Meta-analysis of the global distribution of clinically relevant CYP2C8 alleles and their inferred functional consequences.

BACKGROUND: CYP2C8 is responsible for the metabolism of 5% of clinically prescribed drugs, including antimalarials, anti-cancer and anti-inflammatory drugs. Genetic variability is an important factor that influences CYP2C8 activity and modulates the pharmacokinetics, efficacy and safety of its substrates. RESULTS: We profiled the genetic landscape of CYP2C8 variability using data from 96 original studies and data repositories that included a total of 33,185 unrelated participants across 44 countries and 43 ethnic groups. The reduced function allele CYP2C8*2 was most common in West and Central Africa with frequencies of 16-36.9%, whereas it was rare in Europe and Asia (< 2%). In contrast, CYP2C8*3 and CYP2C8*4 were common throughout Europe and the Americas (6.9-19.8% for *3 and 2.3-7.5% for *4), but rare in African and East Asian populations. Importantly, we observe pronounced differences (> 2.3-fold) between neighboring countries and even between geographically overlapping populations. Overall, we found that 20-60% of individuals in Africa and Europe carry at least one CYP2C8 allele associated with reduced metabolism and increased adverse event risk of the anti-malarial amodiaquine. Furthermore, up to 60% of individuals of West African ancestry harbored variants that reduced the clearance of pioglitazone, repaglinide, paclitaxel and ibuprofen. In contrast, reduced function alleles are only found in < 2% of East Asian and 8.3-12.8% of South and West Asian individuals. CONCLUSIONS: Combined, the presented analyses mapped the genetic and inferred functional variability of CYP2C8 with high ethnogeographic resolution. These results can serve as a valuable resource for CYP2C8 allele frequencies and distribution estimates of CYP2C8 phenotypes that could help identify populations at risk upon treatment with CYP2C8 substrates. The high variability between ethnic groups incentivizes high-resolution pharmacogenetic profiling to guide precision medicine and maximize its socioeconomic benefits, particularly for understudied populations with distinct genetic profiles.

Impact of seasonal malaria chemoprevention based on the number of medicines doses received on malaria burden among children aged 3-59 months in Nigeria: A propensity score-matched analysis.

BACKGROUND: Seasonal malaria chemoprevention using sulfadoxine-pyrimethamine plus amodiaquine (sulfadoxine-pyrimethamine plus amodiaquine on Day 1 and amodiaquine on both Day 2 and Day 3) is delivered to children aged 3-59 months in areas of highly season malaria transmission. While the overall population-level impact of seasonal malaria chemoprevention on malaria control has been documented in various countries and time periods, there is no clear evidence regarding seasonal malaria chemoprevention impact based on the number of medicine doses children receive in one cycle in routine programmatic conditions. METHODS: Data were extracted from Nigeria's routinely collected seasonal malaria chemoprevention end-of-round coverage surveys (2021, 2022). We matched seasonal malaria chemoprevention-targeted children who received specific numbers of seasonal malaria chemoprevention medicines with those who did not receive any doses of seasonal malaria chemoprevention medicines (non-sulfadoxine-pyrimethamine plus amodiaquine) using multiple sets of propensity score matches. We performed multilevel logistic regression for each matched group to evaluate the association between the number of doses of seasonal malaria chemoprevention medicines and monthly confirmed malaria cases (caregiver-reported malaria infection diagnosed by rapid diagnostic test at a health facility following the penultimate cycle of seasonal malaria chemoprevention). RESULTS: Among 21,621 SMC-targeted children, 9.7% received non-sulfadoxine-pyrimethamine plus amodiaquine, 0.5% received only Day 1 sulfadoxine-pyrimethamine plus amodiaquine, 1.0% received Day 1 sulfadoxine-pyrimethamine plus amodiaquine and either Day 2 amodiaquine or Day 3 amodiaquine (sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine), and 88.8% received Day 1 sulfadoxine-pyrimethamine plus amodiaquine and both Day 2 and Day 3 amodiaquine (sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine + amodiaquine). Children receiving only Day 1 sulfadoxine-pyrimethamine plus amodiaquine did not have significant lower odds of rapid diagnostic tests-confirmed malaria than those receiving non-sulfadoxine-pyrimethamine plus amodiaquine (OR 0.77, 0.42-1.42). However, children receiving sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine had significantly lower odds of rapid diagnostic tests-confirmed malaria than those receiving non-sulfadoxine-pyrimethamine plus amodiaquine (OR 0.42, 95% CI 0.28-0.63). Similarly, children receiving sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine + amodiaquine also had significantly lower odds of rapid diagnostic test-confirmed malaria than those receiving non-sulfadoxine-pyrimethamine plus amodiaquine (OR 0.54, 95% CI 0.47-0.62). CONCLUSION: Adherence to at least one daily dose of amodiaquine administration following receipt of Day 1 sulfadoxine-pyrimethamine plus amodiaquine by eligible children is crucial to ensure the effectiveness of seasonal malaria chemoprevention. This demonstrates the importance of enhancing caregiver awareness regarding the importance of amodiaquine and identifying barriers toward amodiaquine administration at the community level.

Receipt of seasonal malaria chemoprevention by age-ineligible children and associated factors in nine implementation states in Nigeria.

BACKGROUND: As part of implementation quality standards, community distributors are expected to ensure that only age-eligible children (aged 3-59 months) receive seasonal malaria chemoprevention (SMC) medicines during monthly campaigns. There is uncertainty about the extent to which SMC medicines are administered to ineligible children. This study aimed to assess the magnitude of this occurrence, while exploring the factors associated with it across nine states where SMC was delivered in Nigeria during the 2022 round. METHODS: This analysis was based on data from representative end-of-round SMC household surveys conducted in nine SMC-implementing states in Nigeria. Data of 3299 age-ineligible children aged > 5 years and their caregivers were extracted from the survey dataset. Prevalence of receipt of SMC medicines by ineligible children was described by child-, caregiver- and SMC-related factors. Mixed-effects multivariable logistic regression models were fitted to explore the factors associated with ineligible receipt of SMC medicines. RESULTS: 30.30% (95% CI 27.80-32.90) of ineligible children sampled received at least one dose of SMC medicines in 2022, the majority (60.60%) of whom were aged 5-6 years while the rest were aged 7-10 years. There were lower odds of an age-ineligible child receiving SMC among caregivers who had knowledge of SMC age eligibility (OR: 0.53, 95% CI 0.37-0.77, p < 0.001), compared with those who were knowledgeable of age eligibility. Higher odds of receipt of SMC were found among age-ineligible children whose caregivers had higher confidence in the protective effect of SMC against malaria (OR: 2.01, 95% CI 1.07-3.72, p = 0.030), compared with those whose caregivers were less confident. Compared with ineligible children of younger caregivers (aged < 20 years), those whose caregivers were older had lower odds of receiving SMC than those whose caregivers were younger; with lower odds among children of caregivers aged 20-39 years (OR: 0.50, 95% CI 0.30-0.82, p = 0.006). CONCLUSIONS: This study contributes important evidence on the magnitude of the receipt of SMC medicines by age-ineligible children, while identifying individual and contextual factors associated with it. The findings provide potentially useful insights that can help inform and guide context-specific SMC implementation quality improvement efforts.

