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      Intermittent Preventive Treatment of Malaria Provides Substantial Protection against Malaria in Children Already Protected by an Insecticide-Treated Bednet in Burkina Faso: A Randomised, Double-Blind, Placebo-Controlled Trial

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          Abstract

          A randomized trial reported by Diadier Diallo and colleagues shows that intermittent preventive treatment for malaria in children who are protected from mosquitoes using insecticide-treated bednets provides substantial protection from malaria.

          Abstract

          Background

          Intermittent preventive treatment of malaria in children (IPTc) is a promising new approach to the control of malaria in areas of seasonal malaria transmission but it is not known if IPTc adds to the protection provided by an insecticide-treated net (ITN).

          Methods and Findings

          An individually randomised, double-blind, placebo-controlled trial of seasonal IPTc was conducted in Burkina Faso in children aged 3 to 59 months who were provided with a long-lasting insecticide-treated bednet (LLIN). Three rounds of treatment with sulphadoxine pyrimethamine plus amodiaquine or placebos were given at monthly intervals during the malaria transmission season. Passive surveillance for malaria episodes was established, a cross-sectional survey was conducted at the end of the malaria transmission season, and use of ITNs was monitored during the intervention period. Incidence rates of malaria were compared using a Cox regression model and generalized linear models were fitted to examine the effect of IPTc on the prevalence of malaria infection, anaemia, and on anthropometric indicators. 3,052 children were screened and 3,014 were enrolled in the trial; 1,505 in the control arm and 1,509 in the intervention arm. Similar proportions of children in the two treatment arms were reported to sleep under an LLIN during the intervention period (93%). The incidence of malaria, defined as fever or history of fever with parasitaemia ≥5,000/µl, was 2.88 (95% confidence interval [CI] 2.70–3.06) per child during the intervention period in the control arm versus 0.87 (95% CI 0.78–0.97) in the intervention arm, a protective efficacy (PE) of 70% (95% CI 66%–74%) ( p<0.001). There was a 69% (95% CI 6%–90%) reduction in incidence of severe malaria ( p = 0.04) and a 46% (95% CI 7%–69%) ( p = 0.03) reduction in the incidence of all-cause hospital admissions. IPTc reduced the prevalence of malaria infection at the end of the malaria transmission season by 73% (95% CI 68%–77%) ( p<0.001) and that of moderately severe anaemia by 56% (95% CI 36%–70%) ( p<0.001). IPTc reduced the risks of wasting (risk ratio [RR]  = 0.79; 95% CI 0.65–1.00) ( p = 0.05) and of being underweight (RR  = 0.84; 95% CI 0.72–0.99) ( p = 0.03). Children who received IPTc were 2.8 (95% CI 2.3–3.5) ( p<0.001) times more likely to vomit than children who received placebo but no drug-related serious adverse event was recorded.

          Conclusions

          IPT of malaria provides substantial protection against malaria in children who sleep under an ITN. There is now strong evidence to support the integration of IPTc into malaria control strategies in areas of seasonal malaria transmission.

          Trial Registration

          ClinicalTrials.gov NCT00738946

          Please see later in the article for the Editors' Summary

          Editors' Summary

          Background

          Malaria accounts for one in five of all childhood deaths in Africa and of the one million annual malarial deaths world-wide, over 75% occur in African children under 5 years old. Malaria also causes severe morbidity in children, such as anemia, low birth weight, and neurological problems, which compromise the health and development of millions of children living in malaria endemic areas. As much of the impact of malaria on African children can be effectively prevented, significant efforts have been made in recent years to improve malaria control, such as the implementation of intermittent preventive treatment of malaria.

          Intermittent preventive treatment (IPT) involves administration of antimalarial drugs at defined time intervals to individuals, regardless of whether they are known to be infected with malaria, to prevent morbidity and mortality. IPT was initially recommended for pregnant women and recently this strategy was extended to include infants (IPTi). Now, there is also IPT of malaria in children (IPTc), which is designed to protect against malaria during the high malaria transmission season.

          Why Was This Study Done?

