OpenUCT :: Browsing by Author "Barnes, Karen"

Browsing by Author "Barnes, Karen"

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Open Access
Effect of dihydroartemisin-piperaquine for malaria intermittent preventive treatment on dolutegravir exposure in pregnant women living with HIV
(2023) Banda, Clifford; Barnes, Karen; Maartens Gary
Background: In sub-Saharan Africa, the disease burden of malaria and HIV infections overlap. In settings with moderate-to-high malaria transmission intensity, pregnant women living with HIV (PWLHIV) require both antiretroviral therapy and malaria intermittent preventive treatment (IPTp). Dihydroartemisinin-piperaquine has been identified as a promising alternative to sulfadoxine-pyrimethamine for malaria prevention in pregnancy. However, another antimalarial drug, artesunate-amodiaquine, similar to dihydroartemisininpiperaquine, was previously shown to reduce dolutegravir exposure in non-pregnant adults. Objective: To investigate the effect of dihydroartemisinin-piperaquine for IPTp on dolutegravir plasma exposure in pregnant women on dolutegravir-based antiretroviral therapy. Methods: We conducted an open-label, non-randomised, fixed sequence, pharmacokinetic study in PWLHIV in Malawi. Dolutegravir concentrations were measured over a 24-hour period, before and after the recommended three-day treatment dose of dihydroartemisininpiperaquine in 12 pregnant women in their 2nd or 3rd trimester. Non-compartmental analysis was performed, and geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were generated to compare dolutegravir pharmacokinetic parameters between the two treatment periods. Results: Co-administration of dihydroartemisinin-piperaquine and dolutegravir increased dolutegravir's overall exposure (AUC0-24hr) and maximum concentration (Cmax) by 30% (GMR,1.30; 90% CI, 1.11-1.52) and 31% (GMR, 1.31; 90% CI,1.13-1.51), respectively. Furthermore, dolutegravir's trough (C24) concentration increased by 42% (GMR,1.42; 90% CI,1.09-1.85). The combined treatments were well tolerated with no serious adverse events observed. Conclusion: Dihydroartemisinin-piperaquine may be administered as IPTp with dolutegravir-based antiretroviral therapy in pregnant women as the modest increase in dolutegravir exposure, similar to pharmacokinetic parameter values published previously, assures its efficacy without any clinically significant adverse events observed in this small study
Open Access
Effects of amodiaquine and artesunate on sulphadoxine-pyrimethamine pharmacokinetic parameters in children under five in Mali
(BioMed Central Ltd, 2011) Tekete, Mamadou; Toure, Sekou; Fredericks, Alfia; Beavogui, Abdoul; Sangare, Cheick; Evans, Alicia; Smith, Peter; Maiga, Hamma; Traore, Zoumana; Doumbo, Ogobara; Barnes, Karen; Djimde, Abdoulaye
BACKGROUND:Sulphadoxine-pyrimethamine, in combination with artesunate or amodiaquine, is recommended for the treatment of uncomplicated malaria and is being evaluated for intermittent preventive treatment. Yet, limited data is available on pharmacokinetic interactions between these drugs. METHODS: In a randomized controlled trial, children aged 6-59 months with uncomplicated falciparum malaria, received either one dose of sulphadoxine-pyrimethamine alone (SP), one dose of SP plus three daily doses of amodiaquine (SP+AQ) or one dose of SP plus 3 daily doses of artesunate (SP+AS). Exactly 100 mul of capillary blood was collected onto filter paper before drug administration at day 0 and at days 1, 3, 7, 14, 21 and 28 after drug administration for analysis of sulphadoxine and pyrimethamine pharmacokinetic parameters. RESULTS: Fourty, 38 and 31 patients in the SP, SP+AQ and SP+AS arms, respectively were included in this study. The concentrations on day 7 (that are associated with therapeutic efficacy) were similar between the SP, SP+AQ and SP+AS treatment arms for sulphadoxine (median [IQR] 35.25 [27.38-41.70], 34.95 [28.60-40.85] and 33.40 [24.63-44.05] mug/mL) and for pyrimethamine (56.75 [46.40-92.95], 58.75 [43.60-98.60] and 59.60 [42.45-86.63] ng/mL). There were statistically significant differences between the pyrimethamine volumes of distribution (4.65 [3.93-6.40], 4.00 [3.03-5.43] and 5.60 [4.40-7.20] L/kg; p = 0.001) and thus elimination half-life (3.26 [2.74 -3.82], 2.78 [2.24-3.65] and 4.02 [3.05-4.85] days; p < 0.001). This study confirmed the lower SP concentrations previously reported for young children when compared with adult malaria patients. CONCLUSION: Despite slight differences in pyrimethamine volumes of distribution and elimination half-life, these data show similar exposure to SP over the critical initial seven days of treatment and support the current use of SP in combination with either AQ or AS for uncomplicated falciparum malaria treatment in young Malian children.