The monthly trends of malaria cases in children under 5 years of age in Guinea: comparative analysis between a seasonal malaria chemoprevention (SMC) and a non-SMC health district.

BACKGROUND: The Republic of Guinea, where malaria represents the leading cause of morbidity and mortality among children, the seasonal malaria chemoprevention (SMC) is deployed only in areas with very seasonal modes of transmission. It should target children at the highest risk of serious illness. The objective of the study was to prevent uncomplicated and serious cases of malaria in the target population. This study aimed to analyse the monthly trends in malaria-related morbidity among children under the age of 5 in Guinea. METHODS: This was a quasi-experimental study with routine data from the National Health Information System (SNIS). The two districts Mamou (the SMC intervention site) and Kindia (the control site) were selected to compare the monthly trends in malaria cases among children under the age of 5, from July to October, covering the years from 2015 to 2020. The statistical analysis used interrupted time series to estimate the effects of the SMC. RESULTS: The SMC programme contributed to a significant average reduction in the number of malaria cases of 225 cases per month in the intervention district (95% CI - 362 to - 88; p = 0.002), compared to the control district. However, the study also revealed that the effect of SMC varied between cycles, presenting different monthly malaria cases. CONCLUSION: The SMC contributed to a significant reduction in malaria cases among children under the age of 5 in the health district of Mamou from 2018 to 2020. However, this reduction varied by monthly SMC cycle. This study suggests extending the SMC in other areas with high perennial seasonal transmission respecting the World Health Organization SMC eligibility criteria, as a strategy in the dynamic of reducing malaria cases in children under the age of 5 in Guinea.

Predictors of accessing seasonal malaria chemoprevention medicines through non-door-to-door distribution in Nigeria.

BACKGROUND: In Nigeria, seasonal malaria chemoprevention (SMC) is typically administered door-to-door to children under five by community medicine distributors during high transmission seasons. While door-to-door distribution (DDD) is exclusively employed in Nigeria as part of standard operating procedures of SMC programmes, some households access SMC through non-DDD channels, such as fixed-point distributions, health facilities, and private purchase. However, analysis of access to SMC medicines through non-DDD has been limited, with little evidence of its outcomes on adherence to the three-day complete course of SMC medicines and caregiver actions in the event of adverse reactions to SMC medicines. METHODS: Data were obtained from SMC end-of-round coverage surveys conducted in Nigeria in 2021 and 2022, including 25,278 households for the analysis. The proportion of households accessing SMC medicine through non-DDD and the distribution of various non-DDD sources of SMC medicines were described. Multivariate random-effects logistic regression models were performed to identify predictors of accessing SMC medicines through non-DDD. The associations between non-DDD, and caregiver-reporting of adherence to complete administration of SMC medicines and caregiver actions in the event of adverse reactions to SMC medicines were also assessed. RESULTS: Less than 2% (314/24003) of households accessed SMC medicines through non-DDD in the states surveyed. Over 60% of non-DDD access was via health facility personnel and community medicine distributors from different locations. Variables associated with non-DDD access included heads of household being born in the local state (OR = 0.68, 95% CI 0.47 to 0.90), households residing in the study state since the first cycle of the SMC round (OR = 0.39, 95% CI 0.17 to 0.88), households with high wealth index (OR = 1.36, 95% CI 1.01 to 1.82), and caregivers hearing about date of SMC delivery in the previous cycle (OR = 0.18, 95%CI 0.14 to 0.24). Furthermore, non-DDD was associated with reduced SMC adherence and higher caregiver non-reporting of adverse reactions to SMC medicines in children compared with DDD. CONCLUSION: This study provides evidence on the characteristics of households accessing SMC medicines through non-DDD and its potential negative outcomes on adherence to SMC medicine and adverse reaction reporting, underscoring potential implementation issues that may arise if non-DDD delivery models are adopted in SMC, particularly in places where DDD had been firstly used.

Urban-rural differences in seasonal malaria chemoprevention coverage and characteristics of target populations in nine states of Nigeria: a comparative cross-sectional study.

BACKGROUND: Differences between urban and rural contexts in terms of sociodemographic characteristics, geographical features and risk perceptions may lead to disparities in coverage and related outcomes of community-based preventive interventions, such as seasonal malaria chemoprevention (SMC). This study investigated urban-rural differences in SMC coverage and other programme outcomes, as well as child and caregiver characteristics of target populations in nine implementing states in Nigeria during the 2022 SMC round. METHODS: This is a comparative cross-sectional study based on comprehensive end-of-round household surveys conducted in nine states where SMC was delivered in Nigeria in 2022. Data of 11,880 caregiver-child pairs were included in the analysis. Rural-urban differences in SMC outcomes and child and caregiver characteristics were assessed, first by using Pearsons' chi-square test for independence for categorical variables. Univariate multilevel mixed-effect logistic regression models, with random intercepts for cluster units, were used to quantify the strength of association between location and each SMC coverage and related outcomes. RESULTS: Significant urban-rural differences were observed in caregivers' sociodemographic characteristics, such as age, gender, level of education, occupation status and health-seeking behaviour for febrile childhood illnesses. Disparities were also seen in terms of SMC coverage and related outcomes, with lower odds of the receipt of Day 1 dose direct observation of the administration of Day 1 dose by community distributors, receipt of the full three-day course of SMC medicines and receipt of SMC in all cycles of the annual round among children residing in urban areas, compared with those residing in rural areas. Similarly, urban-dwelling caregivers had lower odds of being knowledgeable of SMC and believing in the protective effect of SMC than rural-dwelling caregivers. CONCLUSION: Findings highlight observable urban-rural disparities in SMC programme delivery and related outcomes, as well as target population characteristics, underscoring the need for context-specific strategies to ensure optimal delivery of SMC and improve programme implementation outcomes in urban settings.

