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Artemisinin and partner-drug resistance in Plasmodium falciparum are major threats to malaria control and elimination. Triple artemisinin-based combination therapies (TACTs), which combine existing co-formulated ACTs with a second partner drug that is slowly eliminated, might provide effective treatment and delay emergence of antimalarial drug resistance. In this multicentre, open-label, randomised trial, we recruited patients with uncomplicated P falciparum malaria at 18 hospitals and health clinics in eight countries. Eligible patients were aged 2–65 years, with acute, uncomplicated P falciparum malaria alone or mixed with non-falciparum species, and a temperature of 37·5°C or higher, or a history of fever in the past 24 h. Patients were randomly assigned (1:1) to one of two treatments using block randomisation, depending on their location: in Thailand, Cambodia, Vietnam, and Myanmar patients were assigned to either dihydroartemisinin–piperaquine or dihydroartemisinin–piperaquine plus mefloquine; at three sites in Cambodia they were assigned to either artesunate–mefloquine or dihydroartemisinin–piperaquine plus mefloquine; and in Laos, Myanmar, Bangladesh, India, and the Democratic Republic of the Congo they were assigned to either artemether–lumefantrine or artemether–lumefantrine plus amodiaquine. All drugs were administered orally and doses varied by drug combination and site. Patients were followed-up weekly for 42 days. The primary endpoint was efficacy, defined by 42-day PCR-corrected adequate clinical and parasitological response. Primary analysis was by intention to treat. A detailed assessment of safety and tolerability of the study drugs was done in all patients randomly assigned to treatment. This study is registered at ClinicalTrials.gov, NCT02453308, and is complete. Between Aug 7, 2015, and Feb 8, 2018, 1100 patients were given either dihydroartemisinin–piperaquine (183 [17%]), dihydroartemisinin–piperaquine plus mefloquine (269 [24%]), artesunate–mefloquine (73 [7%]), artemether–lumefantrine (289 [26%]), or artemether–lumefantrine plus amodiaquine (286 [26%]). The median age was 23 years (IQR 13 to 34) and 854 (78%) of 1100 patients were male. In Cambodia, Thailand, and Vietnam the 42-day PCR-corrected efficacy after dihydroartemisinin–piperaquine plus mefloquine was 98% (149 of 152; 95% CI 94 to 100) and after dihydroartemisinin–piperaquine was 48% (67 of 141; 95% CI 39 to 56; risk difference 51%, 95% CI 42 to 59; p<0·0001). Efficacy of dihydroartemisinin–piperaquine plus mefloquine in the three sites in Myanmar was 91% (42 of 46; 95% CI 79 to 98) versus 100% (42 of 42; 95% CI 92 to 100) after dihydroartemisinin–piperaquine (risk difference 9%, 95% CI 1 to 17; p=0·12). The 42-day PCR corrected efficacy of dihydroartemisinin–piperaquine plus mefloquine (96% [68 of 71; 95% CI 88 to 99]) was non-inferior to that of artesunate–mefloquine (95% [69 of 73; 95% CI 87 to 99]) in three sites in Cambodia (risk difference 1%; 95% CI −6 to 8; p=1·00). The overall 42-day PCR-corrected efficacy of artemether–lumefantrine plus amodiaquine (98% [281 of 286; 95% CI 97 to 99]) was similar to that of artemether–lumefantrine (97% [279 of 289; 95% CI 94 to 98]; risk difference 2%, 95% CI −1 to 4; p=0·30). Both TACTs were well tolerated, although early vomiting (within 1 h) was more frequent after dihydroartemisinin–piperaquine plus mefloquine (30 [3·8%] of 794) than after dihydroartemisinin–piperaquine (eight [1·5%] of 543; p=0·012). Vomiting after artemether–lumefantrine plus amodiaquine (22 [1·3%] of 1703) and artemether–lumefantrine (11 [0·6%] of 1721) was infrequent. Adding amodiaquine to artemether–lumefantrine extended the electrocardiogram corrected QT interval (mean increase at 52 h compared with baseline of 8·8 ms [SD 18·6] vs 0·9 ms [16·1]; p<0·01) but adding mefloquine to dihydroartemisinin–piperaquine did not (mean increase of 22·1 ms [SD 19·2] for dihydroartemisinin–piperaquine vs 20·8 ms [SD 17·8] for dihydroartemisinin–piperaquine plus mefloquine; p=0·50). Dihydroartemisinin–piperaquine plus mefloquine and artemether–lumefantrine plus amodiaquine TACTs are efficacious, well tolerated, and safe treatments of uncomplicated P falciparum malaria, including in areas with artemisinin and ACT partner-drug resistance. UK Department for International Development, Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and US National Institutes of Health.

