Dataset Information

Temporal changes in prevalence of molecular markers mediating antimalarial drug resistance in a high malaria transmission setting in Uganda.

ABSTRACT: Standard therapy for malaria in Uganda changed from chloroquine to chloroquine + sulfadoxine-pyrimethamine in 2000, and artemether-lumefantrine in 2004, although implementation of each change was slow. Plasmodium falciparum genetic polymorphisms are associated with alterations in drug sensitivity. We followed the prevalence of drug resistance-mediating P. falciparum polymorphisms in 982 samples from Tororo, a region of high transmission intensity, collected from three successive treatment trials conducted during 2003-2012, excluding samples with known recent prior treatment. Considering transporter mutations, prevalence of the mutant pfcrt 76T, pfmdr1 86Y, and pfmdr1 1246Y alleles decreased over time. Considering antifolate mutations, the prevalence of pfdhfr 51I, 59R, and 108N, and pfdhps 437G and 540E were consistently high; pfdhfr 164L and pfdhps 581G were uncommon, but most prevalent during 2008-2010. Our data suggest sequential selective pressures as different treatments were implemented, and they highlight the importance of genetic surveillance as treatment policies change over time.

SUBMITTER: Mbogo GW

PROVIDER: S-EPMC4080569 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Temporal changes in prevalence of molecular markers mediating antimalarial drug resistance in a high malaria transmission setting in Uganda.

Mbogo George W GW Nankoberanyi Sheila S Tukwasibwe Stephen S Baliraine Frederick N FN Nsobya Samuel L SL Conrad Melissa D MD Arinaitwe Emmanuel E Kamya Moses M Tappero Jordan J Staedke Sarah G SG Dorsey Grant G Greenhouse Bryan B Rosenthal Philip J PJ

The American journal of tropical medicine and hygiene 20140505 1

Standard therapy for malaria in Uganda changed from chloroquine to chloroquine + sulfadoxine-pyrimethamine in 2000, and artemether-lumefantrine in 2004, although implementation of each change was slow. Plasmodium falciparum genetic polymorphisms are associated with alterations in drug sensitivity. We followed the prevalence of drug resistance-mediating P. falciparum polymorphisms in 982 samples from Tororo, a region of high transmission intensity, collected from three successive treatment trials ...[more]

PMID: 24799371

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Project description:BackgroundEnvironmental factors such as temperature, rainfall, and vegetation cover play a critical role in malaria transmission. However, quantifying the relationships between environmental factors and measures of disease burden relevant for public health can be complex as effects are often non-linear and subject to temporal lags between when changes in environmental factors lead to changes in malaria incidence. The study investigated the effect of environmental covariates on malaria incidence in high transmission settings of Uganda.MethodsThis study leveraged data from seven malaria reference centres (MRCs) located in high transmission settings of Uganda over a 24-month period. Estimates of monthly malaria incidence (MI) were derived from MRCs' catchment areas. Environmental data including monthly temperature, rainfall, and normalized difference vegetation index (NDVI) were obtained from remote sensing sources. A distributed lag nonlinear model was used to investigate the effect of environmental covariates on malaria incidence.ResultsOverall, the median (range) monthly temperature was 30 °C (26-47), rainfall 133.0 mm (3.0-247), NDVI 0.66 (0.24-0.80) and MI was 790 per 1000 person-years (73-3973). Temperature of 35 °C was significantly associated with malaria incidence compared to the median observed temperature (30 °C) at month lag 2 (IRR: 2.00, 95% CI: 1.42-2.83) and the increased cumulative IRR of malaria at month lags 1-4, with the highest cumulative IRR of 8.16 (95% CI: 3.41-20.26) at lag-month 4. Rainfall of 200 mm significantly increased IRR of malaria compared to the median observed rainfall (133 mm) at lag-month 0 (IRR: 1.24, 95% CI: 1.01-1.52) and the increased cumulative IRR of malaria at month lags 1-4, with the highest cumulative IRR of 1.99(95% CI: 1.22-2.27) at lag-month 4. Average NVDI of 0.72 significantly increased the cumulative IRR of malaria compared to the median observed NDVI (0.66) at month lags 2-4, with the highest cumulative IRR of 1.57(95% CI: 1.09-2.25) at lag-month 4.ConclusionsIn high-malaria transmission settings, high values of environmental covariates were associated with increased cumulative IRR of malaria, with IRR peaks at variable lag times. The complex associations identified are valuable for designing strategies for early warning, prevention, and control of seasonal malaria surges and epidemics.

