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      The challenges of changing national malaria drug policy to artemisinin-based combinations in Kenya

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          Abstract

          Backgound

          Sulphadoxine/sulphalene-pyrimethamine (SP) was adopted in Kenya as first line therapeutic for uncomplicated malaria in 1998. By the second half of 2003, there was convincing evidence that SP was failing and had to be replaced. Despite several descriptive investigations of policy change and implementation when countries moved from chloroquine to SP, the different constraints of moving to artemisinin-based combination therapy (ACT) in Africa are less well documented.

          Methods

          A narrative description of the process of anti-malarial drug policy change, financing and implementation in Kenya is assembled from discussions with stakeholders, reports, newspaper articles, minutes of meetings and email correspondence between actors in the policy change process. The narrative has been structured to capture the timing of events, the difficulties and hurdles faced and the resolutions reached to the final implementation of a new treatment policy.

          Results

          Following a recognition that SP was failing there was a rapid technical appraisal of available data and replacement options resulting in a decision to adopt artemether-lumefantrine (AL) as the recommended first-line therapy in Kenya, announced in April 2004. Funding requirements were approved by the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) and over 60 million US$ were agreed in principle in July 2004 to procure AL and implement the policy change. AL arrived in Kenya in May 2006, distribution to health facilities began in July 2006 coincidental with cascade in-service training in the revised national guidelines. Both training and drug distribution were almost complete by the end of 2006. The article examines why it took over 32 months from announcing a drug policy change to completing early implementation. Reasons included: lack of clarity on sustainable financing of an expensive therapeutic for a common disease, a delay in release of funding, a lack of comparative efficacy data between AL and amodiaquine-based alternatives, a poor dialogue with pharmaceutical companies with a national interest in antimalarial drug supply versus the single sourcing of AL and complex drug ordering, tendering and procurement procedures.

          Conclusion

          Decisions to abandon failing monotherapy in favour of ACT for the treatment of malaria can be achieved relatively quickly. Future policy changes in Africa should be carefully prepared for a myriad of financial, political and legislative issues that might limit the rapid translation of drug policy change into action.

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          Most cited references20

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          Antimalarial drug resistance and combination chemotherapy.

          Antimarial drug resistance develops when spontaneously occurring parasite mutants with reduced susceptibility are selected, and are then transmitted. Drugs for which a single point mutation confers a marked reduction in susceptibility are particularly vulnerable. Low clearance and a shallow concentration-effect relationship increase the chance of selection. Use of combinations of antimalarials that do not share the same resistance mechanisms will reduce the chance of selection because the chance of a resistant mutant surviving is the product of the per parasite mutation rates for the individual drugs, multiplied by the number of parasites in an infection that are exposed to the drugs. Artemisinin derivatives are particularly effective combination partners because (i) they are very active antimalarials, producing up to 10,000-fold reductions in parasite biomass per asexual cycle; (ii) they reduce malaria transmissibility; and (iii) no resistance to these drugs has been reported yet. There are good arguments for no longer using antimalarial drugs alone in treatment, and instead always using a combination with artemisinin or one of its derivatives.
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            Amodiaquine resistant Plasmodium falciparum malaria in vivo is associated with selection of pfcrt 76T and pfmdr1 86Y.

            The choice of partner drug is critical for artemisinine-based combination therapy (ACT) to remain effective and amodiaquine (AQ) is one important candidate to evaluate. We treated 81 children <5 years with uncomplicated Plasmodium falciparum malaria with AQ alone and related the treatment outcome to the possible selection of pfcrt 76T, 152T, 163S, 326S, pfmdr1 86Y and pfmrp 191H, 437S in recurrent infections (recrudescenses and re-infections) and to the blood concentration of desethylamodiaquine (DEAQ). During 21 days follow-up 28 children had a recurrent infection (9 recrudescenses, 13 re-infections and 6 mixed). Neither genotyping of the polymorphisms before treatment nor DEAQ blood concentrations could predict treatment outcome. pfcrt 76T was however significantly selected for in recurrent infections (p=0.020). pfmdr1 86Y was also selected for, but only in recrudescent infections (p=0.048). The study showed high prevalence of AQ resistant parasites in vivo, which appeared to be associated to pfcrt 76T and pfmdr1 86Y.
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              Efficacy and safety of artemether-lumefantrine (Coartem) tablets (six-dose regimen) in African infants and children with acute, uncomplicated falciparum malaria.

              Approximately one million children die from malaria each year. A recently approved artemisinin-based tablet, Coartem (co-artemether), comprising artemether 120 mg plus lumefantrine 20 mg, given in four doses, provides effective antimalarial treatment for children in many sub-Saharan countries. However, this regimen is considered insufficient for non-immune infants and in areas where multidrug-resistant Plasmodium falciparum predominates. This open-label study assessed the efficacy and safety of co-artemether administered to 310 African children weighing 5-25 kg, with acute, uncomplicated falciparum malaria. Six doses of co-artemether were given over 3 days, with follow-up at 7, 14 and 28 days. Treatment rapidly cleared parasitemia and fever. The overall 28-day cure rate was 86.5%, and 93.9% when corrected by PCR for reinfection. Cure rates at 7 and 14 days exceeded 97.0% (uncorrected) and, on day 28, were similar in infants (5-<10 kg) previously exposed to malaria infection (partially immune: 88.6% uncorrected; 93.3% corrected), and in those who were non-immune (82.5% uncorrected; 95.0% corrected). Adverse events were mostly mild. There was no electrocardiographic evidence of cardiotoxicity. The co-artemether six-dose regimen, treating acute uncomplicated falciparum malaria in African children, achieved rapid parasite clearance and a high cure rate. Treatment was generally safe and well tolerated.
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                Author and article information

                Journal
                Malar J
                Malaria Journal
                BioMed Central (London )
                1475-2875
                2007
                29 May 2007
                : 6
                : 72
                Affiliations
                [1 ]Malaria Public Health & Epidemiology Group, Centre for Geographic Medicine Research-Coast, Kenya Medical Research Institute/Wellcome Trust Research Programme, 00100 GPO, P.O. Box 43640, Nairobi, Kenya
                [2 ]Centre for Tropical Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK
                [3 ]WHO-Kenya, P.O. Box 45335-00100, Nairobi, Kenya
                [4 ]Division of Malaria Control, Ministry of Health, 00100 GPO, P.O Box 20750, Nairobi, Kenya
                Article
                1475-2875-6-72
                10.1186/1475-2875-6-72
                1892027
                17535417
                fba61491-cd83-4a75-9036-d8f83b83589e
                Copyright © 2007 Amin 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
                : 30 January 2007
                : 29 May 2007
                Categories
                Research

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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