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Duration of protection against clinical malaria provided by three regimens of intermittent preventive treatment in Tanzanian infants.

ABSTRACT: Intermittent preventive treatment in infants (IPTi) is a new malaria control tool. However, it is uncertain whether IPTi works mainly through chemoprophylaxis or treatment of existing infections. Understanding the mechanism is essential for development of replacements for sulfadoxine-pyrimethamine (SP) where it is no longer effective. This study investigated how protection against malaria given by SP, chlorproguanil-dapsone (CD) and mefloquine (MQ), varied with time since administration of IPTi.A secondary analysis of data from a randomised, placebo-controlled trial in an area of high antifolate resistance in Tanzania was conducted. IPTi using SP, CD, MQ or placebo was given to 1280 infants at 2, 3 and 9 months of age. Poisson regression with random effects to adjust for potential clustering of malaria episodes within children was used to calculate incidence rate ratios for clinical malaria in defined time strata following IPTi. The short-acting antimalarial CD gave no protection against clinical malaria, whereas long-acting MQ gave two months of substantial protection (protective efficacy (PE) 73.1% (95% CI: 23.9, 90.5) and 73.3% (95% CI: 0, 92.9) in the first and second month respectively). SP gave some protection in the first month after treatment (PE 64.5% (95% CI: 10.6, 85.9)) although it did not reduce the incidence of malaria up to 12 months of age. There was no evidence of either long-term protection or increased risk of malaria for any of the regimens.Post-treatment chemoprophylaxis appears to be the main mechanism by which IPTi protects children against malaria. Long-acting antimalarials are therefore likely to be the most effective drugs for IPTi, but as monotherapies could be vulnerable to development of drug resistance. Due to concerns about tolerability, the mefloquine formulation used in this study is not suitable for IPTi. Further investigation of combinations of long-acting antimalarials for IPTi is needed.Clinicaltrials.gov NCT00158574.

SUBMITTER: Cairns M

PROVIDER: S-EPMC2830887 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Duration of protection against clinical malaria provided by three regimens of intermittent preventive treatment in Tanzanian infants.

Cairns Matthew M Gosling Roly R Carneiro Ilona I Gesase Samwel S Mosha Jacklin F JF Hashim Ramadhan R Kaur Harparkash H Lemnge Martha M Mosha Frank W FW Greenwood Brian B Chandramohan Daniel D

PloS one 20100301 3

<h4>Background</h4>Intermittent preventive treatment in infants (IPTi) is a new malaria control tool. However, it is uncertain whether IPTi works mainly through chemoprophylaxis or treatment of existing infections. Understanding the mechanism is essential for development of replacements for sulfadoxine-pyrimethamine (SP) where it is no longer effective. This study investigated how protection against malaria given by SP, chlorproguanil-dapsone (CD) and mefloquine (MQ), varied with time since admi ...[more]

