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Background: Iron deficiency is the most prevalent nutritional disorder worldwide. Iron supplementation has modest efficacy, causes gastrointestinal side-effects that limit compliance, and has been associated with serious adverse outcomes in children across low-income settings. We aimed to compare two hepcidin-guided screen-and-treat regimens designed to reduce overall iron dosage by targeting its administration to periods when children were safe and ready to receive iron supplementation, with WHO's recommendation of universal iron supplementation., Methods: We conducted an individually randomised, three-arm, double-blind, controlled, proof-of-concept, non-inferiority trial in 12 rural communities across The Gambia. Eligible participants were children aged 6-23 months with anaemia. Participants were randomly assigned (1:1:1) to either the WHO recommended regimen of one sachet of multiple micronutrient powder (MMP) daily containing 12·0 mg iron as encapsulated ferrous fumarate (control group); to MMP with 12·0 mg per day iron for the next 7 days if plasma hepcidin concentration was less than 5·5 μg/L, or to MMP without iron for the next 7 days if plasma hepcidin concentration was at least 5·5 μg/L (12 mg screen-and-treat group); or to MMP with 6·0 mg per day iron for the next 7 days if plasma hepcidin concentration was less than 5·5 μg/L, or to MMP without iron for the next 7 days if plasma hepcidin concentration was at least 5·5 μg/L (6 mg screen-and-treat group). Randomisation was done by use of a permuted block design (block size of 9), with stratification by haemoglobin and age, using computer-generated numbers. Participants and the research team (except for the data manager) were masked to group allocation. The primary outcome was haemoglobin concentration, with a non-inferiority margin of -5 g/L. A per-protocol analysis, including only children who had consumed at least 90% of the supplements (ie, supplement intake on ≥75 days during the study), was done to assess non-inferiority of the primary outcome at day 84 using a one-sided t test adjusted for multiple comparisons. Safety was assessed by use of ex-vivo growth tests of Plasmodium falciparum in erythrocytes and three species of sentinel bacteria in plasma samples from participants. This trial is registered with the ISRCTN registry, ISRCTN07210906., Findings: Between April 23, 2014, and Aug 7, 2015, we prescreened 783 children, of whom 407 were enrolled into the study: 135 were randomly assigned to the control group, 136 to the 12 mg screen-and-treat group, and 136 to the 6 mg screen-and-treat group. 345 (85%) children were included in the per-protocol population: 115 in the control group, 116 in the 12 mg screen-and-treat group, and 114 in the 6 mg screen-and-treat group. Directly observed adherence was high across all groups (control group 94·8%, 12 mg screen-and-treat group 95·3%, and 6 mg screen-and-treat group 95·0%). 82 days of iron supplementation increased mean haemoglobin concentration by 7·7 g/L (95% CI 3·2 to 12·2) in the control group. Both screen-and-treat regimens were significantly less efficacious at improving haemoglobin (-5·6 g/L [98·3% CI -9·9 to -1·3] in the 12 mg screen-and-treat group and -7·8 g/L [98·3% CI -12·2 to -3·5] in the 6 mg screen-and-treat group) and neither regimen met the preset non-inferiority margin of -5 g/L. The 12 mg screen-and-treat regimen reduced iron dosage to 6·1 mg per day and the 6 mg screen-and-treat regimen reduced dosage to 3·0 mg per day. 580 adverse events were observed in 316 participants, of which eight were serious adverse events requiring hospitalisation mainly due to diarrhoeal disease (one [1%] participant in the control group, three [2%] in the 12 mg screen-and-treat group, and four [3%] in the 6 mg screen-and-treat group). The most common causes of non-serious adverse events (n=572) were diarrhoea (145 events [25%]), upper respiratory tract infections (194 [34%]), lower respiratory tract infections (62 [11%]), and skin infections (122 [21%]). No adverse events were deemed to be related to the study interventions., Interpretation: The hepcidin-guided screen-and-treat strategy to target iron administration succeeded in reducing overall iron dosage, but was considerably less efficacious at increasing haemoglobin and combating iron deficiency and anaemia than