Cairns, M

Walker, PG

Evidence-Based Medicine

English

PubMed

Spiral - Imperial College Digital Repository

Randomised controlled trialMonthly malaria chemopreventionshows potential in an area of veryhigh, perennial malaria transmission10.1136/ebmed-2015-110173Matthew Cairns,1 Patrick G T Walker21MRC Tropical Epidemiology Group, London School of Hygiene andTropical Medicine, London, UK; 2MRC Centre for Outbreak Analysis &Modelling, Department of Infectious Disease Epidemiology, ImperialCollege London, London, UKCorrespondence to: Dr Matthew Cairns, MRC Tropical EpidemiologyGroup, London School of Hygiene and Tropical Medicine, London WC1E7HT, UK; matthew.cairns@lshtm.ac.ukCommentary on: Bigira V, Kapisi J, Clark TD, et al. Protectiveefficacy and safety of three antimalarial regimens for the preven-tion of malaria in young Ugandan children: a randomizedcontrolled trial. PLoS Med 2014;11:e1001689.ContextNew approaches are needed for malaria control where the burden hasremained high despite scaled up coverage of long-lasting insecticide-treatednets (LLIN) and prompt access to artemisinin-based combination therapies(ACTs).1 Bigira and colleagues evaluated three regimens for chemopreventionof malaria in young children in eastern Uganda, in an area of very high year-round malaria transmission and high resistance to antifolate drugs, includingsulfadoxine-pyrimethamine (SP) and sulfamethoxazole.MethodsChildren between 6 and 24 months of age were randomised to receivedaily trimethoprim-sulfamethoxazole (TS), monthly SP, monthlydihydroartemisinin-piperaquine (DP) or no intervention. All study partici-pants were given LLINs. Follow-up continued to 36 months of age. Theprimary outcome was incidence of uncomplicated malaria, treated withartemether-lumefantrine (AL).FindingsBetween 6 and 24 months of age, children without chemoprevention experi-enced almost seven malaria episodes per person-year, despite apparentlyhigh LLIN use. Monthly SP provided no protection against clinical malariaand possibly increased incidence of moderate–severe anaemia: protectiveefficacy (PE) −70% (95% CI −184% to −2%). Daily TS reduced clinicalmalaria by 28% (95% CI 7% to 44%) despite antifolate resistance. MonthlyDP reduced clinical malaria by 58% (95% CI 45% to 67%) and possibly mod-erate–severe anaemia: PE 47% (95% CI 1% to 72%). Self-reported adherencewas high but the reliability of this was unclear. There were no significant dif-ferences in incidence of complicated malaria or hospitalisation, althoughnumbers were low. Between 24 and 36 months of age, children experiencedclose to 11 episodes per person-year, regardless of prior intervention group.CommentaryA 58% reduction in malaria incidence in an area of such high burdenreflects an important potential public health impact. However, efficacy islower than expected given the regularity of dosing and the high efficacy ofDP. Monthly DP given as directly observed therapy reduced clinicalmalaria by 96% among Ugandan school children.2 This suggests adher-ence to monthly DP was not optimal under trial conditions, which is aconcern. Lack of reliable information on adherence may also underminethe finding that piperaquine did not affect the QTc interval, although otherstudies have partly allayed these concerns.3 ACTs such as DP are not idealfor chemoprevention because the artemisinin component is eliminatedrapidly, leaving the partner drug as monotherapy soon after administra-tion. New regimens specifically for chemoprevention are needed.Chemoprevention requires carefully supervised delivery. This isbecause suboptimal adherence could accelerate development of resistanceto the drugs used, if either incomplete courses are taken, or drugs are notreadministered each month and concentrations fall below subtherapeuticlevels. However, in areas of very high incidence, drug pressure on ACTswill be large even in the absence of chemoprevention: after the interven-tion period, children received 11 courses of AL per person-year.Well-administered chemoprevention may avoid these issues and helpprolong the life of ACTs used for treatment. Community-based healthworkers may be one means to improve adherence, increase coverageoutside the context of a trial, and may be more cost-effective per doseadministered, as for monthly seasonal malaria chemoprevention.4Implications for practiceChemoprevention is currently recommended for children under 5 yearsold in areas of high and seasonal malaria transmission and in infants inareas with high malaria transmission and low SP resistance.5 6 Adaptingchemoprevention to areas with high, year-round transmission and/orhigh SP resistance could have a substantial impact. Additional researchin this area is crucial to inform future changes in practice. Further studiesare needed to evaluate adherence and delivery, the safety and pharmaco-kinetics of repeated treatments and selection for resistant parasites.Despite exceptionally high transmission, the burden of clinical andcomplicated malaria was higher in the postintervention period in thisstudy. Providing chemoprevention to a wider age range could potentiallyincrease impact further. If monthly chemoprevention is given for longer,there may be more scope for rebound morbidity later in life, concernsalso faced by preventive approaches including malaria vaccines.While it is unclear how widely year-round chemoprevention will beappropriate, it will be most cost-effective in areas with very high incidence:control policy needs to be tailored to local epidemiology. Focusing on fewerareas may also limit the impact of chemoprevention on resistance. This willrequire policymakers to have accurate and regularly updated information onmalaria epidemiology and drug resistance markers.Contributors MC wrote the first draft of the commentary. PGTW revisedthe draft. Both the authors approved the final version.Competing interests None declared.Provenance and peer review Commissioned; internally peer reviewed.Open Access This is an Open Access article distributed in accordancewith the Creative Commons Attribution Non Commercial (CC BY-NC 4.0)license, which permits others to distribute, remix, adapt, build upon thiswork non-commercially, and license their derivative works on differentterms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/References1. World Health Organisation. World Malaria Report 2014. Geneva: World HealthOrganisation, 2014.2. Nankabirwa JI, Wandera B, Amuge P, et al. Impact of intermittent preventive treatmentwith dihydroartemisinin-piperaquine on malaria in Ugandan schoolchildren: arandomized, placebo-controlled trial. Clin Infect Dis 2014;58:1404–12.3. Zani B, Gathu M, Donegan S, et al. Dihydroartemisinin-piperaquine for treatinguncomplicated Plasmodium falciparum malaria. Cochrane Database Syst Rev 2014;1:CD010927.4. Bojang KA, Akor F, Conteh L, et al. Two strategies for the delivery of IPTc in an areaof seasonal malaria transmission in the Gambia: a randomised controlled trial.PLoS Med 2011;8:e1000409.5. World Health Organisation. WHO policy recommendation: Seasonal malariachemoprevention (SMC) for Plasmodium falciparum malaria control in highlyseasonal transmission areas of the Sahel sub-region in Africa. 2012.6. World Health Organisation. WHO policy recommendation on intermittentpreventive treatment during infancy with sulphadoxine-pyrimethamine (IPTi-SP) forPlasmodium falciparum malaria control in Africa. 2010.110 Evid Based Med June 2015 | volume 20 | number 3 |Therapeutics/Prevention

Monthly malaria chemoprevention shows potential in an area of very high, perennial malaria transmission

Cairns, Matthew

Walker, Patrick GT

LSHTM Research Online

Monthly malaria chemoprevention shows potential in an area of very high, perennial malaria transmission.

Matthew Cairns

Patrick G T Walker

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http://researchonline.lshtm.ac.uk/2160149/1/110.full%20%281%29.pdf

Monthly malaria chemoprevention shows potential in an area of very high, perennial malaria transmission

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