Modeling clinical malaria episodes in different ecological settings in Mali, 2018-2022.

Objectives: Following the scaling-up of malaria control strategies in Mali, understanding the changes in age-specific prevalence of infection and risk factors associated with remains necessary to determine new priorities to progress toward disease elimination. This study aimed to estimate the risk of clinical malaria using longitudinal data across three different transmission settings in Mali. Methods: Cohort-based longitudinal studies were performed from April 2018 to December 2022. Incidence of malaria was measured through community health center-based passive case detection. Generalized estimation equation model was used to assess risk factors for clinical malaria. Results: A total of 21,453 clinical presentations were reported from 4500 participants, mainly from July to November. Data shows a significant association between malaria episodes, sex, age group, season, and year. Women had lower risk, the risk of clinical episode increased with age up to 14 years then declined, and in both sites, the dry-season risk of clinical episode was significantly lower compared to the rainy season. Conclusion: Determining factors associated with the occurrence of clinical malaria across different ecological settings across the country could help in the development of new strategies aiming to accelerate malaria elimination in an area where malaria transmission remains intense.

Effect of a fifth round of seasonal malaria chemoprevention in children aged 5-14 years in Dangassa, an area of long transmission in Mali.

Despite a significant reduction in the burden of malaria in children under five years-old, the efficient implementation of seasonal malaria chemoprevention (SMC) at large scale remains a major concern in areas with long malaria transmission. Low coverage rate in the unattainable areas during the rainy season, a shift in the risk of malaria to older children and the rebound in malaria incidence after stopping drug administration are mainly reported in these areas. These gaps represent a major challenge in the efficient implementation of SMC measures. An open randomized study was conducted to assess the effect of a fifth additional round to current regime of SMC in older children living in Dangassa, a rural malaria endemic area. Poisson regression Model was used to estimate the reduction in malaria incidence in the intervention group compared to the control group including age groups (5-9 and 10-14 years) and the use of long-lasting insecticidal nets (LLINs; Yes or No) with a threshold at 5%. Overall, a downward trend in participation rate was observed from August (94.3%) to November (87.2%). In November (round 4), the risk of malaria incidence was similar in both groups (IRR = 0.66, 95%CI [0.35-1.22]). In December (round 5), a decrease of 51% in malaria incidence was observed in intervention group compared to control group adjusted for age groups and the use of LLINs (IRR = 0.49, 95%CI [0.26-0.94]), of which 17% of reduction is attributable to the 5th round in the intervention group. An additional fifth round of SMC resulted in a significant reduction of malaria incidence in the intervention group. The number of SMC rounds could be adapted to the local condition of malaria transmission.

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.

Effectiveness and Community Acceptance of Extending Seasonal Malaria Chemoprevention to Children 5 to 14 Years of Age in Dangassa, Mali.

Seasonal malaria chemoprevention (SMC) was adopted in Mali in 2012 for preventing malaria in children younger than 5 years. Although this strategy has been highly effective in reducing childhood malaria, an uptick in malaria occurrence has occurred in children 5 to 15 years of age. This study aimed to investigate the feasibility of providing SMC to older children. A cohort of 350 children age 5 to 14 years were monitored during the 2019 transmission season in Dangassa, Mali. The intervention group received five monthly rounds of sulfadoxine-pyrimethamine plus amodiaquine, whereas the control group consisted of untreated children. Community acceptance for extending SMC was assessed during the final round. Logistic regression models were applied to compare the risk of Plasmodium falciparum malaria infection, anemia, and fever between the intervention and control groups. Kaplan-Meier survival analyses were used to compare the time to P. falciparum parasitemia infection between the groups. The community acceptance rate was 96.5% (139 of 144). Significant declines were observed in the prevalence of P. falciparum parasitemia (adjusted odds ratio, 0.22; 95% CI, 0.11-0.42) and anemia (adjusted odds ratio, 0.15; 95% CI, 0.07-0.28) in the intervention group compared with the control group. The cumulative incidence of P. falciparum infections was significantly greater (75.4%, 104 of 138) in the control group compared with the intervention group (40.7%, 61 of 143, P = 0.001). This study reveals that expanding SMC to older children is likely feasible, has high community acceptance, and is in reducing uncomplicated malaria and anemia in older children.

Ex-vivo Sensitivity of Plasmodium falciparum to Common Anti-malarial Drugs: The Case of Kéniéroba, a Malaria Endemic Village in Mali.