A quasi-experimental study to estimate effectiveness of seasonal malaria chemoprevention in Aweil South County in Northern Bahr El Ghazal, South Sudan.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is an effective intervention to prevent malaria in children in locations where the burden of malaria is high and transmission is seasonal. There is growing evidence suggesting that SMC with sulfadoxine-pyrimethamine and amodiaquine can retain its high level of effectiveness in East and Southern Africa despite resistance concerns. This study aims to generate evidence on the effectiveness of SMC when delivered under programmatic conditions in an area with an unknown anti-malarial drug resistance profile in the Northern Bahr el-Ghazal region of South Sudan. METHODS: A non-randomized quasi experimental study was conducted to compare an intervention county with a control county. Five monthly SMC cycles were delivered between July and November 2022, targeting about 19,000 children 3-59 months old. Data were obtained from repeated cross-sectional household surveys of caregivers of children aged 3-59 months using cluster sampling. Wave 1 survey took place in both counties before SMC implementation; Waves 2 and 3 took place after the second and fourth monthly SMC cycles. Difference-in-differences analyses were performed by fitting logistic regression models with interactions between county and wave. RESULTS: A total of 2760 children were sampled in the study across the three survey waves in both study counties. Children in the intervention arm had 70% lower odds of caregiver-reported fever relative to those in the control arm during the one-month period prior to Wave 2 (OR: 0.30, 95% CI 0.12-0.70, p = 0.003), and 37% lower odds in Wave 3 (OR: 0.63, 95% CI 0.22-1.59, p = 0.306) after controlling for baseline difference between counties in Wave 1. Odds of caregiver-reported RDT-confirmed malaria were 82% lower in the previous 1-month period prior to Wave 2 (OR: 0.18, 95% CI 0.07-0.49, p = 0.001) and Wave 3 (OR: 0.18, 95% CI 0.06-0.54, p = 0.003). CONCLUSION: These results show high effectiveness of SMC using SPAQ in terms of reducing malaria disease during the high transmission season in children 3-59 month. Despite the promising results, additional evidence and insights from chemoprevention efficacy cohort studies, and analyses of relevant resistance markers, are required to assess the suitability of SMC for this specific context.

Barriers to the quality delivery of seasonal malaria chemoprevention in Chad and Burkina Faso: a qualitative exploration of caregivers and community distributors' perspectives.

BACKGROUND: Recommended since 2012 by the World Health Organization (WHO), seasonal malaria chemoprevention (SMC) is a community-based intervention to prevent malaria in children in African regions where malaria transmission follows a seasonal pattern. Following the publication of consolidated WHO guidelines for malaria, SMC is expected to reach more children in new geographies in future years. Though SMC has been shown to reduce malaria-related morbidity and mortality, there is potential for quality improvement of the intervention implementation. Assisted by ten quality standards from a framework developed by Malaria Consortium, this paper aims to better understand the quality of SMC implementation and identify potential barriers to quality delivery of SMC. METHODS: A qualitative thematic analysis on data collected after the annual SMC rounds implemented in Burkina Faso and Chad in 2019 was conducted. Sixteen focus group discussions conducted with caregivers and community distributors were analysed. Three selected quality standards for SMC delivery; planning and enumeration; community engagement; and administration of SMC medicines provided overarching quality themes under which subthemes were identified. RESULTS: Eight subthemes relating to the three quality standards were identified. Although SMC was well accepted by communities in both settings, common barriers to the quality delivery of SMC were identified including difficulty ensuring adherence to the SMC administration protocol; difficulties reaching mobile populations; concerns around adverse drug reactions; rumours, and concerns about SMC safety; and community distributors' working conditions. Context-specific barriers included: the suboptimal timeliness of the SMC round in Burkina Faso, and the lack of involvement of female caregivers in mobilization activities in Chad. CONCLUSION: In the context of increased adoption of SMC, this paper provides relevant insights and recommendations for the improved implementation of SMC programmes. These include the integration of strategies addressing communities' concerns around adverse drug reactions, gender-specific mobilization strategies, and attention to community distributors' working conditions. It also highlights the importance and utility of further, robust research on the quality of SMC delivery.

RéSUMé EN FRANçAIS: BACKGROUND: Recommandée depuis 2012 par l'Organisation mondiale de la santé (OMS), la chimioprévention du paludisme saisonnier (CPS) est une intervention communautaire visant à prévenir le paludisme chez les enfants dans les régions d'Afrique où la transmission du paludisme suit un schéma saisonnier. Suite à la publication des lignes directrices consolidées de l'OMS sur le paludisme, la CPS devrait toucher davantage d'enfants dans de nouvelles zones géographiques dans les années à venir. Bien qu'il ait été démontré que la CPS réduisait la morbidité et la mortalité liées au paludisme, il y a du potentiel pour améliorer la qualité de l'implémentation l'intervention. En s'appuyant sur un cadre de normes de qualité de la CPS développé par le Malaria Consortium, cette publication vise à mieux comprendre la qualité de la mise en œuvre de la CPS et à identifier les obstacles potentiels à la qualité de la mise en œuvre de la CPS. METHODS: Une étude qualitative basée sur l'analyse secondaire des données collectées après les tournées annuelles du SMC mises en œuvre au Burkina Faso et au Tchad en 2019 a été menée. Une analyse thématique de 16 discussions de groupe menées avec des parents/tuteurs et des distributeurs communautaires a été faite. Trois des éléments clés du cadre des normes de qualité pour le déploiement de la CPS ont fourni les thèmes de qualité principaux sous lesquels les sous-thèmes identifiés ont été placés. RéSULTATS: Huit sous-thèmes relatifs aux normes de qualité ; la planification, la sensibilisation et l'engagement des communautés ainsi que l'administration des médicaments de la CPS ont été identifiés. Bien que la CPS ait été bien acceptée par les communautés dans les deux contextes, des obstacles communs à la qualité du déploiement de la CPS ont été identifiés, notamment : la difficulté d'assurer le respect du protocole d'administration de la CPS; atteindre les populations mobiles ; les préoccupations concernant les effets indésirables des médicaments ; les rumeurs et les préoccupations concernant le SMC; et les conditions de travail des distributeurs communautaires. D'autres barrières spécifiques au contexte de déploiement ont été identifiées, telles que le choix sous-optimal de la période de déploiement au Burkina Faso ou le manque d'implication des mères/tutrices dans les activités de mobilisation au Tchad. CONCLUSION: Dans le contexte de l'adoption croissante de la CPS, cette publication fournit des informations et des recommandations pertinentes pour l'amélioration de la mise en œuvre des programmes de CMS, telles que l'intégration de stratégies répondant aux préoccupations des communautés concernant les effets indésirables des médicaments, les stratégies de mobilisation spécifiques au genre, et/ou l'attention portée aux conditions de travail des distributeurs communautaires. Cette publication souligne également l'importance et l'utilité des recherches en cours sur la qualité du déploiement de la CPS.