Open Access
Eliciting harms data from trial participants: how perceptions of illness and treatment mediate recognition of relevant information to report
(BioMed Central Ltd, 2011) Allen, Elizabeth; Barnes, Karen; Mushi, Adiel; Massawe, Isolide; Staedke, Sarah; Mehta, Ushma; Vestergaard, Lasse; Lemnge, Martha; Chandler, Clare
Background: There is no consensus on the ideal methodology for eliciting participant-reported harms, but question methods influence the extent and nature of data detected. This gives potential for measurement error and undermines meta-analyses of adverse effects. We undertook to identify barriers to accurate and complete reporting of harms data, by qualitatively exploring participants’ experiences of illness and treatment, and reporting behaviours; and compared the number and nature of data detected by three enquiry methods. Methods: Participants within antiretroviral/antimalarial interaction trials in South Africa and Tanzania were asked about medical history, treatments and/or adverse events by general enquiries followed by checklists. Those reporting differently between these two question methods were invited to an in-depth interview and focus group discussion. Health narratives were analysed to investigate accuracy and completeness of case record form data and to understand reasons for differential reporting between question methods. Outcomes were the number and nature of data by question method, themes from qualitative analyses and a theoretical interpretation of participants’ experiences. Results: We observed a cumulative increase in sensitivity of detection of all types of reports while progressing from general enquiry, through checklist, to in-depth interview. Questioning detail and terminology influenced participants’ recognition of health issues and treatments. Reporting patterns and vocabulary suggest influence from the relative importance that illnesses and treatments have for participants. Perceptions were often dichotomised (e.g. ‘street’ versus clinic treatments, symptoms experienced versus tests and examinations performed, chronic versus acute illness, persistent versus intermittent symptoms, activity- versus malaria-related symptoms) and this differentiation extended to ideas of relevance to report. South African participants displayed a ‘trial citizenship’, taking responsibility for the impact of their reporting on trial results, and even reaching reporting decisions by consensus. In contrast, Tanzanians perceived their role more as patients than participants; the locus of responsibility for knowing information relevant to the trial fell with trial staff as doctors rather than with themselves. Conclusions: Our observations of how reporting relates to participant perceptions inside and outside trials could help optimise how harms data are elicited. Questions reflecting the different ways that biomedically defined illness and treatment data are perceived by participants may help them understand relevance for reporting. We will theorise how these two disparate trial environments may have influenced how participants understood their role, as this could help researchers achieve empowered participation in similar trials.
Open Access
Evaluating harm associated with anti-malarial drugs: a survey of methods used by clinical researchers to elicit, assess and record participant-reported adverse events and related data
(BioMed Central Ltd, 2013) Allen, Elizabeth; Chandler, Clare; Mandimika, Nyaradzo; Pace, Cheryl; Mehta, Ushma; Barnes, Karen
BACKGROUND:Participant reports of medical histories, adverse events (AE) and non-study drugs are integral to evaluating harm in clinical research. However, interpreting or synthesizing results is complicated if studies use different methods for ascertaining and assessing these data. To explore how these data are obtained in malaria drug studies, a descriptive online survey of clinical researchers was conducted during 2012 and 2013. METHODS: The survey was advertised through e-mails, collaborators and at conferences. Questions aimed to capture the detail, rationale and application of methods used to obtain relevant data within various study designs and populations. Closed responses were analysed using proportions, open responses through identifying repeating ideas and underlying concepts. RESULTS: Of fifty-two respondents from 25 counties, 87% worked at an investigational site and 75% reported about an interventional study. Studies employed a range of methods to elicit, assess and record participant-reported AEs and related data. Questioning about AEs in 31% of interventional studies was a combination of general (open questions about health) and structured (reference to specific health-related items), 26% used structured only and 18% general only. No observational studies used general questioning alone. A minority incorporated pictorial tools. Rationales for the questioning approach included: standardization of assessment or data capture, specificity or comprehensiveness of data sought, avoidance of suggestion, feasibility, and understanding participants' perceptions. Most respondents considered the approach they reported was optimal, though several reconsidered this. Four AE grading, and three causality assessment approaches were reported. Combining general and structured questions about non-study drug use were considered useful for revealing and identifying specific medicines, while pictures could enhance reports, particularly in areas of low literacy. CONCLUSIONS: It is critical to evaluate the safety of anti-malarial drugs being deployed in large, diverse populations. Many studies would be suitable for contributing to a larger body of evidence for answering questions on harm. However this survey showed that various methods are used to obtain relevant data, which could influence study results. As the best practices for obtaining such data are unclear, anti-malarial clinical researchers should work towards consensus about the selection and/or design of optimal methods.
