DDD+NDOT. The primary endpoint was SMC coverage assessed by cross-sectional survey of 2,035 children at the end of intervention period. RESULTS: Coverage defined as the proportion of children who received all three days of SMC treatment during the three monthly rounds based information collected by interview (primary endpoint) was significantly higher in children who received SMC using DDD 74% (95% CI 69% - 80%) compared to FPD 60% (95% CI 50% - 70%); p = 0.009. It was similar in children who received SMC using DOT or NDOT 65%, (95% CI 55% - 76%) versus 68% (95% CI 57% - 79%); p = 0.72. CONCLUSIONS: In summary, door-to-door delivery of SMC provides better coverage than FPD. Directly observed therapy, which requires more time and resources, did not improve coverage with SMC. TRIAL REGISTRATION: ClinicalTrials.gov NCT02646410.

Measuring the impact of seasonal malaria chemoprevention as part of routine malaria control in Kita, Mali.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is a new strategy recommended by WHO in areas of highly seasonal transmission in March 2012. Although randomized controlled trials (RCTs) have shown SMC to be highly effective, evidence and experience from routine implementation of SMC are limited. METHODS: A non-randomized pragmatic trial with pre-post design was used, with one intervention district (Kita), where four rounds of SMC with sulfadoxine + amodiaquine (SP + AQ) took place in August-November 2014, and one comparison district (Bafoulabe). The primary aims were to evaluate SMC coverage and reductions in prevalence of malaria and anaemia when SMC is delivered through routine programmes using existing community health workers. Children aged 3-59 months from 15 selected localities per district, sampled with probability proportional to size, were surveyed and blood samples collected for malaria blood smears, haemoglobin (Hb) measurement, and molecular markers of drug resistance in two cross-sectional surveys, one before SMC (July 2014) and one after SMC (December 2014). Difference-in-differences regression models were used to assess and compare changes in malaria and anaemia in the intervention and comparison districts. Adherence and tolerability of SMC were assessed by cross-sectional surveys 4-7 days after each SMC round. Coverage of SMC was assessed in the post-SMC survey. RESULTS: During round 1, 84% of targeted children received at least the first SMC dose, but coverage declined to 67% by round 4. Across the four treatment rounds, 54% of children received four complete SMC courses. Prevalence of parasitaemia was similar in intervention and comparison districts prior to SMC (23.4 vs 29.5%, p = 0.34) as was the prevalence of malaria illness (2.4 vs 1.9%, p = 0.75). After SMC, parasitaemia prevalence fell to 18% in the intervention district and increased to 46% in the comparison district [difference-in-differences (DD) OR = 0.35; 95% CI 0.20-0.60]. Prevalence of malaria illness fell to a greater degree in the intervention district versus the comparison district (DD OR = 0.20; 95% CI 0.04-0.94) and the same for moderate anaemia (Hb < 8 g/dL) (DD OR = 0.26, 95% CI 0.11-0.65). The frequency of the quintuple mutation (dhfr N51I, C59R and S108N + dhps A437G and K540E) remained low (5%) before and after intervention in both districts. CONCLUSIONS: Routine implementation of SMC in Mali substantially reduced malaria and anaemia, with reductions of similar magnitude to those seen in previous RCTs. Improving coverage could further strengthen SMC impact. Trial registration clinical trial registration number NCT02894294.

The relative roles of ANC and EPI in the continuous distribution of LLINs: a qualitative study in four countries.

BACKGROUND: The continuous distribution of long-lasting insecticidal nets (LLINs) for malaria prevention, through the antenatal care (ANC) and the Expanded Programme on Immunizations (EPI), is recommended by the WHO to improve and maintain LLIN coverage. Despite these recommendations, little is known about the relative strengths and weaknesses of the ANC and EPI-based LLIN distribution. This study aimed to explore and compare the roles of the ANC and EPI for LLIN distribution in four African countries. METHODS: In a qualitative evaluation of continuous distribution through the ANC and EPI, semi-structured, individual and group interviews were conducted in Kenya, Malawi, Mali, and Rwanda. Respondents included national, sub-national, and facility-level health staff, and were selected to capture a range of roles related to malaria, ANC and EPI programmes. Policies, guidelines, and data collection tools were reviewed as a means of triangulation to assess the structure of LLIN distribution, and the methods of data collection and reporting for malaria, ANC and EPI programmes. RESULTS: In the four countries visited, distribution of LLINs was more effectively integrated through ANC than through EPI because of a) stronger linkages and involvement between malaria and reproductive health programmes, as compared to malaria and EPI, and b) more complete programme monitoring for ANC-based distribution, compared to EPI-based distribution. CONCLUSIONS: Opportunities for improving the distribution of LLINs through these channels exist, especially in the case of EPI. For both ANC and EPI, integrated distribution of LLINs has the potential to act as an incentive, improving the already strong coverage of both these essential services. The collection and reporting of data on LLINs distributed through the ANC and EPI can provide insight into the performance of LLIN distribution within these programmes. Greater attention to data collection and use, by both the global malaria community, and the integrated programmes, can improve this distribution channel strength and effectiveness.