was WHO's standard of care, and showed no differences in morbidity or safety outcomes., Funding: Bill & Melinda Gates Foundation and UK Medical Research Council., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Artemisinin combination therapies are the current frontline therapy for falciparum malaria. Artemisinin is activated by heme iron, and the consequent production of reactive oxygen species and carbon-centered radicals results in rapid parasite clearance. Red blood cells (RBCs) from anemic iron-deficient individuals have decreased levels of heme, and such deficiencies are highly prevalent among children and pregnant women in malaria-endemic countries. We, therefore, investigated the possibility that host anemia could impair artemisinin activity and alter the drug sensitivity of artemisinin-resistant strains of Plasmodium falciparum . We collected RBCs from anemic ( n = 35) and nonanemic ( n = 11) Gambian children between the ages of 2 and 24 months. Parasites grown in RBCs from both groups were assessed in vitro using the ring-stage survival assay with artemisinin-resistant and artemisinin-sensitive strains of P. falciparum . No differences were found in artemisinin sensitivity ( P > 0.05), and there was no correlation between artemisinin activity and host hemoglobin levels. Standard antimalarial drug activity assays for representatives of the major classes of antimalarial drugs found no differences in the IC 50 values against P. falciparum between anemic and nonanemic RBCs. We conclude that host anemia does not influence artemisinin activity.

Background: WHO recommends daily iron supplementation for pregnant women, but adherence is poor because of side-effects, effectiveness is low, and there are concerns about possible harm. The iron-regulatory hormone hepcidin can signal when an individual is ready-and-safe to receive iron. We tested whether a hepcidin-guided screen-and-treat approach to combat iron-deficiency anaemia could achieve equivalent efficacy to universal administration, but with lower exposure to iron., Methods: We did a three-arm, randomised, double-blind, non-inferiority trial in 19 rural communities in the Jarra West and Kiang East districts of The Gambia. Eligible participants were pregnant women aged 18-45 years at between 14 weeks and 22 weeks of gestation. We randomly allocated women to either WHO's recommended regimen (ie, a daily UN University, UNICEF, and WHO international multiple-micronutrient preparation [UNIMMAP] containing 60 mg iron), a 60 mg screen-and-treat approach (ie, daily UNIMMAP containing 60 mg iron for 7 days if weekly hepcidin was <2·5 μg/L or UNIMMAP without iron if hepcidin was ≥2·5 μg/L), or a 30 mg screen-and-treat approach (ie, daily UNIMMAP containing 30 mg iron for 7 days if weekly hepcidin was <2·5 μg/L or UNIMMAP without iron if hepcidin was ≥2·5 μg/L). We used a block design stratified by amount of haemoglobin at enrolment (above and below the median amount of haemoglobin on every enrolment day) and stage of gestation (14-18 weeks vs 19-22 weeks). Participants and investigators were unaware of the random allocation. The primary outcome was the amount of haemoglobin at day 84 and was measured as the difference in haemoglobin in each screen-and-treat group compared with WHO's recommended regimen; the non-inferiority margin was set at -5·0 g/L. The primary outcome was assessed in the per-protocol population, which comprised all women who completed the study. This trial is registered with the ISRCTN registry, number ISRCTN21955180., Findings: Between June 16, 2014, and March 3, 2016, 498 participants were randomised, of whom 167 were allocated to WHO's recommended regimen, 166 were allocated to the 60 mg per day screen-and-treat approach, and 165 were allocated to the 30 mg per day screen-and-treat approach. 