Open Access
Evaluating the cost-effectiveness of artemisinin-based combination antimalarial drugs and malaria rapid diagnostic tests within the context of effective vector control : case study of Southern Africa
(2006) Zikusooka, Charlotte Muheki; McIntyre, Di; Barnes, Karen
This study seeks to use the techniques of cost-effectiveness analysis to evaluate, within the context of effective vector control, the change to artemisinin-based combination therapies (ACTs) as first line malaria treatment and to evaluate the relevance of using definitive diagnosis (as opposed to clinical diagnosis) as the basis for initiating malaria treatment, especially when using ACTs for treatment. The cost-effectiveness of ACTs was evaluated in two study sites (i.e. In Kwazulu Natal which switched from SP monotherapy to AL in 2001 and in Mpumalanga which changed from SP monotherapy to AS+SP in 2003) in South Africa. The economic evaluation of use of routine definitive diagnosis as part of malaria case management, using rapid diagnostic tests (ROTs), was undertaken at two districts (Namaacha and Matutuine), in southern Mozambique, where routine use of ROTs and treating malaria patients with an ACT (using artesunate + SP) were implemented at pilot level in 2003.
Open Access
How experiences become data: the process of eliciting adverse event, medical history and concomitant medication reports in antimalarial and antiretroviral interaction trials
(BioMed Central Ltd, 2013) Allen, Elizabeth; Mushi, Adiel; Massawe, Isolide; Vestergaard, Lasse; Lemnge, Martha; Staedke, Sarah; Mehta, Ushma; Barnes, Karen; Chandler, Clare
BACKGROUND:Accurately characterizing a drug's safety profile is essential. Trial harm and tolerability assessments rely, in part, on participants' reports of medical histories, adverse events (AEs), and concomitant medications. Optimal methods for questioning participants are unclear, but different methods giving different results can undermine meta-analyses. This study compared methods for eliciting such data and explored reasons for dissimilar participant responses. METHODS: Participants from open-label antimalarial and antiretroviral interaction trials in two distinct sites (South Africa, n=18 [all HIV positive]; Tanzania, n=80 [86% HIV positive]) were asked about ill health and treatment use by sequential use of (1) general enquiries without reference to particular conditions, body systems or treatments, (2) checklists of potential health issues and treatments, (3) in-depth interviews. Participants' experiences of illness and treatment and their reporting behaviour were explored qualitatively, as were trial clinicians' experiences with obtaining participant reports. Outcomes were the number and nature of data by questioning method, themes from qualitative analyses and a theoretical interpretation of participants' experiences. RESULTS: There was an overall cumulative increase in the number of reports from general enquiry through checklists to in-depth interview; in South Africa, an additional 12 medical histories, 21 AEs and 27 medications; in Tanzania an additional 260 medical histories, 1 AE and 11 medications. Checklists and interviews facilitated recognition of health issues and treatments, and consideration of what to report. Information was sometimes not reported because participants forgot, it was considered irrelevant or insignificant, or they feared reporting. Some medicine names were not known and answers to questions were considered inferior to blood tests for detecting ill health. South African inpatient volunteers exhibited a "trial citizenship", working to achieve researchers' goals, while Tanzanian outpatients sometimes deferred responsibility for identifying items to report to trial clinicians. CONCLUSIONS: Questioning methods and trial contexts influence the detection of adverse events, medical histories and concomitant medications. There should be further methodological work to investigate these influences and find appropriate questioning methods.