RESUMO EM PORTUGUêS: INTRODUçãO: Recomendada desde 2012 pela Organização Mundial de Saúde (OMS), a quimioprevenção sazonal do paludismo (SMC) é uma intervenção de base comunitária para prevenir o paludismo em crianças em zonas da África onde a transmissão do paludismo segue um padrão sazonal. Após a publicação das diretrizes consolidadas da OMS sobre o paludismo, espera-se que a SMC chegue a mais crianças em novas zonas geográficas nos próximos anos. Embora se tenha demonstrado que a SMC reduz a morbilidade e a mortalidade causadas pelo paludismo, há potencial para melhorar a qualidade da implementação da intervenção. Com ajuda dum quadro de padrões de qualidade para a SMC desenvolvido pelo Malaria Consortium, a presente publicação visa compreender melhor a qualidade da implementação da SMC e identificar potenciais barreiras à qualidade da implementação da SMC. MéTODOS: Foi realizado um estudo qualitativo baseado na análise secundária dos dados recolhidos após as rondas anuais da SMC implementadas no Burkina Faso e no Chade em 2019. Foi efectuado uma análise temática de 16 discussões de grupos focais realizadas com cuidadores e distribuidores comunitários. Tres padrões do quadro de normas de qualidade para a implementação da SMC forneceu os principais temas de qualidade sob os quais os subtemas identificados foram colocados. RESULTADOS: Foram identificados oito sub-temas relacionados com padrões de qualidade; planeamento; sensibilização e envolvimento da comunidade; e administração de drogas da SMC. Embora a SMC tenha sido bem aceita pelas comunidades em ambos os contextos, foram identificadas barreiras comuns à implementação duma SMC de qualidade, incluindo: a dificuldade de assegurar o cumprimento do protocolo de administração da SMC; atingir populações móveis; preocupações com reacções adversas aos medicamentos; rumores e preocupações com a SMC; e as condições de trabalho dos distribuidores comunitários. Foram identificados outros obstáculos específicos ao contexto de implantação, tais como a escolha subaproveitada do período de implantação no Burkina Faso ou a falta de envolvimento das cuidadoras femininas nas actividades de mobilização no Chade. CONCLUSãO: No contexto do aumento da adopção da SMC, esta publicação fornece informações e recomendações relevantes para melhorar a implementação de programas de SMC, tais como estratégias integradoras que abordam as preocupações da comunidade sobre reacções adversas aos medicamentos, estratégias de mobilização específicas de género, e/ou atenção às condições de trabalho dos distribuidores comunitários. Salienta igualmente a importância e a utilidade das investigaçãos em curso sobre a qualidade da implementação da SMC.

Using the role model approach to optimise caregiver administration of sulfadoxine-pyrimethamine amodiaquine to children aged 3-59 months in Burkina Faso, Chad and Togo: findings from an evaluation.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is a World Health Organization-recommended intervention for the prevention of malaria among children at high risk in areas with seasonal transmission. During the coronavirus disease 2019 (COVID-19) pandemic, SMC drug distribution was rapidly adapted to reduce contact and mitigate the risk of transmission between communities and community distributors, with caregivers administering doses. To address the challenges and find local solutions to improve administration and adherence, the role model approach was designed, implemented and evaluated in selected communities of Burkina Faso, Chad and Togo. This paper describes the results of this evaluation. METHODS: Focus group discussions were held with primary caregivers in all three countries to understand their perceptions of the approach's acceptability and feasibility. In Burkina Faso and Togo, household surveys assessed the characteristics of caregivers reached by role model activities. Key indicators on SMC coverage and adherence allowed for an assessment of caregiver engagement outcomes related to participation in activities. Statistical associations between participation in study's activities and caregiver beliefs related to SMC had been tested. RESULTS: The majority of caregivers believed the approach to have a positive effect on drug administration, with most adopting the promoted strategies. Greater involvement of fathers in drug administration and acknowledgement of their joint responsibility was a notable positive outcome. However, several barriers to participation were noted and there was criticism of the group approach. In Burkina Faso and Togo, end-of-round survey results revealed that 98.4% of respondents agreed the approach improved their knowledge and skills in malaria prevention, while 100% expressed a desire to continue practicing the behaviours learned. However, there was a relatively low level of awareness of the approach among communities. Participation was strongly associated with participants' self-reported belief in ease of remembering to administer, and ease of administering, SMC medicines. CONCLUSION: Caregivers perceived the role model approach to be beneficial in aiding drug administration, with other positive impacts also reported. Replication and scale-up should utilize the most popular communication channels and existing community structures to ensure activities are promoted effectively. A mixture of group and one-on-one approaches should be used where appropriate and feasible.

Malaria infection and predictor factors among Chadian nomads' children.

