Treatment of malaria restricted to laboratory-confirmed cases: a prospective cohort study in Ugandan children.

BACKGROUND: Presumptive treatment of malaria in febrile children is widely advocated in Africa. This may occur in the absence of diagnostic testing or even when diagnostic testing is performed but fails to detect malaria parasites. Such over-treatment of malaria has been tolerated in the era of inexpensive and safe monotherapy. However, with the introduction of new artemisinin-based combination therapy (ACT), presumptive treatment becomes economically and clinically less acceptable. METHODS: The risks and benefits of only treating children with microscopy confirmed malaria using a prospective cohort design were investigated. A representative sample of 601 children between one and 10 years of age were recruited from a census population in Kampala, Uganda and were followed for all of their health care needs in a study clinic. Standard microscopy was performed each time a child presented with a new episode of fever and antimalarial therapy given only if the blood smear was positive. RESULTS: Of 5,895 visits for new medical problems 40% were for febrile illnesses. Of the 2,359 episodes of new febrile illnesses, blood smears were initially reported as negative in 1,608 (68%) and no antimalarial therapy was given. Six of these initially negative smears were reported to be positive following quality control reading of all blood smears: four of these patients were subsequently diagnosed with uncomplicated malaria and two cleared their parasites without antimalarial treatment. Of the 1,602 new febrile illnesses in which the final blood smear reading was classified as negative, only 13 episodes (0.8%) were diagnosed with malaria in the subsequent 7 days. All 13 of these episodes of malaria were uncomplicated and were successfully treated. CONCLUSION: In this urban setting, malaria was responsible for only 32% of febrile episodes. Withholding antimalarial therapy in febrile children with negative blood smears was safe and saved over 1,600 antimalarial treatments in 601 children over an 18-month period. In the era of expensive ACT, directing resources towards improving diagnostic and treatment practices may provide a cost-effective measure for promoting rational use of antimalarial therapy

Efficacy Studies of Malaria Treatments in Africa: Efficient Estimation with Missing Indicators of Failure

Efficacy studies of malaria treatments can be plagued by indeterminate outcomes for some patients. The study motivating this paper defines the outcome of interest (treatment failure) as recrudescence and for some subjects, it is unclear whether a recurrence of malaria is due to that or new infection. This results in a specific kind of missing data. The effect of missing data in causal inference problems is widely recognized. Methods that adjust for possible bias from missing data include a variety of imputation procedures (extreme case analysis, hot-deck, single and multiple imputation), inverse weighting methods, and likelihood based methods (data augmentation, EM procedures and their extensions). In this article, we focus on multiple imputation, two inverse weighting procedures (the inverse probability of censoring weighted (IPCW) and the doubly robust (DR) estimators), and a likelihood based methodology (G-computation), comparing the methods\u27 applicability to the efficient estimation of malaria treatments effects. We present results from a simulation study as well as results from a data analysis of malaria efficacy studies from Uganda

Safety, tolerability and efficacy of repeated doses of dihydroartemisinin-piperaquine for the prevention and treatment of malaria: A systematic review and meta-analysis