Open Access
Impact of the large-scale deployment of artemether/lumefantrine on the malaria disease burden in Africa: case studies of South Africa, Zambia and Ethiopia
(BioMed Central Ltd, 2009) Barnes, Karen; Chanda, Pascalina; Ab Barnabas, Gebre
Malaria is one of the most significant causes of morbidity and mortality worldwide. Every year, nearly one million deaths result from malaria infection. Malaria can be controlled in endemic countries by using artemisinin-based combination therapy (ACT) in combination with indoor residual spraying (IRS) and insecticide-treated nets (ITNs). At least 40 malaria-endemic countries in sub-Saharan Africa now recommend the use of ACT as first-line treatment for uncomplicated falciparum malaria as a cornerstone of their malaria case management. The scaling up of malaria control strategies in Zambia has dramatically reduced the burden of malaria. Zambia was the first African country to adopt artemether/lumefantrine (AL; Coartem(R)) as first-line therapy in national malaria treatment guidelines in 2002. Further, the vector control with IRS and ITNs was also scaled up. By 2008, the rates of in-patient malaria cases and deaths decreased by 61% and 66%, respectively, compared with the 2001-2002 reference period.Treatment with AL as first-line therapy against a malaria epidemic in the KwaZulu-Natal province of South Africa, in combination with strengthening of vector control, caused the number of malaria-related outpatient cases and hospital admissions to each fall by 99% from 2001 to 2003, and malaria-related deaths decreased by 97% over the same period. A prospective study also showed that gametocyte development was prevented in all patients receiving AL. This reduction in malaria morbidity has been sustained over the past seven years.AL was introduced as first-line anti-malarial treatment in 2004 in the Tigray region of Ethiopia. During a major malaria epidemic from May-October 2005, the district in which local community health workers were operating had half the rate of malaria-related deaths compared with the district in which AL was only available in state health facilities. Over the two-year study period, the community-based deployment of AL significantly lowered the risk of malaria-specific mortality by 37%. Additionally, the malaria parasite reservoir was three-fold lower in the intervention district than in the control district during the 2005 high-transmission season.Artemisinin-based combination therapy has made a substantial contribution to reducing the burden of malaria in sub-Saharan Africa.
Open Access
Implementation of a reference standard and proficiency testing programme by the World Wide Antimalarial Resistance Network (WWARN)
(BioMed Central Ltd, 2010) Lourens, Chris; Watkins, William; Barnes, Karen; Sibley, Carol; Guerin, Philippe; White, Nicholas; Lindegardh, Niklas
BACKGROUND: The Worldwide Antimalarial Resistance Network (WWARN) is a global collaboration to support the objective that anyone affected by malaria receives effective and safe drug treatment. The Pharmacology module aims to inform optimal anti-malarial drug selection. There is an urgent need to define the drug exposure - effect relationship for most anti-malarial drugs. Few anti-malarials have had their therapeutic blood concentration levels defined. One of the main challenges in assessing safety and efficacy data in relation to drug concentrations is the comparability of data generated from different laboratories. To explain differences in anti-malarial pharmacokinetics in studies with different measurement laboratories it is necessary to confirm the accuracy of the assay methods. This requires the establishment of an external quality assurance process to assure results that can be compared. This paper describes this process. METHODS: The pharmacology module of WWARN has established a quality assurance/quality control (QA/QC) programme consisting of two separate components:1. A proficiency testing programme where blank human plasma spiked with certified reference material (CRM) in different concentrations is sent out to participating bioanalytical laboratories.2. A certified reference standard programme where accurately weighed amounts of certified anti-malarial reference standards, metabolites, and internal standards are sent to participating bioanalytical and in vitro laboratories. CONCLUSION: The proficiency testing programme is designed as a cooperative effort to help participating laboratories assess their ability to carry out drug analysis, resolve any potential problem areas and to improve their results - and, in so doing, to improve the quality of anti-malarial pharmacokinetic data published and shared with WWARN.By utilizing the same source of standards for all laboratories, it is possible to minimize bias arising from poor quality reference standards. By providing anti-malarial drug standards from a central point, it is possible to lower the cost of these standards.
