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      Feasibility and acceptability of artemisinin-based combination therapy for the home management of malaria in four African sites

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          Abstract

          Background

          The Home Management of Malaria (HMM) strategy was developed using chloroquine, a now obsolete drug, which has been replaced by artemisinin-based combination therapy (ACT) in health facility settings. Incorporation of ACT in HMM would greatly expand access to effective antimalarial therapy by the populations living in underserved areas in malaria endemic countries. The feasibility and acceptability of incorporating ACT in HMM needs to be evaluated.

          Methods

          A multi-country study was performed in four district-size sites in Ghana (two sites), Nigeria and Uganda, with populations ranging between 38,000 and 60,000. Community medicine distributors (CMDs) were trained in each village to dispense pre-packaged ACT to febrile children aged 6–59 months, after exclusion of danger signs. A community mobilization campaign accompanied the programme. Artesunate-amodiaquine (AA) was used in Ghana and artemether-lumefantrine (AL) in Nigeria and Uganda. Harmonized qualitative and quantitative data collection methods were used to evaluate CMD performance, caregiver adherence and treatment coverage of febrile children with ACTs obtained from CMDs.

          Results

          Some 20,000 fever episodes in young children were treated with ACT by CMDs across the four study sites. Cross-sectional surveys identified 2,190 children with fever in the two preceding weeks, of whom 1,289 (59%) were reported to have received ACT from a CMD. Coverage varied from 52% in Nigeria to 75% in Ho District, Ghana. Coverage rates did not appear to vary greatly with the age of the child or with the educational level of the caregiver. A very high proportion of children were reported to have received the first dose on the day of onset or the next day in all four sites (range 86–97%, average 90%). The proportion of children correctly treated in terms of dose and duration was also high (range 74–97%, average 85%). Overall, the proportion of febrile children who received prompt treatment and the correct dose for the assigned duration of treatment ranged from 71% to 87% (average 77%). Almost all caregivers perceived ACT to be effective, and no severe adverse events were reported.

          Conclusion

          ACTs can be successfully integrated into the HMM strategy.

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          Most cited references22

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          Teaching mothers to provide home treatment of malaria in Tigray, Ethiopia: a randomised trial.

          No satisfactory strategy for reducing high child mortality from malaria has yet been established in tropical Africa. We compared the effect on under-5 mortality of teaching mothers to promptly provide antimalarials to their sick children at home, with the present community health worker approach. Of 37 tabias (cluster of villages) in two districts with hyperendemic to holoendemic malaria, tabias reported to have the highest malaria morbidity were selected. A census was done which included a maternity history to determine under-5 mortality. Tabias (population 70,506) were paired according to under-5 mortality rates. One tabia from each pair was allocated by random number to an intervention group and the other was allocated to the control group. In the intervention tabias, mother coordinators were trained to teach other local mothers to recognise symptoms of malaria in their children and to promptly give chloroquine. In both intervention and control tabias, all births and deaths of under-5s were recorded monthly. From January to December 1997, 190 of 6383 (29.8 per 1000) children under-5 died in the intervention tabias compared with 366 of 7294 (50.2 per 1000) in the control tabias. Under-5 mortality was reduced by 40% in the intervention localities (95% CI from 29.2-50.6; paired t test, p<0.003). For every third child who died, a structured verbal autopsy was undertaken to ascribe cause of mortality as consistent with malaria or possible malaria, or not consistent with malaria. Of the 190 verbal autopsies, 13 (19%) of 70 in the intervention tabias were consistent with possible malaria compared with 68 (57%) of 120 in the control tabias. A major reduction in under-5 mortality can be achieved in holoendemic malaria areas through training local mother coordinators to teach mothers to give under-5 children antimalarial drugs.
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            Amodiaquine alone, amodiaquine+sulfadoxine-pyrimethamine, amodiaquine+artesunate, and artemether-lumefantrine for outpatient treatment of malaria in Tanzanian children: a four-arm randomised effectiveness trial.