Background Intermittent preventive treatment (IPT) for malaria is used in infants, children, adults and pregnant women. Dihydroartemisinin-piperaquine (DP) is an effective, well tolerated artemisinin-based combination therapy. The long half-life of piperaquine makes it attractive for IPT. We conducted a systematic review and meta-analysis to determine the efficacy and safety of repeated treatment with DP. Methods Following PRISMA guidelines, we searched multiple databases on September 1, 2016 with the terms: “human” AND “dihydroartemisinin-piperaquine” OR “DHA-PPQ.”. Prospective studies of IPT-DP or repeat DP courses for case-management were eligible. Random effects models were used. Findings Eleven studies were included: two repeat treatment studies (one in children <5y and one in pregnant women), and nine IPT trials (five in children <5y; one in schoolchildren; one in adults; two in pregnant women). Comparator interventions included placebo, artemether-lumefantrine, sulfadoxine-pyrimethamine (SP), SP-amodiaquine, SP-piperaquine, SP-chloroquine, and trimethoprim-sulfamethoxazole. Of 14,628 participants, 3,935 received multiple DP courses (2-18). Monthly IPT-DP was associated with an 84% reduction in the incidence of malaria parasitaemia measured by microscopy compared to placebo. Monthly IPT-DP was associated with fewer serious adverse events than placebo, daily trimethoprim-sulfamethoxazole, or monthly SP. Among 56 IPT-DP recipients (26 children, 30 pregnant women), all QTc intervals were within normal limits, with no significant increase in QTc prolongation with increasing courses of DP. Interpretation Monthly DP appears well-tolerated and effective for IPT. Additional data are needed in pregnancy and to further explore the cardiac safety with monthly dosing. Funding Source Bill & Melinda Gates Foundation and NI

The effect of varying analytical methods on estimates of anti-malarial clinical efficacy

<p>Abstract</p> <p>Background</p> <p>Analytical approaches for the interpretation of anti-malarial clinical trials vary considerably. The aim of this study was to quantify the magnitude of the differences between efficacy estimates derived from these approaches and identify the factors underlying these differences.</p> <p>Methods</p> <p>Data from studies conducted in Africa and Thailand were compiled and the risk estimates of treatment failure, adjusted and unadjusted by genotyping, were derived by three methods (intention to treat (ITT), modified intention to treat (mITT) and per protocol (PP)) and then compared.</p> <p>Results</p> <p>29 clinical trials (15 from Africa and 14 from Thailand) with a total of 65 treatment arms (38 from Africa and 27 from Thailand) were included in the analysis. Of the 15,409 patients enrolled, 2,637 (17.1%) had incomplete follow up for the unadjusted analysis and 4,489 (33.4%) for the adjusted analysis. Estimates of treatment failure were consistently higher when derived from the ITT or PP analyses compared to the mITT approach. In the unadjusted analyses the median difference between the ITT and mITT estimates was greater in Thai studies (11.4% [range 2.1–31.8]) compared to African Studies (1.8% [range 0–11.7]). In the adjusted analyses the median difference between PP and mITT estimates was 1.7%, but ranged from 0 to 30.9%. The discrepancy between estimates was correlated significantly with the proportion of patients with incomplete follow-up; p < 0.0001. The proportion of studies with a major difference (> 5%) between adjusted PP and mITT was 28% (16/57), with the risk difference greater in African (37% 14/38) compared to Thai studies (11% 2/19). In the African studies, a major difference in the adjusted estimates was significantly more likely in studies in high transmission sites (62% 8/13) compared to studies in moderate transmission sites (24% 6/25); p = 0.035.</p> <p>Conclusion</p> <p>Estimates of anti-malarial clinical efficacy vary significantly depending on the analytical methodology from which they are derived. In order to monitor temporal and spatial trends in anti-malarial efficacy, standardized analytical tools need to be applied in a transparent and systematic manner.</p

The use of genotyping in antimalarial clinical trials: a systematic review of published studies from 1995–2005

BACKGROUND: The use of genotyping to distinguish recrudescent from new infections is currently recommended for all clinical antimalarial efficacy trials by the World Health Organization. However, genotyping-adjusted drug efficacy estimates may vary between trials due to the use of different genotyping methods and to the different settings in which these methods are applied. METHODS: A systematic review of all clinical antimalarial efficacy trials published from 1995–2005 was performed to characterize the use of genotyping, including the methods used and the effect of these methods on estimates of drug efficacy. RESULTS: In a multivariate analysis, the method of interpretation of genotyping results, the studied therapy, the location of the trial, and the duration of study follow-up all had statistically significant effects on the percent of genotyped outcomes classified as new infections. CONCLUSION: Criteria for defining appropriate, standardized genotyping methods for use in different settings are needed to enable more accurate estimates of antimalarial drug efficacy and better comparison between trials. The advantages and disadvantages of different genotyping methods and their potential impact in various settings are discussed

Drug resistance mediating Plasmodium falciparum polymorphisms and clinical presentations of parasitaemic children in Uganda.