Open Access
Joint models for nonlinear longitudinal profiles in the presence of informative censoring
(2018) Chatora, Tinashe; Little, Francesca; Barnes, Karen
Malaria is the parasitic disease which affects the most humans, with Plasmodium falciparum malaria being responsible for the majority of severe malaria and malaria related deaths. The asexual form of the parasite causes the signs and symptoms associated with malaria infection. The sexual form of the parasite, also known as a gametocyte, is the stage responsible for infectivity of the human host (patient) to the mosquito vector, and thus ongoing transmission of malaria and the spread of antimalarial drug resistance. Historically malaria therapeutic efficacy studies have focused mainly on the clearance of asexual parasites. However, malaria in a community can only be truly combated if a treatment program is implemented which is able to clear both asexual and sexual parasites effectively. In this thesis focus will be on the modeling of the key features of gametocytemia. Particular emphasis will be on the modeling of the time to gametocyte emergence, the density of gametocytes and the duration of gametocytemia. It is also of interest to investigate the impact of the administered treatment on the aforementioned features. Gametocyte data has several interesting features. Firstly, the distribution of gametocyte data is zero-inflated with a long tail to the right. The observed longitudinal gametocyte profile also has a nonlinear relationship with time. In addition, since most malaria intervention studies are not designed to optimally measure the evolution of the longitudinal gametocyte profile, there are very few observation points in the time period where the gametocyte profile is expected to peak. Gametocyte data collected from malaria intervention studies are also affected by informative censoring, which leads to incomplete gametocyte profiles. An example of informative censoring is when a patient who experiences treatment failure is “rescued", and withdrawn, from the study in order to receive alternative treatment. This patient can be considered to be in worse health as compared to the patients who remain in this study. There are also competing risks of exit from the study, as a patient can either experience treatment failure or be lost to follow-up. The above mentioned features of gametocyte data make it a statistically appealing dataset to analyze. In literature there are several modeling techniques which can be used to analyze individual features of the data. These techniques include standard survival models for modeling the time to gametocyte emergence and the duration of gametocytemia. The longitudinal nonlinear gametocyte profile would typically be modeled using nonlinear mixed effect models. These nonlinear models could then subsequently be extended to accommodate the zero-inflation in the data, by changing the underlying assumption around the distribution of the response variable. However, it is important to note that these standard techniques do not account for informative censoring. Failure to account for informative censoring leads to bias in parameter estimates. Joint modeling techniques can be used to account for informative censoring. The joint models applied in this thesis combined the longitudinal nonlinear gametocyte densities and the time to censoring due to either lost to follow up or treatment failure. The data analyzed in this thesis were collected from a series of clinical trials conducted be- tween 2002 and 2004 in Mozambique and the Mpumulanga province of South Africa. These trials were a part of the South East African Combination Antimalarial Therapy (SEACAT) evaluation of the phased introduction of combination anti-malarial therapy, nested in the Lubombo Spatial Development Initiative. The aim of these studies was primarily to measure the efficacy of sulfadoxine-pyrimethamine (SP) and a combination of artesunate and sulfadoxine-pyrimethamine (ACT), in eliminating asexual parasites in patients. The patients enrolled in the study had uncomplicated malaria, at a time of increasing resistance to sulfadoxine-pyrimethamine (SP) treatment. Blood samples were taken from patients during the course of 6 weeks on days 0, 1, 2, 3, 7, 14, 21, 28 and 42. Analysis of these blood samples provided longitudinal measurements for asexual 1 parasite densities, gametocyte densities, sulfadoxine drug concentrations and pyrimethamine drug concentrations. The gametocyte data collected in this study was initially analyzed using standard survival modeling techniques. Non-parametric Cox regression models and parametric survival models were applied to the data as part of this initial investigation. These models were used to investigate the factors which affected the time to gametocyte emergence. Subsequently, using the subset of the population which experienced gametocytemia, accelerated failure time models were applied to investigate the factors which affected the duration of gametocytemia. It is evident that the findings from the aforementioned duration investigation would only be able to provide valid duration estimates for patients who were detected to have gametocytemia. This work was extended to allow for population level duration estimates by incorporating the prevalence of gametocytemia into the estimation of duration, for generic patients with specific covariate patterns. The prevalence of gametocytemia was modeled using an underlying binomial distribution. The delta method was subsequently used to derive confidence intervals for the population level duration estimates which were associated with specific covariate patterns. An investigation into the factors affecting the early withdrawal of patients from the study was also conducted. Early exit from the study arose either through loss to follow-up (LTFU) or through treatment failure. The longitudinal gametocyte profile was modeled using joint modeling techniques. The resulting joint model used shared random effects to combine a Weibull survival model, describing the cause- specific hazards of patient exit from the study, with a nonlinear zero-adjusted gamma mixed effect model for the longitudinal gametocyte profile. This model was used to impute the incomplete gametocyte profiles, after adjusting for informative censoring. These imputed profiles were then used to estimate the duration of gametocytemia. It was found, in this thesis, that treatment had a very strong effect on the hazard of gametocyte emergence, density of gametocytes and the duration of gametocytemia. Patients who received a combination of sulfadoxine-pyrimethamine and artesunate were found to have significantly lower hazards of gametocyte emergence, lower predicted durations of gametocytemia and lower predicted longitudinal gametocyte densities as compared to patients who received sulfadoxine-pyrimethamine treatment only.