BACKGROUND: In 2006, the National Malaria Control Program in Mali recommended artemisinin-based combination therapy as the first-line treatment for uncomplicated malaria. Since the introduction of artemisinin-based combination therapy, few reports are available on the level of resistance of Plasmodium falciparum to the most common anti-malarial drugs in Mali. METHODS: From 2016 to 2017, we assessed the ex-vivo drug sensitivity of P. falciparum isolates in Kéniéroba, a village located in a rural area of southern Mali. We collected P. falciparum isolates from malaria-infected children living in Kéniéroba. The isolates were tested for ex-vivo sensitivity to commonly used anti-malarial drugs, namely chloroquine, quinine, amodiaquine, mefloquine, lumefantrine, dihydroartermisinin, and piperaquine. We used the 50% inhibitory concentration determination method, which is based on the incorporation of SYBR® Green into the parasite's genetic material. RESULTS: Plasmodium falciparum isolates were found to have a reduced ex-vivo sensitivity to quinine (25.7%), chloroquine (12.2%), amodiaquine (2.7%), and mefloquine (1.3%). In contrast, the isolates were 100% sensitive to lumefantrine, dihydroartermisinin, and piperaquine. A statistically significant correlation was found between 50% inhibitory concentration values of quinine and amodiaquine (r = 0.80; p < 0.0001). CONCLUSIONS: Plasmodium falciparum isolates were highly sensitive to dihydroartermisinin, lumefantrine, and piperaquine and less sensitive to amodiaquine (n = 2), mefloquine (n = 1), and quinine (n = 19). Therefore, our data support the previously reported increasing trend in chloroquine sensitivity in Mali.

Effect of routine seasonal malaria chemoprevention on malaria trends in children under 5 years in Dangassa, Mali.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is a new strategy to prevent malaria in children under 5 years old. It has been recommended by the World Health Organization since 2012 in malaria-endemic areas with seasonal transmission. This study aimed to assess the changes in malaria indicators through two consecutive years of SMC routine implementation in children under 5 years old in Dangassa, where malaria is endemic with a long and high transmission season. METHODS: From 2012 to 2016, a cohort study was conducted in Dangassa village. The study team based in the village followed all malaria clinical cases in children under 5 years old at the community health centre. During the study, SMC was routinely implemented in collaboration with the National Malaria Control Programme. The Cox regression model was used in order to compare malaria risk during the study. RESULTS: The Cox regression model showed a significant reduction in malaria clinical incidence, both in 2015 (HR = 0.27 (0.18-0.40), 95% CI) and in 2016 (HR = 0.23 (0.15-0.35), 95% CI) of SMC implementation compared to October 2013. Gametocyte and fever prevalence was lower between September and October during SMC implementation (2015 and 2016) compared to the same period before SMC implementation (2013-2014). A slight increase of malaria incidence was observed in December at the end of SMC implementation. CONCLUSION: SMC has significantly reduced both malaria incidence and gametocyte prevalence and improved haemoglobin levels in children under 5 years old after 2 years of routine implementation.

A comprehensive analysis of drug resistance molecular markers and Plasmodium falciparum genetic diversity in two malaria endemic sites in Mali.

BACKGROUND: Drug resistance is one of the greatest challenges of malaria control programme in Mali. Recent advances in next-generation sequencing (NGS) technologies provide new and effective ways of tracking drug-resistant malaria parasites in Africa. The diversity and the prevalence of Plasmodium falciparum drug-resistance molecular markers were assessed in Dangassa and Nioro-du-Sahel in Mali, two sites with distinct malaria transmission patterns. Dangassa has an intense seasonal malaria transmission, whereas Nioro-du-Sahel has an unstable and short seasonal malaria transmission. METHODS: Up to 270 dried blood spot samples (214 in Dangassa and 56 in Nioro-du-Sahel) were collected from P. falciparum positive patients in 2016. Samples were analysed on the Agena MassARRAY® iPLEX platform. Specific codons were targeted in Pfcrt, Pfmdr1, Pfdhfr, and Pfdhps, Pfarps10, Pfferredoxin, Pfexonuclease and Pfmdr2 genes. The Sanger's 101-SNPs-barcode method was used to assess the genetic diversity of P. falciparum and to determine the parasite species. RESULTS: The Pfcrt_76T chloroquine-resistance genotype was found at a rate of 64.4% in Dangassa and 45.2% in Nioro-du-Sahel (p = 0.025). The Pfdhfr_51I-59R-108N pyrimethamine-resistance genotype was 14.1% and 19.6%, respectively in Dangassa and Nioro-du-Sahel. Mutations in the Pfdhps_S436-A437-K540-A581-613A sulfadoxine-resistance gene was significantly more prevalent in Dangassa as compared to Nioro-du-Sahel (p = 0.035). Up to 17.8% of the isolates from Dangassa vs 7% from Nioro-du-Sahel harboured at least two codon substitutions in this haplotype. The amodiaquine-resistance Pfmdr1_N86Y mutation was identified in only three samples (two in Dangassa and one in Nioro-du-Sahel). The lumefantrine-reduced susceptibility Pfmdr1_Y184F mutation was found in 39.9% and 48.2% of samples in Dangassa and Nioro-du-Sahel, respectively. One piperaquine-resistance Exo_E415G mutation was found in Dangassa, while no artemisinin resistance genetic-background were identified. A high P. falciparum diversity was observed, but no clear genetic aggregation was found at either study sites. Higher multiplicity of infection was observed in Dangassa with both COIL (p = 0.04) and Real McCOIL (p = 0.02) methods relative to Nioro-du-Sahel. CONCLUSIONS: This study reveals high prevalence of chloroquine and pyrimethamine-resistance markers as well as high codon substitution rate in the sulfadoxine-resistance gene. High genetic diversity of P. falciparum was observed. These observations suggest that the use of artemisinins is relevant in both Dangassa and Nioro-du-Sahel.