PMID: 20209126

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Project description:BackgroundIntermittent preventive treatment is recommended for pregnant women living in malaria endemic countries due to benefits for both mother and baby. However, the impact may not be the same in HIV-positive pregnant women, as HIV infection impairs a woman's immunity.ObjectivesTo compare intermittent preventive treatment regimens for malaria in HIV-positive pregnant women living in malaria-endemic areas.Search strategyIn June 2011, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE; EMBASE; LILACS, the metaRegister of Controlled Trials (mRCT), reference lists and conference abstracts. We also contacted researchers and organizations for information on relevant trials.Selection criteriaRandomized controlled trials comparing different intermittent preventive treatment regimens for preventing malaria in HIV-positive pregnant women in malaria-endemic areas.Data collection and analysisTwo authors extracted data and assessed risk bias. Dichotomous variables were combined using risk ratios (RR) and mean differences (MD) for continuous outcomes, both with 95% confidence intervals (CI).Main resultsTwo randomized trials with 722 HIV-positive pregnant women were included, comparing monthly regimens of sulfadoxine-pyrimethamine (SP) to the standard 2-dose regimen in the second and third trimesters. There were no statistically significant differences between monthly SP and 2-dose SP in rates of maternal anaemia, low birth weight, and neonatal mortality. In primigravidae and secondigravidiae, the monthly regimen was associated with less placental parasitaemia (RR 0.38, 95% CI 0.21 to 0.70, two trials) and less peripheral parasitaemia (RR 0.25, 95% CI 0.14 to 0.43, two trials), but no effect was demonstrated in multigravid women. Babies born to primigravidae and secundigravida women on monthly SP had a higher mean birth weight (weighted mean difference (WMD) 130 g; 95% CI 120 g to 150 g, two trials) than babies born to mothers on 2-dose SP. Multigravidae women treated with monthly SP had significant higher haemoglobin level than those treated with treated 2 dose SP (WMD 0.21 g/dL, 95% CI 0.15 g/dL to 0.27 g/dL, one trial). There were no trials that assessed other treatment regimens for intermittent preventive treatment in HIV-positive pregnant women.Authors' conclusionsThree or more doses of SP is superior to the standard two doses in HIV-positive pregnant women. However, since SP cannot be administered concurrently with co-trimoxazole - a drug often recommended for infection prophylaxis in HIV-positive pregnant women, new drugs and research is needed to address needs of HIV-positive pregnant women.

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: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.

Project description:BACKGROUND:Intermittent preventive treatment (IPT) of malaria is recommended as policy for certain high-risk populations, but not currently for schoolchildren. A cluster-randomized trial was conducted to evaluate the effect of IPT with dihydroartemisinin-piperaquine (DP) on primary schoolchildren in Jinja, Uganda. Results of the impact of IPT of schoolchildren on community-level transmission have been reported previously. Here, secondary outcomes from a school-based survey are presented. METHODS:Eighty-four clusters (one primary school plus 100 households) were randomized to intervention and control (1:1 ratio). Participants from intervention schools received monthly IPT with DP for up to 6 rounds (June-December 2014). At endline (November-December 2014), randomly selected children from all 84 schools were surveyed (13 per school) and thick blood smears were done. Those with fever or history of fever were tested with rapid diagnostic tests (RDTs) for malaria. Haemoglobin was measured in every fifth participant. Outcome measures included prevalence of asexual parasites and gametocytes (by microscopy), and prevalence of anaemia. Prevalence outcomes were analysed using generalized linear Poisson models with log link function, incorporating a cluster-level random intercept and quantified using prevalence risk ratios. RESULTS:Among 23,280 students listed on the 42 intervention school registers, 10,079 (43.3%) aged 5-20 years were enrolled into the IPT intervention and received at least one dose of DP; of these, 9286 (92.1%) received at least one full (3-day) course. In total, 1092 children were enrolled into the final school survey (546 per arm) and had a thick blood smear done; of these, 255 had haemoglobin measured (129 intervention, 126 control). Children in the intervention arm were less likely to have asexual parasites (9.2% intervention vs 44.1% control, adjusted risk ratio [aRR] 0.22 [95% CI 0.16-0.30] p?<?0.001), gametocytes (3.1% intervention vs 9.5% control, aRR 0.34 [95% CI 0.20-0.56] p?<?0.001), fever (20.2% intervention vs 56.2% control, aRR 0.35 [95% CI 0.25-0.50] p?<?0.001), or symptomatic malaria (5.1% intervention vs 35.7% control, aRR 0.14 [95% CI 0.08-0.26] p?<?0.001). Prevalence of anaemia and mean haemoglobin were similar in both study arms. CONCLUSIONS:School-aged children are a major reservoir of malaria parasites. Delivering IPT to schoolchildren would benefit individual children and may reduce transmission. School-based IPT could help to intensify malaria control toward elimination, and should be considered for policies and programmes. Trial registration Clinicaltrials.gov (NCT02009215), Registered 11 December 2013. https://clinicaltrials.gov/ct2/show/NCT02009215.