Open Access
A mathematical modelling approach for the elimination of malaria in Mpumalanga, South Africa
(2014) Silal, Sheetal Prakash; Little, Francesca; Barnes, Karen; White, Lisa J
Mpumalanga in South Africa is committed to eliminating malaria by 2018 and efforts are increasing beyond that necessary for malaria control. The eastern border of Mpumalanga is most affected by malaria with imported cases in Mpumalanga overtaking local cases in recent years. Mathematical modelling may be used to study the incidence and spread of disease with an important benefit being the ability to enact exogenous change on the system to predict impact without committing any real resources. Three models are developed to simulate malaria transmission: (1) a deterministic non-linear ordinary differential equation model, (2) a stochastic non-linear metapopulation differential equation model and (3) a stochastic hybrid metapopulation differential equation, individual-based model. These models are fitted to weekly case data from Mpumalanga from 2002 to 2008, and validated with data from 2009 to 2012. Interventions such as scaling-up vector control, mass drug administration, focal screen and treat campaign at the Mpumalanga-Maputo border-control point and source reduction are applied to the model to assess their potential impact on transmission and whether they may be used alone or in combination to achieve malaria elimination. The models predicted that scaling up vector control results in substantial decreases in local infections, though with little impact on imported infections. Mass drug administration is a high impacting but short-lived intervention with transmission reverting to pre-intervention levels within three years. Focal screen and treat campaigns are predicted to result in substantial decreases in local infections, though success of the campaign is dependent on the ability to detect low parasitemic infections. Large decreases in local infections are also predicted to be achieved through foreign source reduction. The impact of imported infections is such that malaria elimination is only predicted if all imported infections are treated before entry into Mpumalanga, or are themselves eliminated at their source. Thus a regionally-focused strategy may stand a better chance at achieving elimination in Mpumalanga and South Africa compared to a nationally-focused one. In this manner, mathematical models may form an integral part of the research, planning and evaluation of the research, planning and evaluation of elimination-focused strategies so that malaria elimination is possible in the foreseeable future.
Open Access
A multi-center, open-label trial to compare the efficacy and pharmacokinetics of Artemether-Lumefantrine in children with severe acute malnutrition versus children without severe acute malnutrition: study protocol for the MAL-NUT study
(BioMed Central Ltd, 2015) Denoeud-Ndam, Lise; Dicko, Alassane; Baudin, Elisabeth; Guindo, Ousmane; Grandesso, Francesco; Sagara, Issaka; Lasry, Estrella; Palma, Pedro; Parra, Angeles; Stepniewska, Kasia; Djimde, Abdoulaye; Barnes, Karen; Doumbo, Ogobara; Etard, Jean-Francois
BACKGROUND:Malnutrition and malaria frequently coexist in sub-Saharan African countries. Studies on efficacy of antimalarial treatments usually follow the WHO standardized protocol in which severely malnourished children are systematically excluded.Few studies have assessed the efficacy of chloroquine, sulfadoxine-pyrimethamine and quinine in severe acute malnourished children. Overall, efficacy of these treatments appeared to be reduced, attributed to lower immunity and for some antimalarials altered pharmacokinetic profiles and lower drug concentrations. However, similar research on the efficacy and pharmacokinetic profiles of artemisinin-combination therapies (ACTs) and especially artemether-lumefantrine in malnourished children is currently lacking.The main objective of this study is to assess whether artemether-lumefantrine is less efficacious in children suffering from severe acute malnutrition (SAM) compared to non-SAM children, and if so, to what extent this can be attributed to a sub-optimal pharmacokinetic profile.METHODS/DESIGN:In two sites, Ouelessebougou, Mali