Seasonal malaria chemoprevention: drug design and selection
Authors: Issaka Zongo, Yves Daniel Compaoré
Journal: The Lancet Global Health (2024)

Seasonal malaria chemoprevention (SMC), formerly termed intermittent preventive treatment of malaria, consisting of sulfadoxine–pyrimethamine plus amodiaquine in children aged 3–59 months, is an effective strategy to prevent malaria1Wilson AL A systematic review and meta-analysis of the efficacy and safety of intermittent preventive treatment of malaria in children (IPTc).PLoS One. 2011; 6e16976 Crossref Scopus (93) Google Scholar and has been widely implemented in sub-Saharan Africa over the past 10 years.2Baba E Hamade P Kivumbi H et al.Effectiveness of seasonal malaria chemoprevention at scale in west and central Africa: an observational study.Lancet. 2020; 396: 1829-1840Summary Full Text Full Text PDF PubMed Scopus (90) Google Scholar The strategy is deployed when malaria is at its peak in seasonal transmission settings. The Achieving Catalytic Expansion of SMC in the Sahel (ACCESS-SMC) project, funded by UNITAID, aimed to overcome barriers to the scale-up of SMC in seven countries in 2015 and 2016; the project has substantially improved the availability of SMC drugs and has shown that that SMC can achieve high coverage even though it varies from country to country.2Baba E Hamade P Kivumbi H et al.Effectiveness of seasonal malaria chemoprevention at scale in west and central Africa: an observational study.Lancet. 2020; 396: 1829-1840Summary Full Text Full Text PDF PubMed Scopus (90) Google Scholar Currently, all eligible countries have implemented SMC and reports have shown good acceptability and feasibility.2Baba E Hamade P Kivumbi H et al.Effectiveness of seasonal malaria chemoprevention at scale in west and central Africa: an observational study.Lancet. 2020; 396: 1829-1840Summary Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 3Gatiba P Laury J Steinhardt L et al.Contextual factors to improve implementation of malaria chemoprevention in children: a systematic review.Am J Trop Med Hyg. 2023; 110: 69-78Crossref Scopus (0) Google Scholar The current SMC regimen combines amodiaquine (a 4-aminoquinoline) with sulfadoxine–pyrimethamine (a sulphamide). These drugs are synergically associated to reach the double goal of both prevention and cure. Sulfadoxine–pyrimethamine has a long elimination half-life and is intended to prevent the occurrence of new malaria infections, whereas amodiaquine has a relatively short half-life and represents the curative component expected to rapidly clear existing infections. According to the predictions by Lydia Braunack-Mayer and colleagues,4Braunack-Mayer L Malinga J Masserey T et al.Design and selection of drug properties to increase the public health impact of next-generation seasonal malaria chemoprevention: a modelling study.Lancet Glob Health. 2024; 12: e478-e490Google Scholar published in The Lancet Global Health, the curative capacity of SMC drugs is of low importance if the ultimate objective is high prevention of malaria cases. To put this finding in context, the efficacy of conventional SMC drugs is being threatened in most endemic settings by the rise of rapidly spreading plasmodial resistance to sulfadoxine–pyrimethamine. This resistance is due to high usage of sulfadoxine–pyrimethamine and administration of suboptimal doses—eg, one of the largest pooled analyses of the pharmacokinetics of sulfadoxine–pyrimethamine5de Kock M Tarning J Workman L et al.Population pharmacokinetic properties of sulfadoxine and pyrimethamine: a pooled analysis to inform optimal dosing in African children with uncomplicated malaria.Antimicrob Agents Chemother. 2018; 62: e01317-e01370Crossref Scopus (15) Google Scholar indicated that, under current WHO dosing recommendations, the median day 7 sulfadoxine concentration was suboptimal in individuals who weigh 8–9 kg, 19–24 kg, 46–49 kg, and 74–79 kg, and that the median day 7 pyrimethamine concentration was suboptimal for individuals who weigh 8–9 kg, 14–24 kg, and 42–49 kg. In addition, administration based on age might also lead to underdosing or overdosing.6Barnes KI Watkins WM White NJ Antimalarial dosing regimens and drug resistance.Trends Parasitol. 