Project description:BackgroundSymptomatic malaria cases reflect only a small proportion of all Plasmodium spp infections. Many infected individuals are asymptomatic, and persistent asymptomatic Plasmodium falciparum infections are common in endemic settings. We aimed to quantify the contribution of symptomatic and asymptomatic infections to P falciparum transmission in Tororo, Uganda.MethodsWe did a longitudinal, observational cohort study in Tororo district, Uganda. We recruited participants of all ages from randomly selected households within this district. Participants were eligible if the selected household had no more than nine permanent residents and at least two members younger than 10 years, and the household was their primary residence, and they agreed to come to the study clinic for any fever episode and avoid antimalarial medications outside the study. Participants were followed-up by continuous passive surveillance for the incidence of symptomatic infections; routine assessments (ie, standardised clinical evaluation and blood samples) were done at baseline and at routine visits every 4 weeks for 2 years. P falciparum parasite density, gametocyte density, and genetic composition were determined molecularly using quantitative PCR (qPCR), quantitative reverse transcriptase PCR (qRT-PCR), and amplicon deep sequencing, respectively. Membrane feeding assays were also done to assess infectivity to mosquitoes. The contribution of different populations to the infectious reservoir was estimated for symptomatic infections, asymptomatic but microscopically detected infections, and asymptomatic but qPCR-detected infections; and for age groups younger than 5 years, 5-15 years, and 16 years or older.FindingsBetween Oct 4, 2017, and Oct 31, 2019, 531 individuals were enrolled from 80 randomly selected households and were followed-up for 2 years. At baseline, P falciparum was detected in 28 (5·3%) of 531 participants by microscopy and an additional 64 (12·1%) by qPCR and declined thereafter. In 538 mosquito feeding experiments on 107 individuals, 446 (1·2%) of 37 404 mosquitoes became infected, with mosquito infection rates being strongly associated with gametocyte densities (β=2·11, 95% CI 1·62-2·67; p<0·0001). Considering both transmissibility of infections and their relative frequency, the estimated human infectious reservoir consisted primarily of asymptomatic microscopy-detected infections (83·8%), followed by asymptomatic submicroscopic infections (15·6%), and symptomatic infections (0·6%). Children aged 5-15 years accounted for more than half of the infectious reservoir (58·7%); individuals younger than 5 years (25·8%) and those 16 years or older (15·6%) contributed less. Samples from four children contribued to 279 (62·6%) of 446 infected mosquitoes after multiple mosquito-feeding assays.InterpretationIndividuals with asymptomatic infections were important drivers of malaria transmission. School-aged children contributed to more than half of all mosquito infections, with a small minority of asymptomatic children being highly infectious. Demographically targeted interventions, aimed at school-aged children, could further reduce transmission in areas under effective vector control.FundingUS National Institutes of Health, Bill & Melinda Gates Foundation, and the European Research Council.

Project description:BackgroundAlthough malaria burden in Uganda has declined since 2009 following the scale-up of interventions, the disease is still the leading cause of hospitalization and death. Transmission remains high and is driven by suitable weather conditions. There is a real concern that intervention gains may be reversed by climatic changes in the country. In this study, we investigate the effects of climate on the spatio-temporal trends of malaria incidence in Uganda during 2013-2017.MethodsBayesian spatio-temporal negative binomial models were fitted on district-aggregated monthly malaria cases, reported by two age groups, defined by a cut-off age of 5?years. Weather data was obtained from remote sensing sources including rainfall, day land surface temperature (LSTD) and night land surface temperature (LSTN), Normalized Difference Vegetation Index (NDVI), altitude, land cover, and distance to water bodies. Spatial and temporal correlations were taken into account by assuming a conditional autoregressive and a first-order autoregressive process on district and monthly specific random effects, respectively. Fourier trigonometric functions modeled seasonal fluctuations in malaria transmission. The effects of climatic changes on the malaria incidence changes between 2013 and 2017 were estimated by modeling the difference in time varying climatic conditions at the two time points and adjusting for the effects of intervention coverage, socio-economic status and health seeking behavior.ResultsMalaria incidence declined steadily from 2013 to 2015 and then increased in 2016. The decrease was by over 38% and 20% in children <5?years and individuals ?5?years, respectively. Temporal trends depict a strong bi-annual seasonal pattern with two peaks during April-June and October-December. The annual average of rainfall, LSTD and LSTN increased by 3.7?mm, 2.2?°C and 1.0?°C, respectively, between 2013 and 2017, whereas NDVI decreased by 6.8%. On the one hand, the increase in LSTD and decrease in NDVI were associated with a reduction in the incidence decline. On the other hand, malaria interventions and treatment seeking behavior had reverse effects, that were stronger compared to the effects of climatic changes. Important interactions between interventions with NDVI and LSTD suggest a varying impact of interventions on malaria burden in different climatic conditions.ConclusionClimatic changes in Uganda during the last five years contributed to a favorable environment for malaria transmission, and had a detrimental effect on malaria reduction gains achieved through interventions scale-up efforts. The NMCP should create synergies with the National Meteorological Authority with an ultimate goal of developing a Malaria Early Warning System to mitigate adverse climatic change effects on malaria risk in the country.

Dataset Information

Temporal changes in prevalence of molecular markers mediating antimalarial drug resistance in a high malaria transmission setting in Uganda.

Publications

Temporal changes in prevalence of molecular markers mediating antimalarial drug resistance in a high malaria transmission setting in Uganda.

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