Abstract:Abstract:We compare the frequency of resistant genes of malaria parasites before treatment and at first malaria incidence after treatment. The data come from a clinical trial at two health facilities in Tanzania and concerns single nucleotide polymorphisms (SNPs) at three positions believed to be related to resistance to malaria treatment. A problem is that mixed infections are common, which both obscures the underlying frequency of alleles at each locus as well as the associations between loci in samples wher… Show more
“…A comparison of the baseline model outcomes with literature estimates for 2006 and the published reference, including the percentage error in the 2006 model estimate, for: the rate of population growth; the proportion of each strain of Plasmodium falciparum malaria in humans; the number of P. falciparum cases of malaria in humans; and the human mortality (total and malaria-specific). Description 2006 Model Outcome 2006 Literature Value (Reference) Difference (%) Population growth, % (2006–2007) 2.7559 2.7 ( The World Bank, 2006–2013b ) 2 Malaria cases 10,857,000 8,926,058 ( World Health Organization, 2010b ) 22 Deaths (all) 500,980 404,332 ( The World Bank, 2006–2013b ) 24 Malaria-specific deaths 72,592 74,970 ( The World Bank, 2006-2013b , World Health Organization, 2010b ) −3 Proportion of SP-sensitive infections in humans 0.1625 0.05–0.5 ( Kum et al., 2013 ) Within range Proportion of SP-resistant infections in humans 0.8356 0.42–0.90 ( Kum et al., 2013 , Spalding et al., 2010 ) Within range Proportion of mixed infections in humans 0.0019 0–0.53 ( Assumed ) Within range …”
Section: Resultsmentioning
confidence: 99%
“…Resistance to SP was defined as the presence of DHFR-51 and DHFR-108 pyrimethamine resistance-conferring mutations ( Méndez et al., 2007 ), used as proxy for all low to moderate SP-resistant conferring mutations in P. falciparum ( Sridaran et al., 2010 ). At baseline, the percentage of humans and mosquitoes with SP-resistant infections was set to 42% ( Kum et al., 2013 , Spalding et al., 2010 ) and mixed infections was set to 8% ( Kum et al., 2013 ). Fig.…”
BackgroundThe use of poor quality antimalarial medicines, including the use of non-recommended medicines for treatment such as sulfadoxine-pyrimethamine (SP) monotherapy, undermines malaria control and elimination efforts. Furthermore, the use of subtherapeutic doses of the active ingredient(s) can theoretically promote the emergence and transmission of drug resistant parasites.MethodsWe developed a deterministic compartmental model to quantify the impact of antimalarial medicine quality on the transmission of SP resistance, and validated it using sensitivity analysis and a comparison with data from Kenya collected in 2006. We modelled human and mosquito population dynamics, incorporating two Plasmodium falciparum subtypes (SP-sensitive and SP-resistant) and both poor quality and good quality (artemether-lumefantrine) antimalarial use.FindingsThe model predicted that an increase in human malaria cases, and among these, an increase in the proportion of SP-resistant infections, resulted from an increase in poor quality SP antimalarial use, whether it was full- or half-dose SP monotherapy.InterpretationOur findings suggest that an increase in poor quality antimalarial use predicts an increase in the transmission of resistance. This highlights the need for stricter control and regulation on the availability and use of poor quality antimalarial medicines, in order to offer safe and effective treatments, and work towards the eradication of malaria.
“…A comparison of the baseline model outcomes with literature estimates for 2006 and the published reference, including the percentage error in the 2006 model estimate, for: the rate of population growth; the proportion of each strain of Plasmodium falciparum malaria in humans; the number of P. falciparum cases of malaria in humans; and the human mortality (total and malaria-specific). Description 2006 Model Outcome 2006 Literature Value (Reference) Difference (%) Population growth, % (2006–2007) 2.7559 2.7 ( The World Bank, 2006–2013b ) 2 Malaria cases 10,857,000 8,926,058 ( World Health Organization, 2010b ) 22 Deaths (all) 500,980 404,332 ( The World Bank, 2006–2013b ) 24 Malaria-specific deaths 72,592 74,970 ( The World Bank, 2006-2013b , World Health Organization, 2010b ) −3 Proportion of SP-sensitive infections in humans 0.1625 0.05–0.5 ( Kum et al., 2013 ) Within range Proportion of SP-resistant infections in humans 0.8356 0.42–0.90 ( Kum et al., 2013 , Spalding et al., 2010 ) Within range Proportion of mixed infections in humans 0.0019 0–0.53 ( Assumed ) Within range …”
Section: Resultsmentioning
confidence: 99%
“…Resistance to SP was defined as the presence of DHFR-51 and DHFR-108 pyrimethamine resistance-conferring mutations ( Méndez et al., 2007 ), used as proxy for all low to moderate SP-resistant conferring mutations in P. falciparum ( Sridaran et al., 2010 ). At baseline, the percentage of humans and mosquitoes with SP-resistant infections was set to 42% ( Kum et al., 2013 , Spalding et al., 2010 ) and mixed infections was set to 8% ( Kum et al., 2013 ). Fig.…”
BackgroundThe use of poor quality antimalarial medicines, including the use of non-recommended medicines for treatment such as sulfadoxine-pyrimethamine (SP) monotherapy, undermines malaria control and elimination efforts. Furthermore, the use of subtherapeutic doses of the active ingredient(s) can theoretically promote the emergence and transmission of drug resistant parasites.MethodsWe developed a deterministic compartmental model to quantify the impact of antimalarial medicine quality on the transmission of SP resistance, and validated it using sensitivity analysis and a comparison with data from Kenya collected in 2006. We modelled human and mosquito population dynamics, incorporating two Plasmodium falciparum subtypes (SP-sensitive and SP-resistant) and both poor quality and good quality (artemether-lumefantrine) antimalarial use.FindingsThe model predicted that an increase in human malaria cases, and among these, an increase in the proportion of SP-resistant infections, resulted from an increase in poor quality SP antimalarial use, whether it was full- or half-dose SP monotherapy.InterpretationOur findings suggest that an increase in poor quality antimalarial use predicts an increase in the transmission of resistance. This highlights the need for stricter control and regulation on the availability and use of poor quality antimalarial medicines, in order to offer safe and effective treatments, and work towards the eradication of malaria.