BACKGROUND: In Chad, malaria remains a significant public health concern, particularly among nomadic populations. Geographical factors and the mobility of human populations have shown to be associated with the diversity of Plasmodium species. The study aims to describe the malaria prevalence among nomadic children and to investigate its associated factors. METHODS: A cross-sectional study was conducted in February and October 2021 among nomadic communities in Chad. Blood sample were collected and tested from 187 Arab, Fulani and Dazagada nomadic children aged 3-59 months using malaria rapid diagnostic test (RDT). A structured electronic questionnaire was administered to their parents to collect information about the socio­economic data. Malaria testing results were categorized according to the SD BIOLINE Malaria Ag Pf/Pan RDT procedures. Logistic regression analysis was used to determine key risk factors explaining the prevalence of malaria. STATA version IC 13 was used for statistical analysis. RESULTS: The overall malaria prevalence in nomadic children was 24.60%, with 65.20% being Plasmodium falciparum species and 34.8% mixed species. Boys were twice as likely (COR = 1.83; 95% CI, 0.92-3.62; p = 0.083) to have malaria than girls. Children whose parents used to seek traditional drugs were five times more likely (AOR = 5.59; 95% CI, 1.40-22.30, p = 0.015) to have malaria than children whose parents used to seek health facilities. Children whose parents reported spending the last night under a mosquito net were one-fifth as likely (AOR = 0.17; 95% CI, 0.03-0.90, p = 0.037) to have malaria compared to children whose parents did not used a mosquito net. Furthermore, Daza children were seventeen times (1/0.06) less likely (AOR = 0.06; 95% CI, 0.01-0.70, p = 0.024) to have malaria than Fulani children and children from households piped water as the main source were seven times more likely (AOR = 7.05; 95% CI, 1.69-29.45; p = 0.007) to have malaria than those using surface water. CONCLUSIONS: Malaria remains a significant public health issue in the nomadic communities of Chad. Community education and sensitization programs within nomad communities are recommended to raise awareness about malaria transmission and control methods, particularly among those living in remote rural areas. The National Malaria Control Program (NMCP) should increase both the coverage and use of long-lasting insecticidal nets (LLINs) and seasonal malaria chemoprevention (SMC) in addition to promoting treatment-seeking behaviors in nomadic communities.

Compliance With Guidelines on Seasonal Malaria Chemoprevention in Kwara State, Northcentral Nigeria.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is an effective strategy for reducing malaria morbidity and mortality in children aged 3-59 months in areas with seasonal malaria transmission. Sulphadoxine-pyrimethamine plus amodiaquine is given to an eligible child at monthly intervals during the peak malaria transmission season. The aim of this study was to determine the level of compliance with SMC guidelines by community drug distributors during SMC implementation in Kwara State. METHOD: Caregivers of eligible children from six Local Government Areas were interviewed using a structured questionnaire on the KoboCollect app downloaded on hand-held android devices. The questionnaire was composed of questions on caregiver's demographics, SMC drug administration, and adherence to SMC protocol. RESULTS: A total of 1,314 caregivers were interviewed, most of them were female 1076 (81.9%), married 1200 (91.3%) and literate 795 (60.5%). The mean SMC coverage for the 4 cycles was 1183(88.5%). SMC information was received by 1166 (88.7%) of caregivers. Most of the caregivers 1166 (88.7%) heard about SMC. Overall, SPAQ administration was directly observed in most cases 1169 (91.5%), second dose was given 1226 (96.0%) and drugs were fully ingested 1140(89.3%). Poor compliance was observed in home visits by lead mothers 988 (77.4%). The report of adverse drug reactions was low 132 (10.3% [95% CI: 8.8-12.3%]), the commonest being severe vomiting 50 (37.9%). There were significant (P<0.05) variations in SMC implementation across the 6 LGAs in virtually all the performance indicators. SPAQ administration to over-age children was low 128 (10.0%). CONCLUSION: Overall, the compliance with SMC implementation guidelines in Kwara state was good though significant differences in performance were observed across the six LGAs. Home visits by lead mothers were generally poor. The self-reported coverage of SMC by caregivers was commendable.

CONTEXTE: La chimioprévention saisonnière du paludisme (CSP) est une stratégie efficace pour réduire la morbidité et la mortalité liées au paludisme chez les enfants âgés de 3 à 59 mois dans les zones à transmission saisonnière du paludisme. La sulfadoxine-pyriméthamine associée à l'amodiaquine est administrée à un enfant éligible à intervalles mensuels pendant la saison de transmission maximale du paludisme. L'objectif de cette étude était de déterminer le niveau de conformité aux directives de la CSP par les distributeurs de médicaments communautaires lors de la mise en œuvre de la CSP dans l'État de Kwara. MÉTHODE: Les aidants des enfants éligibles de six zones de gouvernement local ont été interrogés à l'aide d'un questionnaire structuré sur l'application KoboCollect sur des appareils android portables. Le questionnaire comprenait des questions sur les caractéristiques démographiques des aidants, l'administration des médicaments de la CSP et l'adhésion au protocole de la CSP. RÉSULTATS: Au total, 1 314 aidants ont été interrogés, la plupart étaient des femmes 1 076 (81,9 %), mariées 1 200 (91,3 %) et alphabétisées 795 (60,5 %). La couverture moyenne de la CSP pour les 4 cycles était de 1 183 (88,5 %). La plupart des aidants 1 166 (88,7 %) avaient entendu parler de la CSP. Dans l'ensemble, la première administration de SPAQ a été observée directement dans la plupart des cas 1 169 (91,5 %), la deuxième dose a été administrée par 1 226 (96,0 %) aidants et les médicaments ont été entièrement ingérés sans cracher partiellement ou totalement par 1 140 (89,3 %) enfants. Une mauvaise conformité a été observée lors des visites à domicile par les mères responsables 988 (77,4 %). Le signalement des réactions indésirables aux médicaments était faible 132 (10,3 % [IC à 95 % : 8,8-12,3 %]), la plus courante étant les vomissements sévères 50 (37,9 %). Des variations significatives (P<0,05) dans la mise en œuvre de la CSP ont été observées dans les 6 LGAs pour pratiquement tous les indicateurs de performance. L'administration de SPAQ aux enfants plus âgés était faible 128 (10,0 %). CONCLUSION: Dans l'ensemble, la conformité aux directives de mise en œuvre de la CSP dans l'État de Kwara était bonne bien que des différences significatives dans les performances aient été observées dans les six LGAs. Les visites à domicile par les mères responsables étaient généralement mauvaises. La couverture autodéclarée de la CSP par les aidants était louable. MOTS-CLÉS: Chimioprévention saisonnière du paludisme, SPAQ, Conformité, Enfants, Centre-nord du Nigeria, Saison des pluies.