BackgroundPlasmodium falciparum genetic polymorphisms that mediate altered drug sensitivity may impact upon virulence. In a cross-sectional study, Ugandan children with infections mutant at pfcrt K76T, pfmdr1 N86Y, or pfmdr1 D1246Y had about one-fourth the odds of symptomatic malaria compared to those with infections with wild type (WT) sequences. However, results may have been confounded by greater likelihood in those with symptomatic disease of higher density mixed infections and/or recent prior treatment that selected for WT alleles.MethodsPolymorphisms in samples from paired episodes of asymptomatic and symptomatic parasitaemia in 114 subjects aged 4-11 years were followed longitudinally in Tororo District, Uganda. Paired episodes occurred within 3-12 months of each other and had no treatment for malaria in the prior 60 days. The prevalence of WT, mixed, and mutant alleles was determined using multiplex ligase detection reaction-fluorescent microsphere assays.ResultsConsidering paired episodes in the same subject, the odds of symptomatic malaria were lower for infections with mutant compared to WT or mixed sequence at N86Y (OR 0.26, 95% CI 0.09-0.79, p = 0.018), but not K76T or D1246Y. However, symptomatic episodes (which had higher densities) were more likely than asymptomatic to be mixed (for N86Y OR 2.0, 95% CI 1.04-4.0, p = 0.036). Excluding mixed infections, the odds of symptomatic malaria were lower for infections with mutant compared to WT sequence at N86Y (OR 0.33, 95% CI 0.11-0.98, p = 0.046), but not the other alleles. However, if mixed genotypes were grouped with mutants in this analysis or assuming that mixed infections consisted of 50% WT and 50% mutant genotypes, the odds of symptomatic infection did not differ between infections that were mutant or WT at the studied alleles.ConclusionsAlthough infections with only the mutant pfmdr1 86Y genotype were associated with symptomatic infection, this association could primarily be explained by greater parasite densities and therefore greater prevalence of mixed infections in symptomatic children. These results indicate limited association between the tested polymorphisms and risk of symptomatic disease and highlight the value of longitudinal studies for assessing associations between parasite factors and clinical outcomes

Gel versus capillary electrophoresis genotyping for categorizing treatment outcomes in two anti-malarial trials in Uganda

Abstract Background Molecular genotyping is performed in anti-malarial trials to determine whether recurrent parasitaemia after therapy represents a recrudescence (treatment failure) or new infection. The use of capillary instead of agarose gel electrophoresis for genotyping offers technical advantages, but it is unclear whether capillary electrophoresis will result in improved classification of anti-malarial treatment outcomes. Methods Samples were genotyped using both gel and capillary electrophoresis from randomized trials of artemether-lumefantrine (AL) vs. dihydroartemisinin-piperaquine (DP) performed in two areas of Uganda: Kanungu, where transmission is moderate, and Apac, where transmission is very high. Both gel and capillary methods evaluated polymorphic regions of the merozoite surface protein 1 and 2 and glutamine rich protein genes. Results Capillary electrophoresis detected more alleles and provided higher discriminatory power than agarose gel electrophoresis at both study sites. There was only moderate agreement between classification of outcomes with the two methods in Kanungu (kappa = 0.66) and poor agreement in Apac (kappa = 0.24). Overall efficacy results were similar when using gel vs. capillary methods in Kanungu (42-day risk of treatment failure for AL: 6.9% vs. 5.5%, p = 0.4; DP 2.4% vs. 2.9%, p = 0.5). However, the measured risk of recrudescence was significantly higher when using gel vs. capillary electrophoresis in Apac (risk of treatment failure for AL: 17.0% vs. 10.7%, p = 0.02; DP: 8.5% vs. 3.4%, p = 0.03). Risk differences between AL and DP were not significantly different whether gel or capillary methods were used. Conclusions Genotyping with gel electrophoresis overestimates the risk of recrudescence in anti-malarial trials performed in areas of high transmission intensity. Capillary electrophoresis provides more accurate outcomes for such trials and should be performed when possible. In areas of moderate transmission, gel electrophoresis appears adequate to estimate comparative risks of treatment failure

