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selected clusters were invited in 2005 to receive IPTi. Between 47 and 76% of the eligible infants in each of the 12 selected clusters received IPT-SP. In the following year, 2006, the effect of IPTi on malaria and anaemia was assessed in a representative sample of 600 infants. An intention to treat analysis, which includes all eligible infants did not show a statistically significant benefit of IPTi-SP. Parasitaemia prevalence was 31% in the intervention and 38% in the comparison areas (p=0.06). In a ‘per protocol’ analysis, which only included infants who actually received IPTi there was a significant benefit: parasite prevalence was 22%, 19 percentage points lower than comparison children in the control group (p=0.01). This trial showed that IPTi has a protective effect at the individual level but is not effective at the community level. The study had followed up children for two years until 2007 but the findings from the surveillance in 2007 have not been reported.
176:(IOM) convened an expert committee to evaluate the evidence concerning IPTi - SP and provide guidance on the value of continued investment in IPTi-SP. The committee was chaired by Myron M. Levine who has been funded and is currently funded by the BMGF. The committee concluded "… that an intervention with results of this magnitude is worthy of further investment as part of a public health strategy to decrease morbidity from malaria infections in infants." The WHO technical expert group responded to the IOM report "WHO is committed to review the available information each year." Dr. Kochi was ultimately replaced by one of the members of the IPTi consortium, Dr. Robert Newman. In March 2010, i.e. after Dr. Kochi had been replaced, the WHO recommended the co-administration of the antimalarial drug sulfadoxine pyrimethamine with routine childhood vaccinations (
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currently recommended by the WHO because of its safety and efficacy in pregnancy. Several studies have shown the high efficacy of IPTp with SP, compared to placebo or CQ prophylaxis, on placental infection, LBW and/or severe maternal anaemia. More recent findings from
Tanzania also suggest that IPTp using S/P has reached the end of its lifecycle. The authors found that the "use of partially effective anti-malarial agents for IPTp may exacerbate malaria infections in the setting of widespread drug resistance". As for infants, there is no simple readily available replacement of S/P for malaria in pregnancy. Indeed, the fear of teratogenic effects add a layer of complexity how this intervention will evolve.
74:(S/P) was pioneered in Ifakara, Tanzania in 1999. Infants received S/P at ages 3, 6, and 9 months in combination with their routine childhood (EPI) vaccinations. IPTi reduced clinical attacks of malaria by 59% (95% CI, 41%–72%) in Ifakara. Remarkably, protection persisted throughout the second year of life, long after SP had disappeared from circulation. A trial conducted in northern Tanzania using the antimalarial drug amodiaquine instead of S/P was similarly successful. Six subsequent trials showed less encouraging results.
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and measles immunization) in sub-Saharan Africa. The recommendation applies only for areas with high malaria transmission and low resistance against SP, both measures are not free of controversy and only available for few spots in Africa. With the recent drop of malaria transmission in wide stretches
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Dr. Kochi wrote, although it was less and less straightforward that the health agency should recommend IPTi, the agency's objections were met with intense and aggressive opposition from Gates-backed scientists and the foundation. The W.H.O., he wrote, needs to stand up to such pressures and ensure
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The six studies reported subsequent to the first 2 IPTi studies did not confirm the same degree of protection against malaria (59%) nor the protracted period of protective benefit (into the second year of life) seen in that initial study. Subsequent studies indicated that protection lasted about 35
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IPTp consists in the administration of a single curative dose of an efficacious anti-malarial drug at least twice during pregnancy – regardless whether or not the woman is infected. The drug is administered under supervision during antenatal care (ANC) visits. Sulfadoxine-pyrimethamine is the drug
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An added theoretical concern is that the widespread use of antimalarial drugs for prophylaxis will add to the already considerable drug pressure and will facilitate the emergence and spread of drug resistance. McGready summarised IPTi as an intervention which uses the wrong drug, probably in the
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The latest and so far largest IPTi study was an effectiveness study conducted in the South East of
Tanzania. A study area of approximately 250x180km2 with a population of about 900,000 people was subdivided into 24 similar clusters. Half of the 23,400 infants, those residing in 12 of 24 randomly
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technical advisory group reviewed the evidence relevant for the widespread introduction of IPTi available in 2008, and came to the conclusion that the available evidence was not sufficient to recommend the widespread introduction of IPTi -SP. Program officers of the BMGF as well as scientists
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While some controversial aspects e.g. the drug of choice are shared by all forms of intermittent preventive therapy, the controversy has been reported in greatest detail for IPTi (see also politics below). The reasons which make the large scale introduction of IPTi highly controversial include:
287:.Cisse B, Sokhna C, Boulanger D, Milet J, Ba el H, Richardson K, et al. Seasonal intermittent preventive treatment with artesunate and sulfadoxine-pyrimethamine for prevention of malaria in Senegalese children: a randomised, placebo-controlled, double-blind trial. Lancet 2006;367(9511):659-67
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The politics of IPTi are well documented and illustrate the working of contemporary international health politics. The promising results of the first two IPTi studies led to the creation of the IPTi
Consortium, whose brief is to determine the efficacy, safety, relation of efficacy to drug
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Parise ME, Ayisi JG, Nahlen BL, Schultz LJ, Roberts JM, Misore A, et al. Efficacy of sulfadoxine-pyrimethamine for prevention of placental malaria in an area of Kenya with a high prevalence of malaria and human immunodeficiency virus infection. Am J Trop Med Hyg
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There were concerns that any benefits shown in these IPTi-SP trials might be less now that resistance to sulfadoxine-pyrimethamine has worsened. A recent trial of S/P conducted in
Tanzania had to be closed early because of high mortality in children receiving
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Verhoeff FH, Brabin BJ, Chimsuku L, Kazembe P, Russell WB, Broadhead RL. An evaluation of the effects of intermittent sulfadoxine-pyrimethamine treatment in pregnancy on parasite clearance and risk of low birth weight in rural Malawi. Ann Trop Med
Parasitol
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van Eijk AM, Ayisi JG, ter Kuile FO, Otieno JA, Misore AO, Odondi JO, et al. Effectiveness of intermittent preventive treatment with sulphadoxine-pyrimethamine for control of malaria in pregnancy in western Kenya: a hospital-based study. Trop Med Int Health
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Mockenhaupt FP, Reither K, Zanger P, Roepcke F, Danquah I, Saad E, et al. Intermittent preventive treatment in infants as a means of malaria control: a randomized, double-blind, placebo-controlled trial in northern Ghana. Antimicrob Agents
Chemother
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Macete E, Aide P, Aponte JJ, Sanz S, Mandomando I, Espasa M, et al. Intermittent preventive treatment for malaria control administered at the time of routine vaccinations in
Mozambican infants: a randomized, placebo-controlled trial. J Infect Dis
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Committee on the
Perspectives on the Role of Intermittent Preventive Treatment for Malaria in Infants. Assessment of the role of intermittent preventive treatment for malaria in infants: letter report. Washington, DC:Institute f Medicine, 2008.
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Harrington WE, Mutabingwa TK, Muehlenbachs A, Sorensen B, Bolla MC, Fried M, et al. Competitive facilitation of drug-resistant
Plasmodium falciparum malaria parasites in pregnant women who receive preventive treatment. Proc Natl Acad Sci U S A
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Njagi JK, Magnussen P, Estambale B, Ouma J, Mugo B. Prevention of anaemia in pregnancy using insecticide-treated bednets and sulfadoxine-pyrimethamine in a highly malarious area of Kenya: a randomized controlled trial. Trans R Soc Trop Med Hyg
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There was no evidence of mortality reduction. In more than 8,000 children enrolled in IPTi studies, there were 152 deaths in the placebo groups and 157 deaths in the sulfadoxine-pyrimethamine groups: a protective efficacy of –2% (95% CI –22 to
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Dicko A, Sagara I, Sissoko MS, Guindo O, Diallo AI, Kone M, et al. Impact of intermittent preventive treatment with sulphadoxine-pyrimethamine targeting the transmission season on the incidence of clinical malaria in children in Mali. Malar J
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Clarke SE, Jukes MC, Njagi JK, Khasakhala L, Cundill B, Otido J, et al. Effect of intermittent preventive treatment of malaria on health and education in schoolchildren: a cluster-randomised, double-blind, placebo-controlled trial. Lancet
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Raman, J., et al., Five years of large-scale dhfr and dhps mutation surveillance following the phased implementation of artesunate plus sulfadoxine-pyrimethamine in Maputo
Province, Southern Mozambique. Am J Trop Med Hyg, 2010. 82(5): p.
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Treating children with S/P and artesunate in Senegal where malaria is highly seasonal repeatedly during the malaria season reduced malaria attacks by 86% (95% CI 80-90)9. A subsequent trial in Mali showed a protective efficacy of 43% .
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Schellenberg D, Menendez C, Kahigwa E, Aponte J, Vidal J, Tanner M, et al. Intermittent treatment for malaria and anaemia control at time of routine vaccinations in Tanzanian infants: a randomised, placebo-controlled trial. Lancet
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Rogerson SJ, Chaluluka E, Kanjala M, Mkundika P, Mhango C, Molyneux ME. Intermittent sulfadoxine-pyrimethamine in pregnancy: effectiveness against malaria morbidity in Blantyre, Malawi, in 1997-99. Trans R Soc Trop Med Hyg
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Schellenberg D, Menendez C, Aponte JJ, Kahigwa E, Tanner M, Mshinda H, et al. Intermittent preventive antimalarial treatment for Tanzanian infants: follow-up to age 2 years of a randomised, placebo-controlled trial. Lancet
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Massaga JJ, Kitua AY, Lemnge MM, Akida JA, Malle LN, Ronn AM, et al. Effect of intermittent treatment with amodiaquine on anaemia and malarial fevers in infants in Tanzania: a randomised placebo-controlled trial. Lancet
424::Gesase S, Gosling RD, Hashim R, Ord R, Naidoo I, Madebe R, et al. High resistance of Plasmodium falciparum to sulphadoxine/pyrimethamine in northern Tanzania and the emergence of dhps resistance mutation at Codon 581.