Seasonal Malaria Chemoprevention Drug Levels and Drug Resistance Markers in Children With or Without Malaria in Burkina Faso: A Case-Control Study.

BACKGROUND: Despite scale-up of seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine and amodiaquine (SP-AQ) in children 3-59 months of age in Burkina Faso, malaria incidence remains high, raising concerns regarding SMC effectiveness and selection of drug resistance. Using a case-control design, we determined associations between SMC drug levels, drug resistance markers, and presentation with malaria. METHODS: We enrolled 310 children presenting at health facilities in Bobo-Dioulasso. Cases were SMC-eligible children 6-59 months of age diagnosed with malaria. Two controls were enrolled per case: SMC-eligible children without malaria; and older (5-10 years old), SMC-ineligible children with malaria. We measured SP-AQ drug levels among SMC-eligible children and SP-AQ resistance markers among parasitemic children. Conditional logistic regression was used to compute odds ratios (ORs) comparing drug levels between cases and controls. RESULTS: Compared to SMC-eligible controls, children with malaria were less likely to have any detectable SP or AQ (OR, 0.33 [95% confidence interval, .16-.67]; P = .002) and have lower drug levels (P < .05). Prevalences of mutations mediating high-level SP resistance were rare (0%-1%) and similar between cases and SMC-ineligible controls (P > .05). CONCLUSIONS: Incident malaria among SMC-eligible children was likely due to suboptimal levels of SP-AQ, resulting from missed cycles rather than increased antimalarial resistance to SP-AQ.

Monitoring of adverse drug reactions during seasonal malaria chemoprevention campaigns in children aged 3­59 months in Burkina Faso / Surveillance des effets indésirables lors des campagnes de la chimioprévention du paludisme saisonnier chez les enfants de 3-59 mois au Burkina Faso

Introduction: Seasonal malaria chemoprevention (SMC) by mass administration of sulfadoxine pyrimethamine + amodiaquine (SPAQ) reduces the burden of malaria in children aged 3­59 months. The occurrence of adverse drug reaction (ADR) may affect the success of this intervention. There are few studies of SMC adverse event surveillance in sub-Saharan Africa, particularly in Burkina Faso, a highly endemic country. Our main objective was to characterize the ADRs reported during SMC campaigns in Burkina Faso. Secondly, we evaluated the performance of the pharmacovigilance integrated into the SMC program in order to support safe administration of SMC. Method: This was a retrospective descriptive study of SMC individual case safety reports recorded in VigiBase® in Burkina Faso from 2014 to 2021. We used the P-method for the analysis of preventable serious adverse drug reactions and WHO criteria for assessing the performance of pharmacovigilance integrated into the SMC program. Results: A total of 1,105 SMC individual case safety reports were registered in VigiBase® for 23,311,453 doses of SPAQ given between 2014 and 2021. No pharmacovigilance signal was detected. The number of serious cases was 101, of which 23 (22.8%) were preventable. In 38.1% of children, the occurrence of ADRs led to discontinuation of SMC treatment. Vomiting was the most frequently reported adverse drug reaction (48.0%). The proportion of children whose treatment was discontinued due to vomiting was 42.7%, while the proportion of treatment discontinuation for other ADRs was 32.8% (p = 0.01). The SMC program contributed at 46.2% to the national pharmacovigilance database. The reporting rate was 0.03 per 1,000 exposed children in 2021. The median completeness score of the ICSRs was 0.7 (IQR: 0.5­0.7), and the median time to register the ICSRs in VigiBase® was 204 (IQR: 143­333) days. Conclusions: Post-drug administration vomiting may interfere with the purpose of SMC. Measures to manage this adverse drug reaction should be taken to improve the success of the SMC program. Based on the information on reporting time and reporting rate, spontaneous reporting should be supported by active surveillance, including cohort event monitoring, in Burkina Faso.

Introduction: La chimioprévention du paludisme saisonnier (CPS) par l'administration en masse de la sulfadoxine-pyriméthamine + amodiaquine (SPAQ) permet de réduire le fardeau du paludisme chez les enfants de 3-59 mois. La survenue d'effets indésirables (EI) pourrait nuire au succès de cette intervention. Il existe peu d'études sur la surveillance des EI de la CPS en Afrique subsaharienne et plus particulièrement au Burkina Faso, pays de forte endémicité palustre. Notre objectif principal était de caractériser les effets indésirables notifiés au cours des campagnes CPS au Burkina Faso. Secondairement, nous avons évalué la performance de la pharmacovigilance intégrée au programme de CPS dans le but de soutenir la sécurité d'administration de la CPS. Méthodes: Nous avons réalisé une analyse rétrospective à visée descriptive des rapports d'effets indésirables de la CPS enregistrés dans VigiBase® entre le 1er janvier 2014 et le 31 décembre 2021. Nous avons utilisé la P-method pour l'analyse de l'évitabilité des effets indésirables graves et les critères de l'OMS pour évaluer la performance de la pharmacovigilance intégrée au programme de CPS. Résultats: Au total, 1 105 cas individuels de rapports de sécurité de la CPS ont été analysés dans VigiBase® pour 23 311 453 doses administrées. Aucun signal de pharmacovigilance n'a été détecté. Le nombre des cas graves était de 101, dont 23 (22,8 %) évitables. Chez 38,1 % des enfants, la survenue des EI a occasionné l'arrêt de l'administration du traitement de la CPS. Le vomissement était l'effet indésirable le plus fréquemment rapporté (48,0 %). La proportion d'enfants dont le traitement a été arrêté pour motif de vomissement était de 42,7 %, tandis que la proportion d'arrêts de traitement pour les autres EI était de 32,8 % (p=0,01). La pharmacovigilance de la CPS a contribué à 46,2 % à l'alimentation de la base de données nationale de pharmacovigilance. Le taux de notification était de 0,03 pour 1 000 enfants exposés en 2021. Le score d'exhaustivité médian des rapports était de 0,7 (P25-P75 : 0,5-0,7) et le délai médian d'enregistrement des rapports dans VigiBase® était de 204 (P25-P75 : 143-333) jours. Conclusions: Les vomissements peuvent nuire à l'objectif de la CPS. Des mesures de gestion de cet effet indésirable doivent être prises pour améliorer le succès de la CPS. Au regard des informations sur le délai de notification et le taux de notification, la notification spontanée devrait être soutenue par une surveillance active, notamment une « cohort event monitoring ¼ au Burkina Faso.

