The impact of anti-malarial markets on artemisinin resistance: perspectives from Burkina Faso.

BACKGROUND: Widespread artemisinin resistance in Africa could be catastrophic when drawing parallels with the failure of chloroquine in the 1970s and 1980s. This article explores the role of anti-malarial market characteristics in the emergence and spread of arteminisin resistance in African countries, drawing on perspectives from Burkina Faso. METHODS: Data were collected through in-depth interviews and focus group discussions. A representative sample of national policy makers, regulators, public and private sector wholesalers, retailers, clinicians, nurses, and community members were purposively sampled. Additional information was also sought via review of policy publications and grey literature on anti-malarial policies and deployment practices in Burkina Faso. RESULTS: Thirty seven in-depth interviews and 6 focus group discussions were conducted. The study reveals that the current operational mode of anti-malarial drug markets in Burkina Faso promotes arteminisin resistance emergence and spread. The factors are mainly related to the artemisinin-based combination therapy (ACT) supply chain, to ACT quality, ACT prescription monitoring and to ACT access and misuse by patients. CONCLUSION: Study findings highlight the urgent requirement to reform current characteristics of the anti-malarial drug market in order to delay the emergence and spread of artemisinin resistance in Burkina Faso. Four recommendations for public policy emerged during data analysis: (1) Address the suboptimal prescription of anti-malarial drugs, (2) Apply laws that prohibit the sale of anti-malarials without prescription, (3) Restrict the availability of street drugs, (4) Sensitize the population on the value of compliance regarding correct acquisition and intake of anti-malarials. Funding systems for anti-malarial drugs in terms of availability and accessibility must also be stabilized.

Cost of introducing and delivering malaria vaccine (RTS,S/AS01E) in areas of seasonal malaria transmission, Mali and Burkina Faso.

BACKGROUND: The WHO recommends use of the RTS,S/AS01E (RTS,S) malaria vaccine for young children living in areas of moderate to high Plasmodium falciparum malaria transmission and suggests countries consider seasonal vaccination in areas with highly seasonal malaria. Seasonal vaccination is uncommon and may require adaptations with potential cost consequences. This study prospectively estimates cost of seasonal malaria vaccine delivery in Mali and Burkina Faso. METHODS: Three scenarios for seasonal vaccine delivery are costed (1) mass campaign only, (2) routine Expanded Programme on Immunisation (EPI) and (3) mixed delivery (mass campaign and routine EPI)), from the government's perspective. Resource use data are informed by previous new vaccine introductions, supplemented with primary data from a sample of health facilities and administrative units. FINDINGS: At an assumed vaccine price of US $5 per dose, the economic cost per dose administered ranges between $7.73 and $8.68 (mass campaign), $7.04 and $7.38 (routine EPI) and $7.26 and $7.93 (mixed delivery). Excluding commodities, the cost ranges between $1.17 and $2.12 (mass campaign), $0.48 and $0.82 (routine EPI) and $0.70 and $1.37 (mixed delivery). The financial non-commodity cost per dose administered ranges between $0.99 and $1.99 (mass campaign), $0.39 and $0.76 (routine EPI) and $0.58 and $1.28 (mixed delivery). Excluding commodity costs, service delivery is the main cost driver under the mass campaign scenario, accounting for 36% to 55% of the financial cost. Service delivery accounts for 2%-8% and 12%-23% of the total financial cost under routine EPI and mixed delivery scenarios, respectively. CONCLUSION: Vaccine delivery using the mass campaign approach is most costly followed by mixed delivery and routine EPI delivery approaches, in both countries. Our cost estimates provide useful insights for decisions regarding delivery approaches, as countries plan the malaria vaccine rollout.

Ethical considerations in deploying triple artemisinin-based combination therapies for malaria: An analysis of stakeholders' perspectives in Burkina Faso and Nigeria.

