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Intermittent preventive treatment in infants as a means of malaria control: a randomized, double-blind, placebo-controlled trial in northern Ghana.

ABSTRACT: Morbidity and mortality from malaria remain unacceptably high among young children in sub-Saharan Africa. Intermittent preventive treatment in infancy (IPTi) involves the administration of antimalarials alongside routine vaccinations and might be an option in malaria control. In an area of intense, perennial malaria transmission in northern Ghana, 1,200 children received IPTi with sulfadoxine-pyrimethamine or placebo at approximately 3, 9, and 15 months of age. Children were followed up until 24 months of age to assess morbidity and adverse events. During the intervention period (3 to 18 months of age), IPTi reduced the incidences of malaria and severe anemia by 22.5% (95% confidence interval, 12 to 32%) and 23.6% (95% confidence interval, 4 to 39%), respectively, and reduced hospitalizations and episodes of asymptomatic parasitemia by one-third. Protection was pronounced in the first year of life and not discernible in the second. The malaria-protective effect was largely confined to a period of 1 month after sulfadoxine-pyrimethamine treatments. Following the intervention, protection against asymptomatic parasitemia persisted. In contrast, a significant rebound of severe malaria, predominantly severe malarial anemia, occurred among children having received IPTi. Although the treatment was generally well tolerated, one case of moderately severe skin reaction followed sulfadoxine-pyrimethamine treatment. IPTi reduces malaria and anemia in infants in northern Ghana. Extension of IPTi into the second year of life by administering a dose at 15 months of age provided no substantial benefit beyond a 1-month prophylactic effect. Although this simple intervention offers one of the few available malaria-preventive measures for regions where malaria is endemic, the observed rebound of severe malaria advises caution and requires further investigation.

SUBMITTER: Mockenhaupt FP

PROVIDER: S-EPMC2043181 | biostudies-literature | 2007 Sep

REPOSITORIES: biostudies-literature

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Intermittent preventive treatment in infants as a means of malaria control: a randomized, double-blind, placebo-controlled trial in northern Ghana.

Mockenhaupt Frank P FP Reither Klaus K Zanger Philipp P Roepcke Felix F Danquah Ina I Saad Eiman E Ziniel Peter P Dzisi Stephen Y SY Frempong Marc M Agana-Nsiire Patrick P Amoo-Sakyi Felicia F Otchwemah Rowland R Cramer Jakob P JP Anemana Sylvester D SD Dietz Ekkehart E Bienzle Ulrich U

Antimicrobial agents and chemotherapy 20070716 9

Morbidity and mortality from malaria remain unacceptably high among young children in sub-Saharan Africa. Intermittent preventive treatment in infancy (IPTi) involves the administration of antimalarials alongside routine vaccinations and might be an option in malaria control. In an area of intense, perennial malaria transmission in northern Ghana, 1,200 children received IPTi with sulfadoxine-pyrimethamine or placebo at approximately 3, 9, and 15 months of age. Children were followed up until 24 ...[more]

PMID: 17638703

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Project description:BackgroundMalaria is a major cause of morbidity and mortality in early childhood, yet its consequences for health and education during the school-age years remain poorly understood. We examined the effect of intermittent preventive treatment (IPT) in reducing anaemia and improving classroom attention and educational achievement in semi-immune schoolchildren in an area of high perennial transmission.MethodsA stratified, cluster-randomised, double-blind, placebo-controlled trial of IPT was done in 30 primary schools in western Kenya. Schools were randomly assigned to treatment (sulfadoxine-pyrimethamine in combination with amodiaquine or dual placebo) by use of a computer-generated list. Children aged 5-18 years received three treatments at 4-month intervals (IPT n=3535, placebo n=3223). The primary endpoint was the prevalence of anaemia, defined as a haemoglobin concentration below 110 g/L. This outcome was assessed through cross-sectional surveys 12 months post-intervention. Analysis was by both intention to treat, excluding children with missing data, and per protocol. This study is registered with ClinicalTrials.gov, number NCT00142246.Findings2604 children in the IPT group and 2302 in the placebo group were included in the intention-to-treat analysis of the primary outcome; the main reason for exclusion was loss to follow-up. Prevalence of anaemia at 12 months averaged 6.3% in the IPT group and 12.6% in the placebo group (adjusted risk ratio 0.52, 95% CI 0.29-0.93; p=0.028). Significant improvements were also seen in two of the class-based tests of sustained attention, with a mean increase in code transmission test score of 6.05 (95% CI 2.83-9.27; p=0.0007) and counting sounds test score of 1.80 (0.19-3.41; p=0.03), compared with controls. No effect was shown for inattentive or hyperactive-compulsive behaviours or on educational achievement. The per-protocol analysis yielded similar results. 23 serious adverse events were reported within 28 days of any treatment (19 in the IPT group and four in the placebo group); the main side-effects were problems of balance, dizziness, feeling faint, nausea, and/or vomiting shortly after treatment.InterpretationIPT of malaria improves the health and cognitive ability of semi-immune schoolchildren. Effective malaria interventions could be a valuable addition to school health programmes.