Predictors of caregiver adherence to administration of amodiaquine during delivery of seasonal malaria chemoprevention in Nigeria, Burkina Faso, Chad, and Togo.

BACKGROUND: Malaria is the leading cause of morbidity and mortality among infants and children under-five in sub-Saharan Africa. In the Sahel, seasonal malaria chemoprevention (SMC) is delivered door-to-door in monthly cycles. In each cycle, children are administered sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ) on Day 1 by community distributors, and AQ on Day 2 and Day 3 by caregivers. Non-adherence to AQ administration by caregivers has implications for emergence of antimalarial resistance. METHODS: Predictors of non-adherence to administration of AQ on Day 2 and Day 3 among caregivers of children aged 3-59 months who had received Day 1 SP and AQ during the last 2020 SMC cycle (n = 12,730) were analysed using data from SMC coverage surveys in Nigeria, Burkina Faso and Togo, and fitting multivariate random-effects logistic regression models. RESULTS: Previous adverse reaction to SMC medicines by eligible children (OR: 0.29, 95% CI 0.24-0.36, p < 0.001), awareness of the importance of administering Day 2 and Day 3 AQ (OR: 2.19, 95% CI 1.69-2.82, p < 0.001), caregiver age, and home visits to caregivers delivered by the Lead Mothers intervention in Nigeria (OR: 2.50, 95% CI 1.93-2.24, p < 0.001), were significantly associated with caregiver adherence to Day 2 and Day 3 AQ administration. CONCLUSIONS: Increasing caregivers' knowledge of SMC and interventions such as Lead Mothers have the potential to improve full adherence to AQ administration.

Optimizing the role of 'lead mothers' in seasonal malaria chemoprevention (SMC) campaigns: formative research in Kano State, northern Nigeria.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is a safe and effective intervention for preventing malaria in children under 5 years of age. Lead mothers are community health volunteers that help caregivers comply with monthly administration of anti-malarial drugs during SMC campaigns. The lead mother approach is used in several SMC implementing states across Nigeria, but there is lack of evidence about their roles and how effective they are. This study sought to better understand the current role of lead mothers, identify areas for improvement and ways to optimize the role of lead mothers during SMC campaigns. METHODS: This paper reports the formative phase of a three-phased intervention development study. The formative phase involved semi-structured interviews with stakeholders from national, state, local government and community levels (n = 20). Thematic analysis was used to identify key themes, forming the basis of a subsequent co-design workshop with stakeholders routinely involved in SMC campaigns. RESULTS: The findings of the formative phase converged around four overarching themes: skills and attributes required of lead mothers; factors that affect lead mother's roles; how lead mothers interact with Community Health Influencers Promoters Services (CHIPS) agents and re-imagining the role of lead mothers during SMC campaigns. CONCLUSION: This formative work in Kano state indicates that through their strong connection to communities and unique relationship with caregivers, lead mothers can and do influence caregivers to adopt healthy behaviours during SMC campaigns. However, there is room for improvement in how they are recruited, trained and supervised. There is need to improve lead mothers' knowledge and skills through adequate training and supporting materials, so they can deliver targeted health messages to caregivers. Sustainability of the lead mother approach is at risk if policymakers do not find a way of transitioning their role into the existing community health worker infrastructure, for example by using CHIPs agents, and ensuring less reliance on external donor support.

Implementation strategies for the introduction of the RTS,S/AS01 (RTS,S) malaria vaccine in countries with areas of highly seasonal transmission: workshop meeting report.

A workshop on implementation strategies for the introduction of the RTS,S/AS01 (RTS,S) malaria vaccine in countries with areas of highly seasonal transmission, was held as a hybrid meeting in Dakar, Senegal, and online, 23-25 January 2023. Delegates from Expanded Programmes on Immunization (EPI) and National Malaria Control Programmes (NMCPs) from 13 African countries, and representatives from key stakeholders participated. RTS,S is the first malaria vaccine to be recommended by the World Health Organization (WHO). The recommendation followed pilot implementation of the vaccine in Ghana, Kenya and Malawi, which showed that introduction of the vaccine was highly effective at scale, and was associated with a 30% reduction in hospital admissions with severe malaria in age groups eligible to have received the vaccine and no evidence of the safety signals that had been observed in the phase 3 trial. Clinical trials in Mali and Burkina Faso, showed that in children receiving Seasonal Malaria Chemoprevention (SMC), providing the vaccine just prior to high transmission seasons, matching the period of highest efficacy to the peak transmission season, resulted in substantial reduction in the incidence of clinical malaria and of severe malaria. While SMC has been successfully scaled-up despite the challenges of delivery, there is no established platform for seasonal vaccine delivery and no real-world experience. The objectives of this workshop were, therefore, to share experiences from countries that have introduced the RTS,S vaccine in routine child vaccination programmes, with SMC-implementing countries as they consider malaria vaccine introduction, and to explore implementation strategies in countries with seasonal transmission and where EPI coverage may be low especially in the second year of life. Practical implementation challenges, lessons learned for vaccine introduction, and research questions, towards facilitating the introduction of the RTS,S (and other malaria vaccines) in countries with seasonal malaria transmission were discussed.

Using systems thinking to understand the scale-up and sustainability of health innovation: a case study of seasonal malaria chemoprevention processes in Burkina Faso.

BACKGROUND: Scale-up and sustainability are often studied separately, with few studies examining the interdependencies between these two processes and the implementation contexts of innovations towards malaria prevention and control. Researchers and implementers offer much more attention to the content of innovations, as they focus on the technological dimensions and the conditions for expansion. Researchers have often considered innovation a linear sequence in which scaling up and sustainability represented the last stages. Using systems thinking in this manuscript, we analyze complex scaling and sustainability processes through adopting and implementing seasonal malaria chemoprevention (SMC) in Burkina Faso from 2014 to 2018. METHODS: We conducted a qualitative case study involving 141 retrospective secondary data (administrative, press, scientific, tools and registries, and verbatim) spanning from 2012 to 2018. We complemented these data with primary data collected between February and March 2018 in the form of 15 personal semi-structured interviews with SMC stakeholders and non-participant observations. Processual analysis permitted us to conceptualize scale-up and sustainability processes over time according to different vertical and horizontal levels of analysis and their interconnections. RESULTS: Our results indicated six internal and external determinants of SMC that may negatively or positively influence its scale-up and sustainability. These determinants are effectiveness, monitoring and evaluation systems, resources (financial, material, and human), leadership and governance, adaptation to the local context, and other external elements. Our results revealed that donors and implementing actors prioritized financial resources over other determinants. In contrast, our study clearly showed that the sustainability of the innovation, as well as its scaling up, depends significantly on the consideration of the interconnectedness of the determinants. Each determinant can concurrently constitute an opportunity and a challenge for the success of the innovation. CONCLUSION: Our findings highlight the usefulness of the systemic perspective to consider all contexts (international, national, subnational, and local) to achieve large-scale improvements in the quality, equity, and effectiveness of global health interventions. Thus, complex and systems thinking have made it possible to observe emergent and dynamic innovation behaviors and the dynamics particular to sustainability and scaling up processes.