Anti-malarial artemisinin-based combination therapies (ACTs) might be losing efficacy in east Africa, with the spread of artemisinin partial resistance and reduced partner drug activity. Our trial aimed to measure the efficacies of artemether–lumefantrine, artesunate–amodiaquine, dihydroartemisinin–piperaquine, and artesunate–pyronaridine in three sites in Uganda. This randomised, open-label, phase 4 clinical trial was carried out at three sites in the Agago, Arua, and Busia districts of Uganda. Children aged 6 months to 10 years with uncomplicated Plasmodium falciparum malaria were randomly assigned to receive either artemether–lumefantrine (20 mg artemether; 120 mg lumefantrine; twice a day for 3 days) in all sites or dihydroartemisinin–piperaquine (40 mg dihydroartemisinin and 320 mg piperaquine, once a day for 3 days) in Agago, artesunate–amodiaquine (25 mg artesunate and 67·5 mg amodiaquine for children <9 kg or 50 mg artesunate and 135 mg amodiaquine for children ≥9 kg, once a day for 3 days) in Busia; and artesunate–pyronaridine (60 mg artesunate and 180 mg pyronaridine for children >15 kg or 20 mg artesunate and 60 mg pyronaridine for children <15 kg, once a day for 3 days) in Arua, with follow-up to 42 days. Participants were not blinded to group assignments; however, investigators and those assessing outcome were masked. The primary outcome was parasitaemia, assessed by microscopy, either uncorrected or PCR-corrected to distinguish recrudescence from new infection. All participants who received the treatment per protocol and were not lost to follow-up were included in the primary outcome. All participants who were randomly allocated to treatment groups were included in the safety analyses. This study is registered with the Pan African Clinical Trials Registry, number PACTR202301796134887, and is complete. Between Nov 7, 2022, and March 24, 2023, 808 participants (437 [54%] female) were enrolled and assigned to treatment groups; 15 (2%) were lost to follow-up and 793 (98%) completed follow-up. The uncorrected adequate clinical and parasitological response for artemether–lumefantrine was 87 (51·8%; 95% CI 44·0–59·5) of 168 participants in Arua, 88 (51·8%; 44·0–59·4) of 170 and Busia, and 131 (79·4%; 72·3–85·1) of 165 in Agago. This response for artemether–lumefantrine was lower than that of the other ACTs at all sites: 97 (98·0%; 92·2–99·6) of 99 for dihydroartemisinin–piperaquine in Agago, 95 (99·0%; 93·5–99·9) of 96 for artesunate–amodiaquine in Busia, and 73 (73·7%; 63·8–81·8) of 99 for artesunate–pyronaridine in Arua. PCR-corrected 28-day efficacies were 88 (81·5%; 72·6–88·1) of 108 for artemether–lumefantrine and 95 (100%; 95·2–100·0) of 95 for artesunate–amodiaquine in Busia; 131 (97·0%; 92·1–99·0) of 135 for artemether–lumefantrine and 97 (100%; 95·3–100·0) of 97 for dihydroartemisinin–piperaquine in Agago; and 87 (82·1%; 73·2–88·6) of 106 for artemether–lumefantrine and 73 (92·4%; 83·6–96·9) of 79 for artesunate–pyronaridine in Arua. All regimens were well tolerated. The most common adverse events were upper respiratory tract infection, diarrhoea, and anaemia. None of the reported adverse events were attributed to the study drugs. There were two serious adverse events, both cases of severe malaria in Arua, one in each of the treatment groups. Parasite clearance half-lives were prolonged with parasites carrying the PfK13 Cys469Tyr (median 4·2 h; IQR 3·4–4·9) and Ala675Val (4·9 h; 3·4–5·7) mutations compared with wild-type parasites (2·8 h; 2·3–3·6; p<0·0001). Artemether–lumefantrine was associated with a higher risk of recurrent malaria than other antimalarial combinations tested, and K13 mutations were associated with delayed parasite clearance. Changes in first-line therapy for uncomplicated malaria must be considered in response to suboptimal efficacy of artemether–lumefantrine. US President's Malaria Initiative, US Agency for International Development, through the Uganda Malaria Reduction Activity and the National Institutes of Health (AI075045 and AI117001). For the Swahili translation of the abstract see Supplementary Materials section.