          Large clinical trials have shown that IPTc involving the administration of two to three doses of an antimalarial drug (sulphadoxine pyrimethamine [SP] and artesunate [AS] or amodiaquine [AQ]) during the high malaria transmission season effectively reduces the incidence of malaria. However, these studies were conducted in countries where the use of insecticide-treated bednets—an intervention that provides at least 50% protection against morbidity from malaria and is the main tool used for malaria control in most of sub-Saharan Africa—was relatively low. Therefore, it is unclear whether IPTc will be as effective in children who sleep under insecticide-treated bednets as has been previously shown in communities where insecticide-treated bednet usage is low. So to determine the answer to this important question, the researchers conducted a randomized, placebo-controlled trial of IPTc with SP + AQ (chosen because of the effectiveness of this combination in a pilot study) in children who slept under an insecticide-treated bednet in an area of seasonal malaria transmission in Burkina Faso.

          What Did the Researchers Do and Find?

          The researchers enrolled 3,014 eligible children aged 3–59 months into a randomized double-blind, placebo-controlled trial during the 2008 malaria transmission season in Burkina Faso. All children were given a long-lasting insecticide-treated bednet at the start of the study with instructions to their family on the correct use of the net. Children were then randomized into two arms—1,509 were allocated to the intervention group and 1,505 to the control group—to receive three courses of IPTc with SP plus AQ or placebos given at monthly intervals during the peak malaria transmission season. The researchers monitored the incidence of malaria throughout the malaria season and also monitored the use of long-lasting insecticide-treated bednets throughout the study period. In addition, researchers conducted a cross-sectional survey in 150 randomly selected children every week and in every child enrolled in the trial 6 weeks after the last course of IPTc, to measure their temperature, height and weight, and blood hemoglobin and parasite count levels.

          The number of children who slept under their long-lasting insecticide-treated bednet was similar in both arms. During the intervention period, the researchers found that the incidence of clinical malaria (defined as fever or a history of fever and the presence of at least 5,000 asexual forms of P. falciparum per microliter) was 2.88 in the control arm versus 0.87 in the intervention arm—giving a protective efficacy of 70%. There were 13 cases of severe malaria in the control arm and four in the IPTc arm—a 69% reduction in incidence. Additionally, all-cause hospital admission rate was reduced by 46%. At the end of the malaria transmission period, IPTc reduced the proportion of children infected with malaria parasites by 73% and reduced anemia by 33%. In addition, IPTc appeared to reduce the risk of wasting (risk ratio  = 0.79) and of being underweight (risk ratio  = 0.84). However, children who received IPTc were almost three times more likely to vomit than children who received placebo but there were no drug-related serious adverse events.

          What Do These Findings Mean?

          The results of this study show that in peak malarial transmission season in Burkina Faso, IPTc provides substantial additional protection against episodes of clinical malaria, severe malaria, and all-cause hospital admissions in children sleeping under long-lasting insecticide-treated bednets. In addition, intermittent preventive treatment of malaria with SP plus AQ appears to be safe for use in children.

          Additional Information

          Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000408.

          Related collections

          Most cited references 20

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          Severe falciparum malaria. World Health Organization, Communicable Diseases Cluster.

           B Brabin,  E Dorman,  PF Beales (2000)
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            Insecticide-treated bed nets and curtains for preventing malaria.

             C Lengeler (2003)
            Malaria is an important cause of illness and death in many parts of the world, especially in sub-Saharan Africa. There has been a renewed emphasis on preventive measures at community and individual levels. Insecticide-treated nets (ITNs) are the most prominent malaria preventive measure for large-scale deployment in highly endemic areas. To assess the impact of insecticide-treated bed nets or curtains on mortality, malarial illness (life-threatening and mild), malaria parasitaemia, anaemia, and spleen rates. I searched the Cochrane Infectious Diseases Group trials register (January 2003), CENTRAL (The Cochrane Library, Issue 1, 2003), MEDLINE (1966 to October 2003), EMBASE (1974 to November 2002), LILACS (1982 to January 2003), and reference lists of reviews, books, and trials. I handsearched journals, contacted researchers, funding agencies, and net and insecticide manufacturers. Individual and cluster randomized controlled trials of insecticide-treated bed nets or curtains compared to nets without insecticide or no nets. Trials including only pregnant women were excluded. The reviewer and two independent assessors reviewed trials for inclusion. The reviewer assessed trial methodological quality and extracted and analysed data. Fourteen cluster randomized and eight individually randomized controlled trials met the inclusion criteria. Five trials measured child mortality: ITNs provided 17% protective efficacy (PE) compared to no nets (relative rate 0.83, 95% confidence interval (CI) 0.76 to 0.90), and 23% PE compared to untreated nets (relative rate 0.77, 95% CI 0.63 to 0.95). About 5.5 lives (95% CI 3.39 to 7.67) can be saved each year for every 1000 children protected with ITNs. In areas with stable malaria, ITNs reduced the incidence of uncomplicated malarial episodes in areas of stable malaria by 50% compared to no nets, and 39% compared to untreated nets; and in areas of unstable malaria: by 62% for compared to no nets and 43% compared to untreated nets for Plasmodium falciparum episodes, and by 52% compared to no nets and 11% compared to untreated nets for P. vivax episodes. When compared to no nets and in areas of stable malaria, ITNs also had an impact on severe malaria (45% PE, 95% CI 20 to 63), parasite prevalence (13% PE), high parasitaemia (29% PE), splenomegaly (30% PE), and their use improved the average haemoglobin level in children by 1.7% packed cell volume. ITNs are highly effective in reducing childhood mortality and morbidity from malaria. Widespread access to ITNs is currently being advocated by Roll Back Malaria, but universal deployment will require major financial, technical, and operational inputs.
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              A molecular marker for chloroquine-resistant falciparum malaria.