            Many countries in Africa are considering a change to combination treatment for falciparum malaria because of the increase in drug resistance. However, there are few effectiveness data for these combinations. Our aim was to study the effectiveness of three drug combinations that have proven efficacious in east Africa compared with amodiaquine monotherapy. We undertook a randomised trial of antimalarial drug combinations for children (aged 4-59 months) with uncomplicated malaria in Muheza, Tanzania, an area with a high prevalence of resistance to sulfadoxine-pyrimethamine and chloroquine. Children were randomly allocated 3 days of amodiaquine (n=270), amodiaquine +sulfadoxine-pyrimethamine (n=507), or amodiaquine+artesunate (n=515), or a 3-day six-dose regimen of artemether-lumefantrine (n=519). Drugs were taken orally, at home, unobserved by medical staff. The primary endpoint was parasitological failure by day 14 assessed blind to treatment allocation. Secondary endpoints included day 28 follow-up and gametocyte carriage. Analysis was by intention to treat. Of 3158 children screened, 1811 were randomly assigned treatment and 1717 (95%) reached the 14-day follow-up. The amodiaquine group was stopped early by the data and safety monitoring board. By day 14, the parasitological failure rates were 103 of 248 (42%) for amodiaquine, 97 of 476 (20%) for amodiaquine+sulfadoxine-pyrimethamine, 54 of 491 (11%) for amodiaquine+artesunate, and seven of 502 (1%) for artemether-lumefantrine. By day 28, the parasitological failure rates were 182 of 239 (76%), 282 of 476 (61%), 193 of 472 (40%), and 103 of 485 (21%), respectively. The difference between individual treatment groups and the next best treatment combination was significant (p<0.001) in every case. Recrudescence rates by day 28, after correction by genotyping, were 48.4%, 34.5%, 11.2%, and 2.8%, respectively. The study shows how few the options are for treating malaria where there is already a high level of resistance to sulfadoxine-pyrimethamine and amodiaquine. The WHO-packaged six-dose regimen of artemether-lumefantrine is effective taken unsupervised, although cost is a major limitation.
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              Supervised versus unsupervised intake of six-dose artemether-lumefantrine for treatment of acute, uncomplicated Plasmodium falciparum malaria in Mbarara, Uganda: a randomised trial.

              The six-dose regimen of artemether-lumefantrine is effective and is among combination therapies prioritised to replace antimalarials that no longer work in Africa. However, its effectiveness has not been assessed in the field, and could be compromised by poor adherence, incorrect timing of doses, and insufficient intake of fatty foods with every dose. Our aim, therefore, was to assess the effectiveness of artemether-lumefantrine prescribed under routine outpatient conditions, compared with its efficacy when given under supervision to inpatients with acute uncomplicated falciparum malaria. We did a randomised trial to compare the efficacy, safety, and pharmacokinetics of artemether-lumefantrine when given in a supervised (all doses observed with fatty-food intake; n=313) or unsupervised (first dose supervised followed by outpatient treatment with nutritional advice; n=644) setting to patients of all ages (weight >10 kg) with acute, uncomplicated falciparum malaria in Mbarara, Uganda. Our primary endpoint was 28 day, PCR-adjusted, parasitological cure rate. Analysis was by intention to treat and evaluability analysis. 38 patients were lost to follow-up and one withdrew consent. Day-28 cure rates were 97.7% (296 of 303) and 98.0% (603 of 615) in the supervised and unsupervised groups, respectively. We recorded 15 non-severe, drug-related adverse events, all of which resolved. Artemether-lumefantrine has a high cure rate irrespective of whether given under supervision with food or under conditions of routine clinic practice. If used as first-line treatment, artemether-lumefantrine could make a substantial contribution to malaria control in Africa, though cost is an issue.
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                Author and article information

                Journal
                Malar J
                Malaria Journal
                BioMed Central
                1475-2875
                2008
                8 January 2008
                : 7
                : 6
                Affiliations
                [1 ]Malaria Research Laboratories, Institute of Medical Research and Training, College of Medicine, University of Ibadan, Nigeria
                [2 ]Department of Community Health, School of Medical Sciences, KNUST, Kumasi, Ghana
                [3 ]Health Research Unit, Ghana Health Service, Accra, Ghana
                [4 ]Department of Sociology, Makerere University, Kampala, Uganda
                [5 ]Institute for Development Studies, College of Humanities and Social Studies, University of Nairobi, Nairobi, Kenya
                [6 ]Infectious Diseases Epidemiology Unit, London School of Hygiene and Tropical Medicine, London, UK
                [7 ]Implementation Research & Methods Unit, UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), Geneva, Switzerland
                Article
                1475-2875-7-6
                10.1186/1475-2875-7-6
                2254635
                18182114
                51b55bea-3465-4d2d-b0e5-6d1fac822080
                Copyright © 2008 Ajayi et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 22 October 2007
                : 8 January 2008
                Categories
                Research

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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