Operational challenges to continuous LLIN distribution: a qualitative rapid assessment in four countries.

BACKGROUND: The World Health Organization recommends that long-lasting insecticidal nets (LLINs) for malaria prevention should be distributed continuously through antenatal care (ANC) and the expanded programme on immunization (EPI) in addition to mass campaigns. Despite these recommendations, the continuous distribution (CD) of LLIN distribution through ANC and EPI is not policy in many countries, and where there is a policy, implementation is incomplete. This study aims to identify the operational strengths and weaknesses of LLINs CD in four country programmes in sub-Saharan Africa. METHODS: A qualitative rapid assessment process was conducted using semi-structured individual and group interviews at the national, sub-national, and facility level in four countries. Seventy participants were included (23 in Kenya, 13 in Malawi, 18 in Mali and 16 in Rwanda), drawn from malaria programmes, ANC and EPI programmes, government logistics units, and partner organizations. Interviews were structured to identify themes within a health systems approach. Policy and guideline documents and data collection tools were reviewed as a means of triangulation. Data analysis focused on pre-determined and emergent themes. RESULTS: The four countries used a wide variety of management systems for the supply of LLINs to routine services. Issues related to quantification, supply logistics and data collection all contributed to stock-outs at facility level. None of the four countries had guidelines for responding to stock-outs or system enabling local staff to request additional supplies of LLINs. In all four countries, data collection of LLIN distribution was incomplete or absent at facility level, and such data were not used for planning. Training of staff at the facility level was implemented less frequently than national and sub-national staff would have preferred. Logistics systems, independent of other commodities, and in-country partner support strengthened the continuous distribution of LLINs. CONCLUSIONS: In these countries, stock-outs were the most important single obstacle to the smooth operations of continuous LLIN distribution. Stock-outs can be avoided if facilities have the capacity to place orders for LLIN resupply as needed. Revised data collection and management systems for LLIN distribution have the potential to increase coverage of the target populations by improving LLIN stock-out response, and strengthening monitoring and evaluation of distribution.

Acceptability of multiple micronutrient supplements by pregnant and lactating women in Mali.

BACKGROUND: In Mali, an estimated 73% of pregnant women are anaemic largely due to iron deficiency. National policy recommends women to take iron and folic acid supplements daily from first prenatal contact until 3 months postpartum. However, many pregnant women in Mali could benefit from multiple micronutrient supplements. OBJECTIVE: To assess pregnant women's acceptability of and adherence to a daily multiple micronutrient supplementation scheme compared with the current daily iron and folic acid supplementation scheme. DESIGN: Seventy pregnant women were allocated to either the daily multiple micronutrient or daily iron and folic acid supplementation scheme. Women started receiving supplements at the end of the first trimester of pregnancy until delivery and throughout the first 3 months postpartum. RESULTS: No significant differences were observed between comparison groups with respect to women's perceptions about supplement size, colour, taste or flavour. Adherence to the multiple micronutrient supplementation scheme was better (257.5+/-20.9 tablets; average adherence 95.4%) than that to the iron and folic acid supplementation scheme (238.5+/-32.7 tablets; average adherence 92.2%; P=0.008) although both were very good, as were women's perceptions about the benefits of micronutrient supplements to their health and that of their newborns. CONCLUSION: Malian women adhere to prenatal/postpartum micronutrient supplementation - no matter what supplement is chosen - when access to supplements is guaranteed and when they are provided with minimum, consistent and easily understandable information and counselling, indicating that these are key elements to ensure effective programmes. These findings, together with those of the global research agenda on the efficacy of multiple micronutrient supplements for pregnant women, will inform policy development in Mali for the effective control of iron deficiency and iron-deficiency anaemia in pregnant women.