BACKGROUND: Artemisinin-based combination therapies (ACTs) are the recommended treatment for uncomplicated Plasmodium falciparum malaria in all malaria endemic countries. Artemisinin resistance, partner drug resistance, and subsequent ACT failure are widespread in Southeast Asia. The more recent independent emergence of artemisinin resistance in Africa is alarming. In response, triple artemisinin-based combination therapies (TACTs) are being developed to mitigate the risks associated with increasing drug resistance. Since ACTs are still effective in Africa, where malaria is mainly a paediatric disease, the potential deployment of TACTs raises important ethical questions. This paper presents an analysis of stakeholders' perspectives regarding key ethical considerations to be considered in the deployment of TACTs in Africa provided they are found to be safe, well-tolerated and effective for the treatment of uncomplicated malaria. METHODS: We conducted a qualitative study in Burkina Faso and Nigeria assessing stakeholders' (policy makers, suppliers and end-users) perspectives on ethical issues regarding the potential future deployment of TACTs through 68 in-depth interviews and 11 focus group discussions. FINDINGS: Some respondents suggested that there should be evidence of local artemisinin resistance before they consider deploying TACTs, while others suggested that TACTs should be deployed to protect the efficacy of current ACTs. Respondents suggested that additional side effects of TACTs compared to ACTs should be minimal and the cost of TACTs to end-users should not be higher than the cost of current ACTs. There was some disagreement among respondents regarding whether patients should have a choice of treatment options between ACTs and TACTs or only have TACTs available, while ACTs are still effective. The study also suggests that community, public and stakeholder engagement activities are essential to support the introduction and effective uptake of TACTs. CONCLUSION: Addressing ethical issues regarding TACTs and engaging early with stakeholders will be important for their potential deployment in Africa.

Ethical, Regulatory and Market related aspects of Deploying Triple Artemisinin-Based Combination Therapies for Malaria treatment in Africa: A study protocol.

Introduction: According to the World Malaria Report 2019, Africa accounts for 94% of the global malaria deaths. While malaria prevalence and mortality have declined over the years, recent reports suggest that these gains may stand the risk of being reversed if resistance to Artemisinin Combination Therapies (ACTs) spreads from Southeast Asia to Africa. Efforts are being made to develop new treatments that will address the looming threat of ACT resistance, including the development of triple artemisinin combination therapies (TACTs). The proposed study seeks to explore the views of stakeholders on the key ethical, regulatory and market-related issues that should be considered in the potential introduction of triple artemisinin combination therapies (TACTs) in Africa. Methods: The study employed qualitative research methods involving in-depth interviews and focus group discussions (FGDs) with stakeholders, who will be directly affected by the potential deployment of triple artemisinin combination treatments, as regulators, suppliers and end-users. Participants will be purposively selected and will include national regulatory authorities, national malaria control programs, clinicians, distributors and retailers as well as community members in selected districts in Burkina Faso and Nigeria. Discussion: The proposed study is unique in being one of the first studies that seeks to understand the ethical, social, regulatory and market position issues prior to the development of a prospective antimalarial medicine.

To what extent are the antimalarial markets in African countries ready for a transition to triple artemisinin-based combination therapies?

INTRODUCTION: Triple artemisinin-based combination therapies (TACTs) are being developed as a response to artemisinin and partner drug resistance in the treatment of falciparum malaria in Southeast Asia. In African countries, where current artemisinin-based combination therapies (ACTs) are still effective, TACTs have the potential to benefit the larger community and future patients by mitigating the risk of drug resistance. This study explores the extent to which the antimalarial drug markets in African countries are ready for a transition to TACTs. METHODS: A qualitative study was conducted in Nigeria and Burkina Faso and comprised in-depth interviews (n = 68) and focus group discussions (n = 11) with key actor groups in the innovation system of antimalarial therapies. RESULTS: Evidence of ACT failure in African countries and explicit support for TACTs by the World Health Organization (WHO) and international funders were perceived important determinants for the market prospects of TACTs in Nigeria and Burkina Faso. At the country level, slow regulatory and implementation procedures were identified as potential barriers towards rapid TACTs deployment. Integrating TACTs in public sector distribution channels was considered relatively straightforward. More challenges were expected for integrating TACTs in private sector distribution channels, which are characterized by patient demand and profit motives. Finally, several affordability and acceptability issues were raised for which ACTs were suggested as a benchmark. CONCLUSION: The market prospects of TACTs in Nigeria and Burkina Faso will depend on the demonstration of the added value of TACTs over ACTs, their advocacy by the WHO, the inclusion of TACTs in financial and regulatory arrangements, and their alignment with current distribution and deployment practices. Further clinical, health-economic and feasibility studies are required to inform decision makers about the broader implications of a transition to TACTs in African counties. The recent reporting of artemisinin resistance and ACT failure in Africa might change important determinants of the market readiness for TACTs.

Nutritional status in young children prior to the malaria transmission season in Burkina Faso and Mali, and its impact on the incidence of clinical malaria.