Primaquine and methylene blue are gametocytocidal compounds that could prevent Plasmodium falciparum transmission to mosquitoes. We aimed to assess the efficacy and safety of primaquine and methylene blue in preventing human to mosquito transmission of P falciparum among glucose-6-phosphate dehydrogenase (G6PD)-normal, gametocytaemic male participants. This was a phase 2, single-blind, randomised controlled trial done at the Clinical Research Centre of the Malaria Research and Training Centre (MRTC) of the University of Bamako (Bamako, Mali). We enrolled male participants aged 5–50 years with asymptomatic P falciparum malaria. G6PD-normal participants with gametocytes detected by blood smear were randomised 1:1:1:1 in block sizes of eight, using a sealed-envelope design, to receive either sulfadoxine-pyrimethamine and amodiaquine, sulfadoxine-pyrimethamine and amodiaquine plus a single dose of 0·25 mg/kg primaquine, dihydroartemisinin-piperaquine, or dihydroartemisinin-piperaquine plus 15 mg/kg per day methylene blue for 3 days. Laboratory staff, investigators, and insectary technicians were masked to the treatment group and gametocyte density of study participants. The study pharmacist and treating physician were not masked. Participants could request unmasking. The primary efficacy endpoint, analysed in all infected patients with at least one infectivity measure before and after treatment, was median within-person percentage change in mosquito infectivity 2 and 7 days after treatment, assessed by membrane feeding. This study is registered with ClinicalTrials.gov, number NCT02831023. Between June 27, 2016, and Nov 1, 2016, 80 participants were enrolled and assigned to the sulfadoxine-pyrimethamine and amodiaquine (n=20), sulfadoxine-pyrimethamine and amodiaquine plus primaquine (n=20), dihydroartemisinin-piperaquine (n=20), or dihydroartemisinin-piperaquine plus methylene blue (n=20) groups. Among participants infectious at baseline (54 [68%] of 80), those in the sulfadoxine-pyrimethamine and amodiaquine plus primaquine group (n=19) had a median 100% (IQR 100 to 100) within-person reduction in mosquito infectivity on day 2, a larger reduction than was noted with sulfadoxine-pyrimethamine and amodiaquine alone (n=12; −10·2%, IQR −143·9 to 56·6; p<0·0001). The dihydroartemisinin-piperaquine plus methylene blue (n=11) group had a median 100% (IQR 100 to 100) within-person reduction in mosquito infectivity on day 2, a larger reduction than was noted with dihydroartemisinin-piperaquine alone (n=12; −6·0%, IQR −126·1 to 86·9; p<0·0001). Haemoglobin changes were similar between gametocytocidal arms and their respective controls. After exclusion of blue urine, adverse events were similar across all groups (59 [74%] of 80 participants had 162 adverse events overall, 145 [90%] of which were mild). Adding a single dose of 0·25 mg/kg primaquine to sulfadoxine-pyrimethamine and amodiaquine or 3 days of 15 mg/kg per day methylene blue to dihydroartemisinin-piperaquine was highly efficacious for preventing P falciparum transmission. Both primaquine and methylene blue were well tolerated. Bill & Melinda Gates Foundation, European Research Council.