and Maradi, Niger, children with uncomplicated microscopically-confirmed P. falciparum malaria aged between 6 and 59 months will be enrolled. Two non-SAM children will be enrolled after the enrolment of each SAM case. Children with severe manifestations of malaria or complications of acute malnutrition needing intensive treatment will be excluded.Treatment intakes will be supervised and children will be followed-up for 42 days, according to WHO guidance for surveillance of antimalarial drug efficacy. Polymerase Chain Reaction genotyping will be used to distinguish recrudescence from re-infection. SAM children will also benefit from the national nutritional rehabilitation program.Outcomes will be compared between the SAM and non-SAM populations. The primary outcome will be adequate clinical and parasitological response at day 28 after PCR correction, estimated by Kaplan-Meier analysis. To assess the pharmacokinetic profile of lumefantrine, a sparse sampling approach will be used with randomized allocation of sampling times (5 per child). A total of 180 SAM children and 360 non-SAM children will be recruited during the 2013 and 2014 malaria seasons.DISCUSSION:This study will provide important information that is currently lacking on the effect of SAM on therapeutic efficacy and pharmacokinetic profile of artemether-lumefantrine. If it shows lower therapeutic efficacy and decreased lumefantrine concentrations, it would inform dose optimization studies in SAM children.TRIAL REGISTRATION:ClinicalTrials.gov: NCT01958905
Open Access
Multivariate muti-level non-linear mixed-effect models and their application to the modeling of drug-concentration time curves
(2011) Mauff, Katya; Little, Francesca; Barnes, Karen
This thesis discusses the techniques involved in the fitting of nonlinear mixed effect (NLME) models. In particular, it looks at the application of these techniques to the analysis of concentration-time data for the aforementioned antimalarial compounds, and details the necessary extensions to the basic modeling process that were required in order to accommodate multiple responses and multiple observation phases (pregnant and postpartum).
Open Access
Nonlinear mixed effects modeling of gametocyte carriage in patients with uncomplicated malaria
(BioMed Central Ltd, 2010) Distiller, Greg; Little, Francesca; Barnes, Karen
BACKGROUND:Gametocytes are the sexual form of the malaria parasite and the main agents of transmission. While there are several factors that influence host infectivity, the density of gametocytes appears to be the best single measure that is related to the human host's infectivity to mosquitoes. Despite the obviously important role that gametocytes play in the transmission of malaria and spread of anti-malarial resistance, it is common to estimate gametocyte carriage indirectly based on asexual parasite measurements. The objective of this research was to directly model observed gametocyte densities over time, during the primary infection. METHODS: Of 447 patients enrolled in sulphadoxine-pyrimethamine therapeutic efficacy studies in South Africa and Mozambique, a subset of 103 patients who had no gametocytes pre-treatment and who had at least three non-zero gametocyte densities over the 42-day follow up period were included in this analysis. RESULTS: A variety of different functions were examined. A modified version of the critical exponential function was selected for the final model given its robustness across different datasets and its flexibility in assuming a variety of different shapes. Age, site, initial asexual parasite density (logged to the base 10), and an empirical patient category were the co-variates that were found to improve the model. CONCLUSIONS: A population nonlinear modeling approach seems promising and produced a flexible function whose estimates were stable across various different datasets. Surprisingly, dihydrofolate reductase and dihydropteroate synthetase mutation prevalence did not enter the model. This is probably related to a lack of power (quintuple mutations n = 12), and informative censoring; treatment failures were withdrawn from the study and given rescue treatment, usually prior to completion of follow up.
