Efficacy and safety of hepcidin-based screen-and-treat approaches using two different doses versus a standard universal approach of iron supplementation in young children in rural Gambia: a double-blind randomised controlled trial

Abstract

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 Heightfor-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.

Anemia Offers Stronger Protection Than Sickle Cell Trait Against the Erythrocytic Stage of Falciparum Malaria and This Protection Is Reversed by Iron Supplementation

“…The blood samples for the parasite assays were taken from children enrolled in the control arm of a randomized trial testing the efficacy and safety of a hepcidin-guided screen-and-treat strategy for combatting anemia (see published protocol for full details) (Wegmüller et al, 2016). (Note we also assayed RBCs from children in the other two arms of this trial, but only for observation at baseline, pre-randomization/pre-intervention.)…”

The Iron Metabolism in Children Is Normal Also at Infectious Diseases

“…Cледует признать, что в исследовании Wegmüller и соавт. (2016) гепсидин фигурировал среди ис-пользуемых маркеров метаболизма Fe, но взаимосвязь ЖДА с инфекционно-воспалительными заболеваниями при этом специально не изучалась [54].…”

“…(2016) исследовали содержание гепсидина в крови в качестве основного критерия адекват-ности дотации Fe детям раннего возраста в различных ре-жимах дозирования [54]. Авторы пришли к выводу, что скрининг-исследования с определением гепсидина потен-циально позволяют сделать назначение препаратов Fe бо-лее безопасным в регионах, где распространенность ин-фекционных заболеваний считается высокой [54].…”

Clinical Implications of New Insights into Hepcidin-Mediated Regulation of Iron Absorption and Metabolism

“…Using longitudinal hepcidin measurements (weekly for 12 weeks) in over 400 participants from the children's trial [35] we have shown that each child maintains a remarkably consistent level of hepcidin over the 3 months of study (albeit gradually rising in response to the iron supplementation). Fifty percent of the children consistently maintain their hepcidin above the 5.5 ng/mL, indicating that they are blocking iron absorption (Prentice et al, manuscript in preparation).…”

“…In children the defined threshold (5.5 ng/mL, using the Bachem ELISA) also distinguished iron absorbers from nonabsorbers [33] . With support from the Bill & Melinda Gates Foundation, we have recently completed 2 randomized controlled trials in Gambian pregnant women and children under the umbrella of the HIGH Consortium (Hepcidin and Iron in Global Health) [35,36] . These trials are testing whether it would be possible to develop a point-of-care diagnostic for hepcidin-guided iron administration on the principle that a hepcidin level below 5.5 ng/mL in children (or 2.5 ng/mL in pregnant women [34] ) would signal that the subject was "safe and ready to receive iron."…”