Project description:BackgroundPrevious studies have shown that in areas of seasonal malaria transmission, intermittent preventive treatment of malaria in children (IPTc), targeting the transmission season, reduces the incidence of clinical malaria. However, these studies were conducted in communities with low coverage with insecticide-treated nets (ITNs). Whether IPTc provides additional protection to children sleeping under an ITN has not been established.Methods and findingsTo assess whether IPTc provides additional protection to children sleeping under an ITN, we conducted a randomised, double-blind, placebo-controlled trial of IPTc with sulphadoxine pyrimethamine (SP) plus amodiaquine (AQ) in three localities in Kati, Mali. After screening, eligible children aged 3-59 mo were given a long-lasting insecticide-treated net (LLIN) and randomised to receive three rounds of active drugs or placebos. Treatments were administered under observation at monthly intervals during the high malaria transmission season in August, September, and October 2008. Adverse events were monitored immediately after the administration of each course of IPTc and throughout the follow-up period. The primary endpoint was clinical episodes of malaria recorded through passive surveillance by study clinicians available at all times during the follow-up. Cross-sectional surveys were conducted in 150 randomly selected children weekly and in all children at the end of the malaria transmission season to assess usage of ITNs and the impact of IPTc on the prevalence of malaria, anaemia, and malnutrition. Cox regression was used to compare incidence rates between intervention and control arms. The effects of IPTc on the prevalence of malaria infection and anaemia were estimated using logistic regression. 3,065 children were screened and 3,017 (1,508 in the control and 1,509 in the intervention arm) were enrolled in the study. 1,485 children (98.5%) in the control arm and 1,481 (98.1%) in the intervention arm completed follow-up. During the intervention period, the proportion of children reported to have slept under an ITN was 99.7% in the control and 99.3% in intervention arm (p = 0.45). A total of 672 episodes of clinical malaria defined as fever or a history of fever and the presence of at least 5,000 asexual forms of Plasmodium falciparum per microlitre (incidence rate of 1.90; 95% confidence interval [CI] 1.76-2.05 episodes per person year) were observed in the control arm versus 126 (incidence rate of 0.34; 95% CI 0.29-0.41 episodes per person year) in the intervention arm, indicating a protective effect (PE) of 82% (95% CI 78%-85%) (p<0.001) on the primary endpoint. There were 15 episodes of severe malaria in children in the control arm compared to two in children in the intervention group giving a PE of 87% (95% CI 42%-99%) (p = 0.001). IPTc reduced the prevalence of malaria infection by 85% (95% CI 73%-92%) (p<0.001) during the intervention period and by 46% (95% CI 31%-68%) (p<0.001) at the end of the intervention period. The prevalence of moderate anaemia (haemoglobin [Hb] <8 g/dl) was reduced by 47% (95% CI 15%-67%) (p<0.007) at the end of intervention period. The frequencies of adverse events were similar between the two arms. There was no drug-related serious adverse event.ConclusionsIPTc given during the malaria transmission season provided substantial protection against clinical episodes of malaria, malaria infection, and anaemia in children using an LLIN. SP+AQ was safe and well tolerated. These findings indicate that IPTc could make a valuable contribution to malaria control in areas of seasonal malaria transmission alongside other interventions.Trial registrationClinicalTrials.gov NCT00738946. Please see later in the article for the Editors' Summary.

Project description:Intermittent preventive antimalarial treatment in infants (IPTi) is currently evaluated as a malaria control strategy. Among the factors influencing the extent of protection that is provided by IPTi are the transmission intensity, seasonality, drug resistance patterns, and the schedule of IPTi administrations. The aim of this study was to determine how far the protective efficacy of IPTi depends on spatio-temporal variations of the prevailing incidence of malaria.One thousand seventy infants were enrolled in a registered controlled trial on the efficacy of IPTi with sulphadoxine-pyrimethamine (SP) in the Ashanti Region, Ghana, West Africa (ClinicalTrial.gov: NCT00206739). Stratification for the village of residence and the month of birth of study participants demonstrated that the malaria incidence was dependent on spatial (range of incidence rates in different villages 0.6-2.0 episodes/year) and temporal (range of incidence rates in children of different birth months 0.8-1.2 episodes/year) factors. The range of spatio-temporal variation allowed ecological analyses of the correlation between malaria incidence rates, anti-Plasmodium falciparum lysate IgG antibody levels and protective efficacies provided by IPTi.Protective efficacy of the first SP administration was positively correlated with malaria incidences in children living in a distinct village or born in a distinct month (R2 0.48, p < 0.04 and R2 0.63, p < 0.003, respectively). Corresponding trends were seen after the second and third study drug administration. Accordingly, IgG levels against parasite lysate increased with malaria incidence. This correlation was stronger in children who received IPTi, indicating an effect modification of the intervention.The spatial and temporal variations of malaria incidences in a geographically and meteorologically homogeneous study area exemplify the need for close monitoring of local incidence rates in all types of intervention studies. The increase of the protective efficacy of IPTi with malaria incidences may be relevant for IPTi implementation strategies and, possibly, for other malaria control measures.