Project description:BACKGROUND: Intermittent preventive treatment in infants (IPTi) has been shown to decrease clinical malaria by approximately 30% in the first year of life and is a promising malaria control strategy for Sub-Saharan Africa which can be delivered alongside the Expanded Programme on Immunisation (EPI). To date, there have been limited data on the cost-effectiveness of this strategy using sulfadoxine pyrimethamine (SP) and no published data on cost-effectiveness using other antimalarials. METHODS: We analysed data from 5 countries in sub-Saharan Africa using a total of 5 different IPTi drug regimens; SP, mefloquine (MQ), 3 days of chlorproguanil-dapsone (CD), SP plus 3 days of artesunate (SP-AS3) and 3 days of amodiaquine-artesunate (AQ3-AS3).The cost per malaria episode averted and cost per Disability-Adjusted Life-Year (DALY) averted were modeled using both trial specific protective efficacy (PE) for all IPTi drugs and a pooled PE for IPTi with SP, malaria incidence, an estimated malaria case fatality rate of 1.57%, IPTi delivery costs and country specific provider and household malaria treatment costs. FINDINGS: In sites where IPTi had a significant effect on reducing malaria, the cost per episode averted for IPTi-SP was very low, USD 1.36-4.03 based on trial specific data and USD 0.68-2.27 based on the pooled analysis. For IPTi using alternative antimalarials, the lowest cost per case averted was for AQ3-AS3 in western Kenya (USD 4.62) and the highest was for MQ in Korowge, Tanzania (USD 18.56). Where efficacious, based only on intervention costs, IPTi was shown to be cost effective in all the sites and highly cost-effective in all but one of the sites, ranging from USD 2.90 (Ifakara, Tanzania with SP) to USD 39.63 (Korogwe, Tanzania with MQ) per DALY averted. In addition, IPTi reduced health system costs and showed significant savings to households from malaria cases averted. A threshold analysis showed that there is room for the IPTi-efficacy to fall and still remain highly cost effective in all sites where IPTi had a statistically significant effect on clinical malaria. CONCLUSIONS: IPTi delivered alongside the EPI is a highly cost effective intervention against clinical malaria with a range of drugs in a range of malaria transmission settings. Where IPTi did not have a statistically significant impact on malaria, generally in low transmission sites, it was not cost effective.

Project description:BACKGROUND: Achieving the Millennium Development Goals for health requires a massive scaling-up of interventions in Sub Saharan Africa. Intermittent Preventive Treatment in infants (IPTi) is a promising new tool for malaria control. Although efficacy information is available for many interventions, there is a dearth of data on the resources required for scaling up of health interventions. METHOD: We worked in partnership with the Ministry of Health and Social Welfare (MoHSW) to develop an IPTi strategy that could be implemented and managed by routine health services. We tracked health system and other costs of (1) developing the strategy and (2) maintaining routine implementation of the strategy in five districts in southern Tanzania. Financial costs were extracted and summarized from a costing template and semi-structured interviews were conducted with key informants to record time and resources spent on IPTi activities. RESULTS: The estimated financial cost to start-up and run IPTi in the whole of Tanzania in 2005 was US$1,486,284. Start-up costs of US$36,363 were incurred at the national level, mainly on the development of Behaviour Change Communication (BCC) materials, stakeholders' meetings and other consultations. The annual running cost at national level for intervention management and monitoring and drug purchase was estimated at US$459,096. Start-up costs at the district level were US$7,885 per district, mainly expenditure on training. Annual running costs were US$170 per district, mainly for printing of BCC materials. There was no incremental financial expenditure needed to deliver the intervention in health facilities as supplies were delivered alongside routine vaccinations and available health workers performed the activities without working overtime. The economic cost was estimated at 23 US cents per IPTi dose delivered. CONCLUSION: The costs presented here show the order of magnitude of expenditures needed to initiate and to implement IPTi at national scale in settings with high Expanded Programme on Immunization (EPI) coverage. The IPTi intervention appears to be affordable even within the budget constraints of Ministries of Health of most sub-Saharan African countries.

Dataset Information

Duration of protection against clinical malaria provided by three regimens of intermittent preventive treatment in Tanzanian infants.

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Duration of protection against clinical malaria provided by three regimens of intermittent preventive treatment in Tanzanian infants.

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