78 participants were withdrawn or lost to follow-up during the study; thus, the per-protocol population comprised 140 women assigned to WHO's recommended regimen, 133 allocated to the 60 mg screen-and-treat approach, and 147 allocated to the 30 mg screen-and-treat approach. The screen-and-treat approaches did not exceed the non-inferiority margin. Compared with WHO's recommended regimen, the difference in the amount of haemoglobin at day 84 was -2·2 g/L (95% CI -4·6 to 0·1) with the 60 mg screen-and-treat approach and -2·7 g/L (-5·0 to -0·5) with the 30 mg screen-and-treat approach. Adherence, reported side-effects, and adverse events were similar between the three groups. The most frequent side-effect was stomachache, which was similar in the 60 mg screen-and-treat group (82 cases per 1906 person-weeks) and with WHO's recommended regimen (81 cases per 1974 person-weeks; effect 1·0, 95% CI 0·7 to 1·6); in the 30 mg screen-and-treat group the frequency of stomachache was slightly lower than with WHO's recommended regimen (58 cases per 2009 person-weeks; effect 0·7, 95% CI 0·5 to 1·1). No participants died during the study., Interpretation: The hepcidin-guided screen-and-treat approaches had no advantages over WHO's recommended regimen in terms of adherence, side-effects, or safety outcomes. Our results suggest that the current WHO policy for iron administration to pregnant women should remain unchanged while more effective approaches continue to be sought., Funding: Bill & Melinda Gates Foundation and the UK Medical Research Council., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Iron deficiency prevalence rates frequently exceed 50 % in young children in low-income countries. The World Health Organization (WHO) recommended universal supplementation of young children where anaemia rates are >40 %. However, large randomized trials have revealed that provision of iron to young children caused serious adverse effects because iron powerfully promotes microbial growth. Hepcidin - the master regulator of iron metabolism that integrates signals of infection and iron deficiency - offers the possibility of new solutions to diagnose and combat global iron deficiency. We aim to evaluate a hepcidin-screening-based iron supplementation intervention using hepcidin cut-offs designed to indicate that an individual requires iron, is safe to receive it and will absorb it., Methods: The study is a proof-of-concept, three-arm, double blind, randomised controlled, prospective, parallel-group non-inferiority trial. Children will be randomised to receive, for a duration of 12 weeks, one of three multiple micronutrient powders (MNP) containing: A) 12 mg iron daily; B) 12 mg or 0 mg iron daily based on a weekly hepcidin screening indicating if iron can be given for the next seven days or not; C) 6 mg or 0 mg iron daily based on a weekly hepcidin screening indicating if iron can be given for the next seven days or not. The inclusion criteria are age 6-23 months, haemoglobin (Hb) concentration between 7 and 11 g/dL, z-scores for Height-for-Age, Weight-for-Age and Weight-for-Height > -3 SD and free of malaria. Hb concentration at 12 weeks will be used to test whether the screen-and-treat approaches are non-inferior to universal supplementation. Safety will be assessed using caregiver reports of infections, in vitro bacterial and P. falciparum growth assays and by determining the changes in the gut microbiota during the study period., Discussion: A screen-and-treat approach using hepcidin has the potential to make iron administration safer in areas with widespread infections. If this proof-of-concept study shows promising results the development of a point-of-care diagnostic test will be the next step., Trial Registration: ISRCTN07210906 , 07/16/2014.

Iron deficiency and malaria have similar global distributions, and frequently co-exist in pregnant women and young children. Where both conditions are prevalent, iron supplementation is complicated by observations that iron deficiency anaemia protects against falciparum malaria, and that iron supplements increase susceptibility to clinically significant malaria, but the mechanisms remain obscure. Here, using an in vitro parasite culture system with erythrocytes from iron-deficient and replete human donors, we demonstrate that Plasmodium falciparum infects iron-deficient erythrocytes less efficiently. In addition, owing to merozoite preference for young erythrocytes, iron supplementation of iron-deficient individuals reverses the protective effects of iron deficiency. Our results provide experimental validation of field observations reporting protective effects of iron deficiency and harmful effects of iron administration on human malaria susceptibility. Because recovery from anaemia requires transient reticulocytosis, our findings imply that in malarious regions iron supplementation should be accompanied by effective measures to prevent falciparum malaria.