Project description:BackgroundIntermittent 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 findingsAn 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.ConclusionsIPT 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 registrationClinicalTrials.govNCT00738946. Please see later in the article for the Editors' Summary.

Project description:BackgroundAlthough IPTp-SP is a lifesaving World Health Organization (WHO) recommended preventive intervention for pregnant women in malaria-endemic regions, IPTp-SP uptake in the Northern region of Ghana is much lower than the sub-optimal national coverage level. Assessing the extent of health workers' compliance and its associated factors will generate valuable pointers to be targeted at the program level. The study examined the factors influencing health workers' compliance with the WHO recommended guidelines for IPTp-SP in the Northern Region.MethodsA cross-sectional study among 315 health workers in the Northern region was conducted. Semi-structured questionnaires were used to collect data on health workers' sociodemographic characteristics, facility-based factors and knowledge level. Data were collected on health workers' compliance with the recommended practices through covert observations using a checklist. Facility observations were carried out using a checklist. Crude and adjusted logistic regression were used to determine predictors of health workers' compliance, at a 5% significance level adjusting for clustering.ResultsOf the 315 health workers studied, the median age was 29 years (26-34 years). Females constituted (80.5%; 252) of the 313 workers. The majority (47.4%;148) of the 312 health workers were midwives. Overall, 56.2% (CI 51.0 - 62.0) were adequately complying with the recommended guidelines. Lower levels of compliance were recorded in health centres 15.6% (5.0 - 33.0) and CHPS compounds 21.2% (11.0 - 35.0). The factors associated with compliance included health workers' knowledge (aOR = 7.64, 95% CI 4.21 - 13.87, p < 0.001), job satisfaction (aOR 10.87, 95% CI 7.04 - 16.79, p < 0.001), in-service training (aOR 10.11, 95% CI 4.53 - 22.56, p < 0.001), supervision (aOR 4.01, 95% CI 2.09 - 7.68, p < 0.001), availability of job aids (aOR 3.61, 95% CI 2.44 - 5.35, p < 0.001), health workers experience (aOR = 10.64, 95% CI 5.99 - 18.91, p < 0.001) and facility type (aOR 0.03, 95% CI 0.01-0.07, p < 0.001).ConclusionCompliance with the recommended IPTp-SP guidelines is suboptimal in the region, with lower-level health facilities recording the least compliance levels. Health centres and CHPS facilities should be prioritized in distributing limited resources to improve health worker quality of care for antenatal care clients.

Project description:BackgroundTrials of intermittent preventive treatment against malaria in infants (IPTi) using sulphadoxine-pyrimethamine (SP) have shown a positive, albeit variable, protective efficacy against clinical malaria episodes. The impact of IPTi in different epidemiological settings and over time is unknown and predictions are hampered by the lack of knowledge about how IPTi works. We investigated mechanisms proposed for the action of IPTi and made predictions of the likely impact on morbidity and mortality.Methods/principal findingsWe used a comprehensive, individual-based, stochastic model of malaria epidemiology to simulate recently published trials of IPTi using SP with site-specific characteristics as inputs. This baseline model was then modified to represent hypotheses concerning the duration of action of SP, the temporal pattern of fevers caused by individual infections, potential benefits of avoiding fevers on immunity and the effect of sub-therapeutic levels of SP on parasite dynamics. The baseline model reproduced the pattern of results reasonably well. None of the models based on alternative hypotheses improved the fit between the model predictions and observed data. Predictions suggest that IPTi would have a beneficial effect across a range of transmission intensities. IPTi was predicted to avert a greater number of episodes where IPTi coverage was higher, the health system treatment coverage lower, and for drugs which were more efficacious and had longer prophylactic periods. The predicted cumulative benefits were proportionately slightly greater for severe malaria episodes and malaria-attributable mortality than for acute episodes in the settings modelled. Modest increased susceptibility was predicted between doses and following the last dose, but these were outweighed by the cumulative benefits. The impact on transmission intensity was negligible.ConclusionsThe pattern of trial results can be accounted for by differences between the trial sites together with known features of malaria epidemiology and the action of SP. Predictions suggest that IPTi would have a beneficial impact across a variety of epidemiological settings.

Dataset Information

Intermittent preventive treatment in infants as a means of malaria control: a randomized, double-blind, placebo-controlled trial in northern Ghana.

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Intermittent preventive treatment in infants as a means of malaria control: a randomized, double-blind, placebo-controlled trial in northern Ghana.

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