In 2006, Senegal adopted artemisinin-based combination therapy (ACT) as first-line treatment in the management of uncomplicated malaria. This study aimed to update the status of antimalarial efficacy more than ten years after their first introduction. This was a randomized, three-arm, open-label study to evaluate the efficacy and safety of artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ) and dihydroartemisinin-piperaquine (DP) in Senegal. Malaria suspected patients were screened, enrolled, treated, and followed for 28 days for AL and ASAQ arms or 42 days for DP arm. Clinical and parasitological responses were assessed following antimalarial treatment. Genotyping ( msp1 , msp2 and 24 SNP-based barcode) were done to differentiate recrudescence from re-infection; in case of PCR-confirmed treatment failure, Pfk13 propeller and Pfcoronin genes were sequenced. Data was entered and analyzed using the WHO Excel-based application. A total of 496 patients were enrolled. In Diourbel, PCR non-corrected/corrected adequate clinical and parasitological responses (ACPR) was 100.0% in both the AL and ASAQ arms. In Kedougou, PCR corrected ACPR values were 98.8%, 100% and 97.6% in AL, ASAQ and DP arms respectively. No Pfk13 or Pfcoronin mutations associated with artemisinin resistance were found. This study showed that AL, ASAQ and DP remain efficacious and well-tolerated in the treatment of uncomplicated P. falciparum malaria in Senegal.

Seasonal malaria chemoprevention (SMC) with sulfadoxine–pyrimethamine combined with amodiaquine (SPAQ) effectively protects eligible children from malaria in areas of high and seasonal transmission. However, concerns about parasite resistance to sulfadoxine–pyrimethamine in East and Southern Africa necessitate evaluating alternative drug regimens. This study assessed the effectiveness of SPAQ and dihydroartemisinin–piperaquine for SMC in Uganda. This three-arm, open-label, non-inferiority and superiority, cluster-randomised, controlled trial was conducted in Karamoja subregion, Uganda, among children aged 3–59 months and 6–59 months for SPAQ and dihydroartemisinin–piperaquine, respectively. Of 427 villages, 380 were randomly assigned (1:1) to the SPAQ group and dihydroartemisinin–piperaquine group, and 47 were assigned to the control group (no SMC). The superiority component compared the SPAQ and dihydroartemisinin–piperaquine groups with the control group, whereas the non-inferiority component compared the dihydroartemisinin–piperaquine group with the SPAQ group. The primary endpoint was confirmed malaria incidence using rapid diagnostic tests or microscopy. Survival analyses were done on an intention-to-treat basis (in all randomised participants), with adjustments made for covariate imbalances at baseline. Additionally, molecular markers associated with resistance to sulfadoxine–pyrimethamine and amodiaquine were analysed on 750 malaria-positive blood samples from children younger than 5 years before and after five SMC cycles. This trial was registered with ClinicalTrials.gov, NCT05323721, and has been completed. During June 18–30, 2022, 3881 children were enrolled; 1755 in SPAQ, 1736 in dihydroartemisinin–piperaquine, and 390 in control villages. Of these children, 3629 were analysed. Incidence rates were 0·90 cases per 100 person-months in the SPAQ group, 0·80 cases per 100 person-months in the dihydroartemisinin–piperaquine group, and 18·26 cases per 100 person-months in the control group. SPAQ and dihydroartemisinin–piperaquine reduced malaria risk by 94% (hazard ratio [HR] 0·06 [95% CI 