              Chloroquine-resistant Plasmodium falciparum malaria is a major health problem, particularly in sub-Saharan Africa. Chloroquine resistance has been associated in vitro with point mutations in two genes, pfcrt and pfmdr 1, which encode the P. falciparum digestive-vacuole transmembrane proteins PfCRT and Pgh1, respectively. To assess the value of these mutations as markers for clinical chloroquine resistance, we measured the association between the mutations and the response to chloroquine treatment in patients with uncomplicated falciparum malaria in Mali. The frequencies of the mutations in patients before and after treatment were compared for evidence of selection of resistance factors as a result of exposure to chloroquine. The pfcrt mutation resulting in the substitution of threonine (T76) for lysine at position 76 was present in all 60 samples from patients with chloroquine-resistant infections (those that persisted or recurred after treatment), as compared with a base-line prevalence of 41 percent in samples obtained before treatment from 116 randomly selected patients (P<0.001), indicating absolute selection for this mutation. The pfmdr 1 mutation resulting in the substitution of tyrosine for asparagine at position 86 was also selected for, since it was present in 48 of 56 post-treatment samples from patients with chloroquine-resistant infections (86 percent), as compared with a base-line prevalence of 50 percent in 115 samples obtained before treatment (P<0.001). The presence of pfcrt T76 was more strongly associated with the development of chloroquine resistance (odds ratio, 18.8; 95 percent confidence interval, 6.5 to 58.3) than was the presence of pfmdr 1 Y86 (odds ratio, 3.2; 95 percent confidence interval, 1.5 to 6.8) or the presence of both mutations (odds ratio, 9.8; 95 percent confidence interval, 4.4 to 22.1). This study shows an association between the pfcrt T76 mutation in P. falciparum and the development of chloroquine resistance during the treatment of malaria. This mutation can be used as a marker in surveillance for chloroquine-resistant falciparum malaria.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Med
                PLoS
                plosmed
                PLoS Medicine
                Public Library of Science (San Francisco, USA )
                1549-1277
                1549-1676
                February 2011
                February 2011
                1 February 2011
                : 8
                : 2
                Affiliations
                [1 ]Centre National de Recherche et de Formation sur le Paludisme, Ouagadougou, Burkina Faso
                [2 ]London School of Hygiene & Tropical Medicine, London, United Kingdom
                University of Melbourne, Australia
                Author notes

                ICMJE criteria for authorship read and met: ATK JBY AZO AD AG IS DTK YK EO AO ABT INO DC SC PJM SBS BG DAD. Agree with the manuscript's results and conclusions: ATK JBY AZO AD AG IS DTK YK EO AO ABT INO DC SC PJM SBS BG DAD. Designed the experiments/the study: AZO EO AO ABT INO DC SC PJM SBS BG DAD. Analyzed the data: ATK AZO EO AO PJM DAD. Collected data/did experiments for the study: ATK JBY AD AG IS DTK YK EO AO INO SBS. Enrolled patients: ATK JBY AD DTK YK EO AO SBS. Wrote the first draft of the paper: ATK YK AO DAD. Contributed to the writing of the paper: ATK YK AO ABT INO DC SC PJM SBS BG DAD. Supervised field work: AG. Contributed to the design of the study; helped to write some of the computer programs for data analysis: SC.

                Article
                10-PLME-RA-5297R2
                10.1371/journal.pmed.1000408
                3032552
                21304925
                Konaté et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 14
                Categories
                Research Article
                Public Health and Epidemiology/Infectious Diseases

                Medicine

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