BACKGROUND: Malaria and malnutrition remain major problems in Sahel countries, especially in young children. The direct effect of malnutrition on malaria remains poorly understood, and may have important implications for malaria control. In this study, nutritional status and the association between malnutrition and subsequent incidence of symptomatic malaria were examined in children in Burkina Faso and Mali who received either azithromycin or placebo, alongside seasonal malaria chemoprevention. METHODS: Mid-upper arm circumference (MUAC) was measured in all 20,185 children who attended a screening visit prior to the malaria transmission season in 2015. Prior to the 2016 malaria season, weight, height and MUAC were measured among 4149 randomly selected children. Height-for-age, weight-for-age, weight-for-height, and MUAC-for-age were calculated as indicators of nutritional status. Malaria incidence was measured during the following rainy seasons. Multivariable random effects Poisson models were created for each nutritional indicator to study the effect of malnutrition on clinical malaria incidence for each country. RESULTS: In both 2015 and 2016, nutritional status prior to the malaria season was poor. The most prevalent form of malnutrition in Burkina Faso was being underweight (30.5%; 95% CI 28.6-32.6), whereas in Mali stunting was most prevalent (27.5%; 95% CI 25.6-29.5). In 2016, clinical malaria incidence was 675 per 1000 person-years (95% CI 613-744) in Burkina Faso, and 1245 per 1000 person-years (95% CI 1152-1347) in Mali. There was some evidence that severe stunting was associated with lower incidence of malaria in Mali (RR 0.81; 95% CI 0.64-1.02; p = 0.08), but this association was not seen in Burkina Faso. Being moderately underweight tended to be associated with higher incidence of clinical malaria in Burkina Faso (RR 1.27; 95% CI 0.98-1.64; p = 0.07), while this was the case in Mali for moderate wasting (RR 1.27; 95% CI 0.98-1.64; p = 0.07). However, these associations were not observed in severely affected children, nor consistent between countries. MUAC-for-age was not associated with malaria risk. CONCLUSIONS: Both malnutrition and malaria were common in the study areas, high despite high coverage of seasonal malaria chemoprevention and long-lasting insecticidal nets. However, no strong or consistent evidence was found for an association between any of the nutritional indicators and the subsequent incidence of clinical malaria.

Effect of adding azithromycin to the antimalarials used for seasonal malaria chemoprevention on the nutritional status of African children.

OBJECTIVES: Mass administration of azithromycin has reduced mortality in children in sub-Saharan Africa but its mode of action is not well characterised. A recent trial found that azithromycin given alongside seasonal malaria chemoprevention was not associated with a reduction in mortality or hospital admissions in young children. We investigated the effect of azithromycin on the nutritional status of children enrolled in this study. METHODS: A total of 19 578 children in Burkina Faso and Mali were randomised to receive either azithromycin or placebo alongside seasonal malaria chemoprevention with sulfadoxine-pyrimethamine plus amodiaquine monthly for three malaria transmission seasons (2014-2016). After each transmission season, anthropometric measurements were collected from approximately 4000 randomly selected children (2000 per country) at a cross-sectional survey and used to derive nutritional status indicators. Binary and continuous outcomes between treatment arms were compared by Poisson and linear regression. RESULTS: Nutritional status among children was poor in both countries with evidence of acute and chronic malnutrition (24.9-33.3% stunted, 15.8-32.0% underweight, 7.2-26.4% wasted). There was a suggestion of improvement in nutritional status in Burkina Faso and deterioration in Mali over the study period. At the end of each malaria transmission season, nutritional status of children did not differ between treatment arms (seasonal malaria chemoprevention plus azithromycin or placebo) in either the intention-to-treat or per-protocol analyses (only children with at least three cycles of SMC in the current intervention year). CONCLUSIONS: The addition of azithromycin to seasonal malaria chemoprevention did not result in an improvement of nutritional outcomes in children in Burkina Faso and Mali.