“…The first model (3) was used to study which combinations of M, R, and S seemed to best explain the outcome. Two other models (4) and (5) respectively, were used to test whether the outcome varied with time and age of the children.…”
Section: Proposed Modelsmentioning
confidence: 99%
“…The data came from a clinical trial conducted in Tanzania in 2004 to compare the efficacy of ACTs with alternative treatments without artemisinin. For a better understanding of this paper, we will give a brief description of the study in Section 2 but a detailed description is found in [4,5].…”
Section: Introductionmentioning
confidence: 99%
“…In the article [5], we developed a probability model for the estimation of haplotype frequencies and used it to compare the proportion of parasites with resistance genes at baseline and at first recurrences, and also study the effects of malaria treatment on parasite drug resistance. Results in that article confirmed that ACTs are more effective in treating malaria without increasing drug resistance in the remaining parasites.…”
Many investigations have shown that artemisinin-based combination therapies are effective in the treatment of uncomplicated malaria and that they do not increase parasite resistance to treatment as much as treatment with single substance. We study the relation between some biological covariates and the time to first recurrence of malaria for children treated for malaria in a clinical trial. One group received artesunate plus sulfadoxine-pyrimethamine and the other only sulfadoxine-pyrimethamine. We consider the event malaria-free for the first 42 (and 84) days. We use logistic regression models for the analyses. The main results show that the probability of no recurrence is higher if the parasite density in the blood is high. The results are inconclusive for other explanatory biological variables. The infecting parasites having genes that indicate resistance, gave different results at the two different treatment centres. There was no appreciable difference in the effects of treatment over the two follow-up periods and these treatments do not have any effect on the probability of a recurrence.
BackgroundReliable measures of anti-malarial resistance are crucial for malaria control. Resistance is typically a complex trait: multiple mutations in a single parasite (a haplotype or genotype) are necessary for elaboration of the resistant phenotype. The frequency of a genetic motif (proportion of parasite clones in the parasite population that carry a given allele, haplotype or genotype) is a useful measure of resistance. In areas of high endemicity, malaria patients generally harbour multiple parasite clones; they have multiplicities of infection (MOIs) greater than one. However, most standard experimental procedures only allow measurement of marker prevalence (proportion of patient blood samples that test positive for a given mutation or combination of mutations), not frequency. It is misleading to compare marker prevalence between sites that have different mean MOIs; frequencies are required instead.MethodsA Bayesian statistical model was developed to estimate Plasmodium falciparum genetic motif frequencies from prevalence data collected in the field. To assess model performance and computational speed, a detailed simulation study was implemented. Application of the model was tested using datasets from five sites in Uganda. The datasets included prevalence data on markers of resistance to sulphadoxine-pyrimethamine and an average MOI estimate for each study site.ResultsThe simulation study revealed that the genetic motif frequencies that were estimated using the model were more accurate and precise than conventional estimates based on direct counting. Importantly, the model did not require measurements of the MOI in each patient; it used the average MOI in the patient population. Furthermore, if a dataset included partially genotyped patient blood samples, the model imputed the data that were missing. Using the model and the Ugandan data, genotype frequencies were estimated and four biologically relevant genotypes were identified.ConclusionsThe model allows fast, accurate, reliable estimation of the frequency of genetic motifs associated with resistance to anti-malarials using prevalence data collected from malaria patients. The model does not require per-patient MOI measurements and can easily analyse data from five markers. The model will be a valuable tool for monitoring markers of anti-malarial drug resistance, including markers of resistance to artemisinin derivatives and partner drugs.
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