Randomised controlled trial of weekly chloroquine to re-establish normal erythron iron flux and haemoglobin recovery in postmalarial anaemia

Abstract

ObjectiveTo determine if low-dose weekly chloroquine (CQ) therapy improves recovery from malaria-associated anaemia.DesignProof of concept randomised clinical trial.SettingWest Kiang District, Lower River Region, The Gambia.ParticipantsChildren resident in participating communities, aged 12–72 months, with uncomplicated malaria identified using active case detection over two consecutive malaria transmission seasons.InterventionsIn 2007, eligible children were randomised to chloroquine-sulfadoxine/pyrimethamine (CQ-SP) or co-artemether (ACT) antimalarial therapy, and after parasite clearance on day 3 were subsequently re-randomised (double-blind) to weekly low-dose CQ (5 mg/kg) or placebo. In 2008, all eligible children were treated with ACT and subsequently randomised to CQ or placebo.Outcome measuresThe primary outcome was a change in haemoglobin from baseline (day 3 of antimalarial treatment) to day 90 in the CQ and placebo treatment arms. Secondary outcomes were changes in urinary neopterin as a marker of macrophage activation, markers of erythropoietic response and prevalence of submicroscopic parasitaemia. Change in haemoglobin in the placebo arm by initial antimalarial treatment was also assessed.ResultsIn 2007, 101 children with uncomplicated malaria were randomised to antimalarial treatment with CQ-SP or ACT and 65 were subsequently randomised to weekly CQ or placebo. In 2008, all children received ACT antimalarial treatment and 31 were subsequently randomised to receive weekly CQ or placebo. Follow-up to day 90 was 96%. There was no effect of weekly CQ vs placebo on change in haemoglobin at day 90 (CQ+10.04 g/L (95% CI 6.66 to 13.42) vs placebo +7.61 g/L (95% CI 2.88 to 12.35)). There was no effect on the secondary outcomes assessed, or effect of initial antimalarial therapy on haemoglobin recovery. Higher day 90 haemoglobin correlated independently with older age, not being stunted, higher haemoglobin at day 0 and adequate iron status at day 3.ConclusionsWeekly low-dose CQ after effective antimalarial treatment is not effective in improving recovery from postmalarial anaemia.Trial registrationThe clinical trial registration number is NCT00473837 (ClinicalTrials.gov).

Intermittent preventive antimalarial treatment for children with anaemia

“…All included trials were conducted in malaria‐endemic areas. Three trials were conducted in low endemicity areas: two in The Gambia ( Bojang 2010 GMB ; Cox 2013 GMB ) and one in eastern Kenya ( Verhoef 2002 KEN ). Three trials were conducted in high endemicity areas: one in western Kenya ( Desai 2003 KEN ), one in southern Malawi ( Phiri 2012 MWI ) and one in western Tanzania ( Tomashek 2001 TNZ ).…”

“…The remaining trial enrolled children with Hb levels less than 7 g/dL ( Bojang 2010 GMB ). In one trial, children had severe malaria ( Phiri 2012 MWI ), two trials included children with uncomplicated malaria ( Cox 2013 GMB ; Desai 2003 KEN ), for two trials malaria was not part of the inclusion criteria ( Bojang 2010 GMB ; Tomashek 2001 TNZ ) and one trial excluded children with clinical malaria ( Verhoef 2002 KEN ). Three trials ( Bojang 2010 GMB ; Phiri 2012 MWI ; Tomashek 2001 TNZ ) recruited children that attended outpatient clinics or were admitted to hospital, while three trials recruited children from the community ( Cox 2013 GMB ; Desai 2003 KEN ; Verhoef 2002 KEN ).…”

“…In two of these trials, all children were given a single dose of SP ( Desai 2003 KEN ; Tomashek 2001 TNZ ). In one trial ( Cox 2013 GMB ) children received either CQ and SP or artemether‐lumefantrine (AL) before randomization to intervention and placebo groups. Phiri 2012 MWI treated all children with intravenous quinine and blood transfusion while in hospital and AL at discharge.…”

“…This finding was supported by another study in the same country which found less genetic amplification of P. falciparum to Coartem ( Haildar 2009 ). CQ syrup (5 mg/kg) given as a weekly dose (three day course) for 12 weeks ( Cox 2013 GMB ). CQ sensitivity studies conducted in the early 2000s in The Gambia and Mali revealed low efficacy of CQ ( Tekete 2009 ) with evidence of increased resistance of CQ to P. falciparum ( Ord 2007 ).…”

“…CQ syrup (5 mg/kg) given as a weekly dose (three day course) for 12 weeks ( Cox 2013 GMB ). CQ sensitivity studies conducted in the early 2000s in The Gambia and Mali revealed low efficacy of CQ ( Tekete 2009 ) with evidence of increased resistance of CQ to P. falciparum ( Ord 2007 ).…”