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Shulman CE, Dorman EK, Cutts F, Kawuondo K, Bulmer JN, Peshu N, et al. Intermittent sulphadoxine-pyrimethamine to prevent severe anaemia secondary to malaria in pregnancy: a randomised placebo-controlled trial. Lancet
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episodes in infants (IPTi), children (IPTc), schoolchildren (IPTsc) and pregnant women (IPTp). The intervention builds on two tested malaria control strategies to clear existing parasites (treatment effect seen in
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Grobusch MP, Lell B, Schwarz NG, Gabor J, Dornemann J, Potschke M, et al. Intermittent preventive treatment against malaria in infants in Gabon--a randomized, double-blind, placebo-controlled trial. J Infect Dis
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Kayentao K, Kodio M, Newman RD, Maiga H, Doumtabe D, Ongoiba A, et al. Comparison of intermittent preventive treatment with chemoprophylaxis for the prevention of malaria during pregnancy in Mali. J Infect Dis
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Kobbe R, Kreuzberg C, Adjei S, Thompson B, Langefeld I, Thompson PA, et al. A randomized controlled trial of extended intermittent preventive antimalarial treatment in infants. Clin Infect Dis 2007;45(1):16-25
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funded by the BMGF criticised the WHO conclusions. The criticism from the BMGF in turn triggered a memorandum of the WHO malaria chief Dr. Akira Kochi to the director general of the WHO which was leaked to
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Challis K, Osman NB, Cotiro M, Nordahl G, Dgedge M, Bergstrom S. Impact of a double dose of sulphadoxine-pyrimethamine to reduce prevalence of pregnancy malaria in southern Mozambique. Trop Med Int Health
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Armstrong Schellenberg, J.R., et al., Community effectiveness of Intermittent Preventive Treatment for infants (IPTi) in rural southern Tanzania. Am J Trop Med Hyg, 2010. 82(5): p. 772-81.
527:"WHO | WHO Policy recommendation on Intermittent Preventive Treatment during infancy with sulphadoxine-pyrimethamine (SP-IPTi) for Plasmodium falciparum malaria control in Africa"
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Gesase, S., et al., High resistance of Plasmodium falciparum to sulphadoxine/pyrimethamine in northern Tanzania and the emergence of dhps resistance mutation at Codon 581.
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There was uncertainty over the true incidence of serious adverse effects, notably the cutaneous reactions that stopped the use of sulfadoxine pyrimethamine as prophylaxis.
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WHO. A strategic framework for malaria prevention and control during pregnancy in the Africa Region. Geneva: WorldHealthOrganization, 2004 AFR/MAL/04/01
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O'Meara, W.P., et al., Effect of a fall in malaria transmission on morbidity and mortality in Kilifi, Kenya. Lancet, 2008. 372(9649): p. 1555-62. 3.
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Ceesay, S.J., et al., Changes in malaria indices between 1999 and 2007 in The Gambia: a retrospective analysis. Lancet, 2008. 372(9649): p. 1545-54
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sensitivity, cost-effectiveness, and acceptability of this intervention. The IPTi Consortium received approximately US$ 28 million from the
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of intermittent preventive treatment for malaria in infants in area of high, seasonal transmission in Ghana. BMJ 2005;331(7519):727-33
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Assessment of the Role of Intermittent Preventive Treatment for Malaria in Infants: Letter Report | The National Academies Press
446:.Schellenberg D, Cisse B, Menendez C. The IPTi Consortium: research for policy and action. Trends Parasitol 2006;22(7):296-300
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of Africa and a steady increase in SP resistance few malaria control programs will hurry to implement this intervention.
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McGready, R., Intermittent preventive treatment of malaria in infancy. Lancet, 2009. 9700(374): p. 1478-80.
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days after each treatment dose, which translates into an overall protective efficacy in infancy of 20–33%.
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Chandramohan D, Owusu-Agyei S, Carneiro I, Awine T, Amponsa-Achiano K, Mensah N, et al.
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At the request of Dr. Brandling-Bennett of the BMGF and with funding from the BMGF, the
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Intermittent preventive antimalarial treatment in infancy. Lancet 2008;372(9647):1383-4
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significantly improved anaemia (RR 0.52, 95% CI 0.29-0.93).
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