0·04–0·08]; p<0·001) and 96% (0·04 [0·03–0·06]; p<0·001), respectively. Based on the prespecified non-inferiority margin of 1·4, there was non-inferiority between the protective effectiveness of dihydroartemisinin–piperaquine and that of SPAQ (HR 0·90 [95% CI 0·58–1·39]). Prevalence of mutations linked to moderate (Plasmodium falciparum dihydrofolate reductase [PfDHFR] and P falciparum dihydropteroate synthetase reductase [PfDHPS]) and high (PfDHFR Ile164Leu and PfDHPS Ala581Gly) sulfadoxine–pyrimethamine resistance were more than 88% and less than 5%, respectively. Mutations associated with 4-aminoquinolone resistance (P falciparum multidrug resistance protein-1 [PfMDR1] Asp1246Tyr and PfMDR1 Asn86Tyr) were less than 1%. There was no significant increase in the prevalence of antifolate and artemisinin partial resistance-associated mutations, but a decrease was observed for key aminoquinoline resistance-associated alleles: P falciparum chloroquine resistance transporter protein Lys76Thr, P falciparum multidrug resistance protein Asn86Tyr, and PfMDR1 Asp1246Tyr (p<0·001). No serious or fatal adverse events were reported. SPAQ and dihydroartemisinin–piperaquine effectively reduced malaria in children younger than 5 years, with no safety concerns. There was no evidence of resistance selection by SMC. Although these findings support SPAQ-based SMC in Eastern and Southern Africa, ongoing resistance surveillance and efficacy monitoring are essential for sustained impact. GiveWell. For the Swahili translation of the abstract see Supplementary Materials section.

Several interventional strategies have been implemented in malaria endemic areas where the burden is high, that include among others, intermittent preventive treatment (IPT), a tactic that blocks transmission and can reduce disease morbidity. However, the implementation IPT strategies raises a genuine concern, intervening the development of naturally acquired immunity to malaria which requires continuous contact with parasite antigens. This study investigated whether dihydroartemisinin-piperaquine (DP) or artesunate-amodiaquine (ASAQ) IPT in schoolchildren (IPTsc) impairs IgG reactivity to six malaria antigens. An IPTsc trial in north-eastern Tanzania administered three doses of DP or ASAQ at four-monthly intervals and the schoolchildren were followed up. This study compared IgG reactivity against GLURP-R2, MSP1, MSP3, and CIDR domains (CIDRa1.1, CIDRa1.4, and CIDRa1.5) of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP-1) in intervention and control groups using enzyme linked immunosorbent assay (ELISA) technique. During the study, 369 schoolchildren were available for analysis, 119, 134 and 116 participants in the control, DP and ASAQ groups, respectively. Breadth of malaria antigen recognition increased significantly during and after the intervention phases and did not differ between the study groups (Trend test: DP, z-score = 5.92, p < 0.001, ASAQ, z-score = 6.64, p < 0.001 and control, z-score = 5.85, p < 0.001). There were no differences between the control and ASAQ group in the recognition of any of the tested antigens at all visits. In the DP group, however, during the intervention period IPTsc did not impair antibody against MSP1, MSP3, CIDRa1.1, CIDRa1.4 and CIDRa1.5, but it did impair against GLURP-R2. The current study has shown that effective IPTsc with DP or ASAQ does not interfere with the development of antibodies against malaria antigens of the blood stages, suggesting that the advancement of naturally acquired immunity to malaria is not impeded by IPTsc interventions.