OBJECTIFS: L'administration massive d'azithromycine a réduit la mortalité infantile en Afrique subsaharienne mais son mode d'action n'est pas bien caractérisé. Un essai récent a révélé que l'azithromycine administrée parallèlement à la chimioprévention du paludisme saisonnier n'était pas associée à une réduction de la mortalité ou des hospitalisations chez les jeunes enfants. Nous avons étudié l'effet de l'azithromycine sur l'état nutritionnel des enfants inscrits à cette étude. MÉTHODES: 19.578 enfants au Burkina Faso et au Mali ont été randomisés pour recevoir soit de l'azithromycine soit un placebo parallèlement à une chimioprévention du paludisme saisonnier avec du sulfadoxine-pyriméthamine plus de l'amodiaquine par mois pendant trois saisons de transmission du paludisme (2014-2016). Après chaque saison de transmission, des mesures anthropométriques ont été recueillies auprès d'environ 4.000 enfants sélectionnés au hasard (2.000 par pays) lors d'une enquête transversale et utilisées pour dériver des indicateurs de l'état nutritionnel. Les résultats binaires et continus entre les bras de traitement ont été comparés par la régression linéaire et de Poisson. RÉSULTATS: L'état nutritionnel des enfants était médiocre dans les deux pays avec des signes de malnutrition aiguë et chronique (24,9 à 33,3% de retard de croissance, 15,8 à 32,0% d'insuffisance pondérale, 7,2 à 26,4% d'émaciation). Il a été suggéré une amélioration de l'état nutritionnel au Burkina Faso et une détérioration au Mali au cours de la période d'étude. A la fin de chaque saison de transmission du paludisme, l'état nutritionnel des enfants ne différait pas entre les bras de traitement (chimioprévention contre le paludisme saisonnier plus azithromycine ou placebo) dans les analyses en intention de traiter ou selon le protocole (seulement les enfants avec au moins trois cycles de chimioprévention dans l'année d'intervention en cours). CONCLUSIONS: L'ajout d'azithromycine à la chimioprévention du paludisme saisonnier n'a pas entraîné d'amélioration des résultats nutritionnels chez les enfants au Burkina Faso et au Mali.

Household demand persistence for child micronutrient supplementation.

Addressing early-life micronutrient deficiencies can improve short- and long-term outcomes. In most contexts, private supply chains will be key to effective and efficient preventative supplementation. With established vendors, we conducted a 60-week market trial for a food-based micronutrient supplement in rural Burkina Faso with randomized price and non-price treatments. Repeat purchases - critical for effective supplementation - are extremely price sensitive. Loyalty cards boost demand more than price discounts, particularly in non-poor households where the father is the cardholder. A small minority of households achieved sufficient supplementation for their children through purely retail distribution, suggesting the need for more creative public-private delivery platforms informed by insights into household demand persistence and heterogeneity.

Effect of zinc added to a daily small-quantity lipid-based nutrient supplement on diarrhoea, malaria, fever and respiratory infections in young children in rural Burkina Faso: a cluster-randomised trial.

OBJECTIVE: Preventive zinc supplementation in the form of tablets or syrup reduces the incidence of diarrhoea and acute lower respiratory tract infections (RTI), but its effect on malaria is inconsistent. When zinc is administered with other micronutrients or foods, its effect is also uncertain. We assessed the effects of different amounts and sources of zinc on the frequency of diarrhoea, malaria, fever and RTI in young children. DESIGN, SETTING AND POPULATIONS: This community-based, double-blind, placebo-controlled, cluster-randomised trial of 2435 children 9 months of age was carried out between April 2010 and July 2012 in rural southwestern Burkina Faso. INTERVENTIONS: Participants were randomly assigned at the concession level to receive daily 1 of 4 interventions for 9 months: (1) 20 g small-quantity lipid-based nutrient supplement (SQ-LNS) without zinc and placebo tablet, (2) 20 g SQ-LNS with 5 mg zinc and placebo tablet, (3) 20 g SQ-LNS with 10 mg zinc and placebo tablet or (4) 20 g SQ-LNS without zinc and 5 mg zinc tablet. Participants were visited weekly in their homes for morbidity surveillance for 9 months, and those with uncomplicated diarrhoea and malaria received treatment from the study field workers in the community. MAIN OUTCOMES: Incidence and longitudinal prevalence of diarrhoea, malaria, fever, and lower and upper RTI by intervention group. RESULTS: The incidence of diarrhoea, malaria and fever was 1.10 (±1.03 SD), 0.61 (±0.66 SD) and 1.49 (±1.12 SD) episodes per 100 child-days at risk, respectively, and did not differ by intervention group (p=0.589, p=0.856 and p=0.830, respectively). The longitudinal prevalence of acute lower RTI (0.1%; 95% IC 0.1-0.2%) and of upper RTI (7.8%; 95% IC 7.1-8.4%) did not differ among groups (p=0.234 and p=0.501, respectively). CONCLUSIONS: Inclusion of 5 or 10 mg zinc in SQ-LNS and provision of 5 mg zinc dispersible tablet along with SQ-LNS had no impact on the incidence of diarrhoea, malaria and fever or the longitudinal prevalence of RTI compared with SQ-LNS without zinc in this population. TRIAL REGISTRATION NUMBER: NCT00944281.