The duration of protection against clinical malaria provided by the combination of seasonal RTS,S/AS01E vaccination and seasonal malaria chemoprevention versus either intervention given alone.

BACKGROUND: A recent trial of 5920 children in Burkina Faso and Mali showed that the combination of seasonal vaccination with the RTS,S/AS01E malaria vaccine (primary series and two seasonal boosters) and seasonal malaria chemoprevention (four monthly cycles per year) was markedly more effective than either intervention given alone in preventing clinical malaria, severe malaria, and deaths from malaria. METHODS: In order to help optimise the timing of these two interventions, trial data were reanalysed to estimate the duration of protection against clinical malaria provided by RTS,S/AS01E when deployed seasonally, by comparing the group who received the combination of SMC and RTS,S/AS01E with the group who received SMC alone. The duration of protection from SMC was also estimated comparing the combined intervention group with the group who received RTS,S/AS01E alone. Three methods were used: Piecewise Cox regression, Flexible parametric survival models and Smoothed Schoenfeld residuals from Cox models, stratifying on the study area and using robust standard errors to control for within-child clustering of multiple episodes. RESULTS: The overall protective efficacy from RTS,S/AS01E over 6 months was at least 60% following the primary series and the two seasonal booster doses and remained at a high level over the full malaria transmission season. Beyond 6 months, protective efficacy appeared to wane more rapidly, but the uncertainty around the estimates increases due to the lower number of cases during this period (coinciding with the onset of the dry season). Protection from SMC exceeded 90% in the first 2-3 weeks post-administration after several cycles, but was not 100%, even immediately post-administration. Efficacy begins to decline from approximately day 21 and then declines more sharply after day 28, indicating the importance of preserving the delivery interval for SMC cycles at a maximum of four weeks. CONCLUSIONS: The efficacy of both interventions was highest immediately post-administration. Understanding differences between these interventions in their peak efficacy and how rapidly efficacy declines over time will help to optimise the scheduling of SMC, malaria vaccination and the combination in areas of seasonal transmission with differing epidemiology, and using different vaccine delivery systems. TRIAL REGISTRATION: The RTS,S-SMC trial in which these data were collected was registered at clinicaltrials.gov: NCT03143218.

Effectiveness of seasonal malaria chemoprevention in three regions of Togo: a population-based longitudinal study from 2013 to 2020.

BACKGROUND: In 2012, the World Health Organization (WHO) recommended seasonal malaria chemoprevention (SMC) in areas of high seasonal transmission. Though implemented since 2013, the effectiveness of SMC in Togo was never evaluated. METHODS: This study concerned routine data from 2013 to 2020 mass SMC campaigns for children under five in all health facilities of three Regions of Togo. Treatment coverage, reasons for non-treatment, and SMC-attributable adverse reactions were analysed per year and treatment round. Random effect logistic models estimated SMC effectiveness per health district, year, and treatment round. RESULTS: The overall coverage was 98% (7,971,877 doses for 8,129,668 children). Contraindication was the main reason for non-administration. Over the study period, confirmed malaria cases decreased from 11,269 (1st round of 2016) to 1395 (4th round of 2020). Only 2,398 adverse reactions were reported (prevalence: 3/10,000), but no severe Lyell syndrome or Stevens-Johnson-type skin reaction. Compared to 2016, malaria prevalence decrease was estimated at 22.6% in 2017 (p < 0.001) and 75% in 2020 (p < 0.001). SMC effectiveness ranged from 76.6% (2nd round) to 96.2% (4th round) comparison with the 1st round. CONCLUSIONS: SMC reduced significantly malaria cases among children under five. The results reassure all actors and call for effort intensification to reach the WHO goals for 2030.

Analysis of attitudes and practices influencing adherence to seasonal malaria chemoprevention in children under 5 years of age in the Dosso Region of Niger.

BACKGROUND: Seasonal malaria chemoprevention (SMC) consists of the intermittent administration of a 3 day course of anti-malarial medications during the months of highest malaria risk in the Sahel region, where malaria transmission is highly seasonal. SMC is an effective intervention to reduce episodes of uncomplicated and severe malaria in children. However, morbidity cannot be lowered without adherence to medications. The objective of this study was to examine SMC medication adherence and to identify the attitudes and practices of caregivers during the 2020 SMC campaign in the Dosso region. METHODS: This study was conducted based on data from independent monitoring using random cluster sampling. Adherence levels and the attitudes and practices of caregivers were evaluated using data from caregivers' self-reports and analysed according to Bernard Vrijens' taxonomy. RESULTS: At the initiation of treatment phase, 99% of children (N = 2296) received their first administration of medication, with 90% of caregivers (N = 1436) knowing that the medications help prevent malaria. However, only 56% of caregivers (N = 1856) reported that treatment initiation took place under direct observation by the distributor. At the implementation of treatment phase, 90% of children (N = 2132) took their medication on the second day and 84% (N = 1068) took it the third day. "Forgetting," "not having time," and "the mother's absence" were the main reasons caregivers gave to explain discontinuation of the 3 day course of medication. CONCLUSION: This simple, low-cost survey demonstrated that coverage of SMC and adherence by caregivers to completing the full 3 day medication course was high. The survey also showed that knowledge, attitudes, and practices of some caregivers regarding adherence to medications during the SMC campaign could be improved. Expanding distributors' training, developing and providing them with tools for interpersonal communication, and strengthening supervision could lead to even higher adherence.