Artemisinin‐based combination therapy (ACT) is the first‐line recommended treatment for uncomplicated malaria. Pharmacokinetic (PK) properties in pregnant women are often based on small studies and need to be confirmed and validated in larger pregnant patient populations. This study aimed to evaluate the PK properties of amodiaquine and its active metabolite, desethylamodiaquine, and piperaquine in women in their second and third trimester of pregnancy with uncomplicated P. falciparum infections. Eligible pregnant women received either artesunate‐amodiaquine (200/540 mg daily, n = 771) or dihydroartemisinin‐piperaquine (40/960 mg daily, n = 755) for 3 days (NCT00852423). Population PK properties were evaluated using nonlinear mixed‐effects modeling, and effect of gestational age and trimester was evaluated as covariates. 1071 amodiaquine and 1087 desethylamodiaquine plasma concentrations, and 976 piperaquine plasma concentrations, were included in the population PK analysis. Amodiaquine concentrations were described accurately with a one‐compartment disposition model followed by a two‐compartment disposition model of desethylamodiaquine. The relative bioavailability of amodiaquine increased with gestational age (1.25% per week). The predicted exposure to desethylamodiaquine was 2.8%–32.2% higher in pregnant women than that reported in non‐pregnant women, while day 7 concentrations were comparable. Piperaquine concentrations were adequately described by a three‐compartment disposition model. Neither gestational age nor trimester had significant impact on the PK of piperaquine. The predicted exposure and day 7 concentrations of piperaquine were similar to that reported in non‐pregnant women. In conclusion, the exposure to desethylamodiaquine and piperaquine was similar to that in non‐pregnant women. Dose adjustment is not warranted for women in their second and their trimester of pregnancy.

Background WHO and the Lancet reported that malaria and malnutrition form a double health burden in low and middle-income countries. Despite the massive implementation of malaria control interventions, there is scarce evidence on the impact of intermittent preventive therapy (IPTsc) for malaria on the nutritional status of school-age children. In this study, we aimed to determine malnutrition risk factors and evaluate the impact of IPTsc for malaria on the nutritional status of school-age children in Muheza, Tanga, Tanzania. Methods We analysed secondary data from a cross-sectional baseline survey and a randomized controlled open-label trial conducted in Muheza, Tanga, Tanzania. Participants of our study were children of age 5–15 years. Baseline data collection was carried out between February-April 2019. The study continued through December 2020, during which participants were randomly assigned to one of the three groups: dihydroartemisinin-piperaquine (DP), artesunate-amodiaquine (ASAQ), or a control group, using a 3-arms balanced block design with a 1:1:1 allocation ratio. Intervention treatments were administered at recruitment, 4 months, and 8 months of the trial. Data were analysed using logistic regression and a linear mixed model. Findings At baseline, the prevalence of malaria was 27%. The prevalence of being underweight among children of ≤ 10 years was 23%. Among all children surveyed at baseline, 21% were stunted and 28% were either thin or severely thin. The odds of stunting were 78% higher (AOR = 1.78, 95%CI = [1.36, 2.33], P  < 0.001) among children who had malaria compared with those who did not have malaria. Children from low socioeconomic status (SES) had higher odds of being underweight (AOR = 1.50, 95%CI = [1.13,2.01], P  = 0.006) compared with their high SES counterparts. During the intervention, change in mean weight, height, and BMI over time as estimated from age-treatment interaction was not significantly different in the dihydroartemisinin-piperaquine (DP) and Artesunate amodiaquine (ASAQ) treatment groups compared with the control group. Conclusion Although substantial efforts to control malaria are ongoing in the study setting, the dual burden of malaria and malnutrition remains significant. Anti-malaria use for preventive purpose may not be sufficient to improve nutritional status, reinforcing that integrated interventions are required to address both malaria and malnutrition. Public health efforts should combine malaria control with nutrition programs, including community-driven strategies to enhance sustainable nutrition education and access to adequate food at home and school. Protocol for the parent study that generated these data was registered with ClinicalTrials.gov (NCT03640403) on Aug 21, 2018.