2008; 24: 127-134Summary Full Text Full Text PDF PubMed Scopus (126) Google Scholar In a randomised non-inferiority trial of dihydroartemisinin–piperaquine compared with sulfadoxine–pyrimethamine plus amodiaquine for SMC in Burkina Faso, the duration of protection against malaria with sulfadoxine–pyrimethamine plus amodiaquine was about 3–4 weeks.7Zongo I Milligan P Compaore YD et al.Randomized noninferiority trial of dihydroartemisinin-piperaquine compared with sulfadoxine-pyrimethamine plus amodiaquine for seasonal malaria chemoprevention in Burkina Faso.Antimicrob Agents Chemother. 2015; 59: 4387-4396Crossref PubMed Scopus (44) Google Scholar Despite the continued efficacy of sulfadoxine–pyrimethamine in endemic areas, high levels of dihydrofolate reductase and dihydropteroate synthase mutations in Plasmodium falciparum have been reported by some studies8Bertin G Briand V Bonaventure D et al.Molecular markers of resistance to sulphadoxine-pyrimethamine during intermittent preventive treatment of pregnant women in Benin.Malar J. 2011; 10: 196Crossref Scopus (28) Google Scholar (although not others9Gikunju SW Agola EL Ondondo RO et al.Prevalence of pfdhfr and pfdhps mutations in Plasmodium falciparum associated with drug resistance among pregnant women receiving IPTp-SP at Msambweni County Referral Hospital, Kwale County, Kenya.Malar J. 2020; 19: 190Crossref Scopus (6) Google Scholar), so the need for alternative or next-generation drugs is warranted. Regarding the current SMC regimen, we could speculate that most of its efficacy is based on the relatively long elimination half-life of sulfadoxine–pyrimethamine, which is given as a single dose, since the effective uptake of amodiaquine doses administered by parents is questionable. It is now appropriate to consider the next generation of SMC drugs, and the study by Braunack-Mayer and colleagues provides particular insights.4Braunack-Mayer L Malinga J Masserey T et al.Design and selection of drug properties to increase the public health impact of next-generation seasonal malaria chemoprevention: a modelling study.Lancet Glob Health. 2024; 12: e478-e490Google Scholar The first key element to take into account when selecting an SMC drug is the drug half-life, which is associated with the provided duration of protection. SMC is currently distributed on a monthly basis and this frequency is now accepted and adopted in the communities where the strategy is implemented. Any SMC optimisation process that attempts to alter the interval between two cycles could potentially affect community engagement and jeopardise the main parameter: coverage. Therefore, any new delivery scheme (accounting for drug pharmacokinetics) should be carefully evaluated to avoid engagement disruption. A second important point to consider is the drug formulation, which should be as attractive as possible to enhance compliance in children. The bitter taste of amodiaquine was overcome with a child-friendly dispersible formulation adopted a few years after SMC was scaled up. A more adaptive and child-friendly formulation is crucial to achieve high coverage of and compliance with SMC. Finally, combining two long-acting drugs is key to enhancing efficacy by reducing the likelihood of resistance, and therefore increasing the likelihood of both curing existing infection and preventing new infection. Early evaluations of intermittent preventive treatment of malaria in children studied sulfadoxine–pyrimethamine plus piperaquine, two long-acting drugs.10Cisse B Cairns M Faye E et al.Randomized trial of piperaquine with sulfadoxine-pyrimethamine or dihydroartemisinin for malaria intermittent preventive treatment in children.PLoS One. 2009; 4e7164 Crossref PubMed Scopus (67) Google Scholar Since then, several promising drug combinations have been identified and need further consideration in terms of efficacy, safety, acceptability, and feasibility; these combinations include pyronaridine plus sulfadoxine–pyrimethamine as a possible transitional drug regimen in areas where sulfadoxine–pyrimethamine continues to retain efficacy, pyronaridine plus piperaquine, and other associated mefloquine regimens, and could be valuable areas of research for the selection of next-generation SMC drugs. We declare no competing interests. Design and selection of drug properties to increase the public health impact of next-generation seasonal malaria chemoprevention: a modelling studyAlthough efficacy is crucial for malaria prevalence reductions, chemoprevention development should select drug candidates for their duration of protection to maximise burden reductions, with the duration half-life determining cycle timing. Explicitly designing or selecting drug properties to increase community uptake is paramount. Full-Text PDF Open Access