Indoor residual spraying of insecticide and malaria morbidity in a high transmission intensity area of Uganda.

BackgroundRecently the use of indoor residual spraying of insecticide (IRS) has greatly increased in Africa; however, limited data exist on the quantitative impacts of IRS on health outcomes in highly malaria endemic areas.Methodology/principal findingsRoutine data were collected on more than 90,000 patient visits at a single health facility over a 56 month period covering five rounds of IRS using three different insecticides. Temporal associations between the timing of IRS and the probability of a patient referred for microscopy having laboratory confirmed malaria were estimated controlling for seasonality and age. Considering patients less than five years of age there was a modest decrease in the odds of malaria following the 1(st) round of IRS using DDT (OR = 0.76, p&lt;0.001) and the 2(nd) round using alpha-cypermethrin (OR = 0.83, p = 0.002). Following rounds 3-5 using bendiocarb there was a much greater decrease in the odds of malaria (ORs 0.34, 0.16, 0.17 respectively, p&lt;0.001 for all comparisons). Overall, the impact of IRS was less pronounced among patients 5 years or older.Conclusions/significanceIRS was associated with a reduction in malaria morbidity in an area of high transmission intensity in Uganda and the benefits appeared to be greatest after switching to a carbamate class of insecticide

Anti-malarial prescription practices among outpatients with laboratory-confirmed malaria in the setting of a health facility-based sentinel site surveillance system in Uganda.

BACKGROUND: Most African countries have adopted artemisinin-based combination therapy (ACT) as the first-line treatment for uncomplicated malaria. The World Health Organization now recommends limiting anti-malarial treatment to those with a positive malaria test result. Limited data exist on how these policies have affected ACT prescription practices. METHODS: Data were collected from all outpatients presenting to six public health facilities in Uganda as part of a sentinel site malaria surveillance programme. Training in case management, encouragement of laboratory-based diagnosis of malaria, and regular feedback were provided. Data for this report include patients with laboratory confirmed malaria who were prescribed anti-malarial therapy over a two-year period. Patient visits were analysed in two groups: those considered ACT candidates (defined as uncomplicated malaria with no referral for admission in patients ≥ 4 months of age and ≥ 5 kg in weight) and those who may not have been ACT candidates. Associations between variables of interest and failure to prescribe ACT to patients who were ACT candidates were estimated using multivariable logistic regression. RESULTS: A total of 51,355 patient visits were included in the analysis and 46,265 (90.1%) were classified as ACT candidates. In the ACT candidate group, 94.5% were correctly prescribed ACT. Artemether-lumefantrine made up 97.3% of ACT prescribed. There were significant differences across the sites in the proportion of patients for whom there was a failure to prescribe ACT, ranging from 3.0-9.3%. Young children and woman of childbearing age had higher odds of failure to receive an ACT prescription. Among patients who may not have been ACT candidates, the proportion prescribed quinine versus ACT differed based on if the patient had severe malaria or was referred for admission (93.4% vs 6.5%) or was below age or weight cutoffs for ACT (41.4% vs 57.2%). CONCLUSIONS: High rates of compliance with recommended ACT use can be achieved in resource-limited settings. The unique health facility-based malaria surveillance system operating at these clinical sites may provide a framework for improving appropriate ACT use at other sites in sub-Saharan Africa