Background Artemisinin-based combination therapy (ACT) is recommended to improve malaria treatment efficacy and limit drug-resistant parasites selection in malaria endemic areas. 5 years after they were adopted, the efficacy and safety of artemether–lumefantrine (AL) and artesunate–amodiaquine (ASAQ), the first-line treatments for uncomplicated malaria were assessed in Burkina Faso. Methods In total, 440 children with uncomplicated Plasmodium falciparum malaria were randomized to receive either AL or ASAQ for 3 days and were followed up weekly for 42 days. Blood samples were collected to investigate the ex vivo susceptibility of P. falciparum isolates to lumefantrine, dihydroartemisinin (the active metabolite of artemisinin derivatives) and monodesethylamodiaquine (the active metabolite of amodiaquine). The modified isotopic micro test technique was used to determine the 50% inhibitory concentration (IC50) values. Primary endpoints were the risks of treatment failure at days 42. Results Out of the 440 patients enrolled, 420 (95.5%) completed the 42 days follow up. The results showed a significantly higher PCR unadjusted cure rate in ASAQ arm (71.0%) than that in the AL arm (49.8%) on day 42, and this trend was similar after correction by PCR, with ASAQ performing better (98.1%) than AL (91.1%). Overall adverse events incidence was low and not significantly different between the two treatment arms. Ex vivo results showed that 6.4% P. falciparum isolates were resistant to monodesthylamodiaquine. The coupled in vivo / ex vivo analysis showed increased IC50 values for lumefantrine and monodesethylamodiaquine at day of recurrent parasitaemia compared to baseline values while for artesunate, IC50 values remained stable at baseline and after treatment failure (p > 0.05). Conclusion These findings provide substantial evidence that AL and ASAQ are highly efficacious for the treatment of uncomplicated malaria in children in Burkina Faso. However, the result of P. falciparum susceptibility to the partner drugs advocates the need to regularly replicate such surveillance studies. This would be particularly indicated when amodiaquine is associated in seasonal malaria chemoprophylaxis (SMC) mass drug administration in children under 5 years in Burkina Faso. Trial registration clinicaltrials, NCT00808951. Registered 05 December 2008,https://clinicaltrials.gov/ct2/show/NCT00808951?cond=NCT00808951&rank=1

Background Seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine and amodiaquine (SP + AQ) involves the monthly administration of therapeutic doses to children under five years of age during periods of high risk of malaria in regions where malaria transmission is highly seasonal. Current SMC guidelines recommend administering the same treatment to both non-infected and asymptomatic Plasmodium falciparum- infected children. However, a critical knowledge gap remains the impact asymptomatic infection on the efficacy of SMC in preventing clinical malaria over a four-week period. This study aimed to evaluate the risk of clinical malaria and its association with children's infection status during SMC treatment. Methods This study was conducted in the Koulikoro health district of Mali and focused on children under 10 years of age. A total of 726 children in 2019 and 1452 children in 2020 were randomly selected and followed throughout the SMC campaigns. The prevalence of asymptomatic P. falciparum infection was assessed in each round using microscopy prior to SMC drug administration. Children were passively monitored over a four-week period to record the incidence of clinical malaria. Data analysis was performed using R-Studio software. The risk of clinical malaria based on infection status was estimated through logistic regression analysis, and a Kaplan–Meier curve was used to compare survival times between infected and uninfected children. Proportions were compared using the Pearson Chi-square test, with statistical significance set at p < 0.05. Results The average prevalence of asymptomatic P. falciparum infection was 11.0% across study years. Prevalence was notably higher among children aged 5 to 9 years old in 2019 (p < 0.001) and 2020 (p = 0.016). Asymptomatic infected children had a significantly higher risk of clinical malaria during both transmission seasons: 2019: (RR = 3.05, CI [2.04–4.72]) and 2020 (RR = 1.43, CI [1.04–1.97]). Furthermore, the time to the first malaria episode was significantly shorter among infected children in both years (p < 0.001 for 2019, p = 0.01 for 2020). Conclusion These findings demonstrate an elevated risk of clinical malaria in asymptomatic infected children during SMC implementation. Screening and treating P. falciparum infections prior to SMC administration could substantially enhance the effectiveness of this strategy in reducing malaria morbidity in endemic areas.