Small-quantity lipid-based nutrient supplements, regardless of their zinc content, increase growth and reduce the prevalence of stunting and wasting in young burkinabe children: a cluster-randomized trial.

UNLABELLED: Small-quantity lipid-based nutrient supplements (SQ-LNS) are promising home fortification products, but the optimal zinc level needed to improve growth and reduce morbidity is uncertain. We aimed to assess the impact of providing SQ-LNS with varied amounts of zinc, along with illness treatment, on zinc-related outcomes compared with standard care. In a placebo-controlled, cluster-randomized trial, 34 communities were stratified to intervention (IC) or non-intervention cohorts (NIC). 2435 eligible IC children were randomly assigned to one of four groups:1) SQ-LNS without zinc, placebo tablet; 2) SQ-LNS containing 5mg zinc, placebo tablet; 3) SQ-LNS containing 10mg zinc, placebo tablet; or 4) SQ-LNS without zinc and 5mg zinc tablet from 9­18 months of age. During weekly morbidity surveillance, oral rehydration salts were provided for reported diarrhea and antimalarial therapy for confirmed malaria. Children in NIC (n = 785) did not receive SQ-LNS, tablets, illness surveillance or treatment. At 9 and 18 months, length, weight and hemoglobin were measured in all children. Reported adherence was 97 ± 6% for SQ-LNS and tablets. Mean baseline hemoglobin was 89 ± 15g/L. At 18 months, change in hemoglobin was greater in IC than NIC (+8 vs -1g/L, p<0.0001), but 79.1% of IC were still anemic (vs. 91.1% in NIC). Final plasma zinc concentration did not differ by group. During the 9-month observation period, the incidence of diarrhea was 1.10 ± 1.03 and of malaria 0.54 ± 0.50 episodes per 100 child-days, and did not differ by group. Length at 18 months was significantly greater in IC compared to NIC (77.7 ± 3.0 vs. 76.9 ± 3.4 cm; p<0.001) and stunting prevalence was significantly lower in IC (29.3%) than NIC (39.3%; p<0.0001), but did not differ by intervention group within IC. Wasting prevalence was also significantly lower in IC (8.7%) than in NIC (13.5%; p = 0.0003). Providing SQ-LNS daily with or without zinc, along with malaria and diarrhea treatment, significantly increased growth and reduced stunting, wasting and anemia prevalence in young children. TRIAL REGISTRATION: ClinicalTrials.gov NCT00944281.

Comparison of methods to assess adherence to small-quantity lipid-based nutrient supplements (SQ-LNS) and dispersible tablets among young Burkinabé children participating in a community-based intervention trial.

Adherence to supplementation provided during an intervention trial can affect interpretation of study outcomes. We compared different approaches for estimating adherence to small-quantity lipid-based nutrient supplements (SQ-LNS) and dispersible tablets in a randomised clinical trial in Burkina Faso. A total of 2435 children (9-18 months) were randomly assigned to receive daily 20 g SQ-LNS with varying contents of zinc and a dispersible tablet containing 0 or 5 mg zinc. Adherence to SQ-LNS and tablets was assessed for all children through weekly caregiver interviews, and disappearance rate was calculated based on empty and unused packages returned during home visits. Additional adherence data were collected in different randomly selected subgroups of children: 12-h home observations were completed for children 11 and 16 months of age (n = 192) to assess consumption of SQ-LNS and dispersible tablets, and plasma zinc concentration was measured at baseline and 18 months (n = 310). Apparent adherence to SQ-LNS and dispersible tablets differed according to the assessment method used. Average daily caregiver-reported adherence to both SQ-LNS and dispersible tablets was 97 ± 6%. Disappearance rates showed similarly high average weekly adherence (98 ± 4%). In contrast, only 63% and 54% of children at 11 and 16 months, respectively, received SQ-LNS during the 12-h home observation periods, and fewer (32% and 27%) received a tablet. The lack of change in plasma zinc concentration after 9 months of supplementation suggests low adherence to the zinc tablet. Better methods are needed to assess adherence in community-based supplementation trials.