Open Access
Nonlinear mixed effects modeling of gametocyte carriage in patients with uncomplicated malaria
(2007) Distiller, G B; Little, Francesca; Barnes, Karen
Includes bibliographical references (leaves 96-102)
Open Access
Predicting the impact of border control on malaria transmission: a simulated focal screen and treat campaign
(BioMed Central Ltd, 2015) Silal, Sheetal; Little, Francesca; Barnes, Karen; White, Lisa
BACKGROUND: South Africa is one of many countries committed to malaria elimination with a target of 2018 and all malaria-endemic provinces, including Mpumalanga, are increasing efforts towards this ambitious goal. The reduction of imported infections is a vital element of an elimination strategy, particularly if a country is already experiencing high levels of imported infections. Border control of malaria is one tool that may be considered. METHODS: A metapopulation, non-linear stochastic ordinary differential equation model is used to simulate malaria transmission in Mpumalanga and Maputo province, Mozambique (the source of the majority of imported infections) to predict the impact of a focal screen and treat campaign at the Mpumalanga-Maputo border. This campaign is simulated by nesting an individual-based model for the focal screen and treat campaign within the metapopulation transmission model. RESULTS: The model predicts that such a campaign, simulated for different levels of resources, coverage and take-up rates with a variety of screening tools, will not eliminate malaria on its own, but will reduce transmission substantially. Making the campaign mandatory decreases transmission further though sub-patent infections are likely to remain undetected if the diagnostic tool is not adequately sensitive. Replacing screening and treating with mass drug administration results in substantially larger decreases as all (including sub-patent) infections are treated before movement into Mpumalanga. CONCLUSIONS: The reduction of imported cases will be vital to any future malaria control or elimination strategy. This simulation predicts that FSAT at the Mpumalanga-Maputo border will be unable to eliminate local malaria on its own, but may still play a key role in detecting and treating imported infections before they enter the country. Thus FSAT may form part of an integrated elimination strategy where a variety of interventions are employed together to achieve malaria elimination.
Open Access
The relationship between the haemoglobin concentration and the haematocrit in Plasmodium falciparum malaria
(BioMed Central Ltd, 2008) Lee, Sue; Stepniewska, Kasia; Anstey, Nicholas; Ashley, Elizabeth; Barnes, Karen; Binh, Tran; D'Alessandro, Umberto; Day, Nicholas; de Vries, Peter; Dorsey, Grant; Guthmann, Jean-Paul; Mayxay, Mayfong; Newton, Paul; Nosten, Francois; Olliaro, Piero
BACKGROUND:Malaria is a very important cause of anaemia in tropical countries. Anaemia is assessed either by measurement of the haematocrit or the haemoglobin concentration. For comparisons across studies, it is often necessary to derive one measure from the other. METHODS: Data on patients with slide-confirmed uncomplicated falciparum malaria were pooled from 85 antimalarial drug trials conducted in 25 different countries, to assess the haemoglobin/haematocrit relationship at different time points in malaria. Using a linear random effects model, a conversion equation for haematocrit was derived based on 3,254 measurements from various time points (ranging from day 0 to day 63) from 1,810 patients with simultaneous measurements of both parameters. Haemoglobin was also estimated from haematocrit with the commonly used threefold conversion. RESULTS: A good fit was obtained using Haematocrit = 5.62 + 2.60 * Haemoglobin. On average, haematocrit/3 levels were slightly higher than haemoglobin measurements with a mean difference (+/- SD) of -0.69 (+/- 1.3) for children under the age of 5 (n = 1,440 measurements from 449 patients). CONCLUSION: Based on this large data set, an accurate and robust conversion factor both in acute malaria and in convalescence was obtained. The commonly used threefold conversion is also valid.
Open Access
Should countries implementing an artemisinin-based combination malaria treatment policy also introduce rapid diagnostic tests?
(BioMed Central Ltd, 2008) Zikusooka, Charlotte; McIntyre, Diane; Barnes, Karen
BACKGROUND: Within the context of increasing antimalarial costs and or decreasing malaria transmission, the importance of limiting antimalarial treatment to only those confirmed as having malaria parasites becomes paramount. This motivates for this assessment of the cost-effectiveness of routine use of rapid diagnostic tests (RDTs) as an integral part of deploying artemisinin-based combination therapies (ACTs). METHODS: The costs and cost-effectiveness of using RDTs to limit the use of ACTs to those who actually have Plasmodium falciparum parasitaemia in two districts in southern Mozambique were assessed. To evaluate the potential impact of introducing definitive diagnosis using RDTs (costing $0.95), five scenarios were considered, assuming that the use of definitive diagnosis would find that between 25% and 75% of the clinically diagnosed malaria patients are confirmed to be parasitaemic. The base analysis compared two ACTs, artesunate plus sulfadoxine/pyrimethamine (AS+SP) costing $1.77 per adult treatment and artemether-lumefantrine (AL) costing $2.40 per adult treatment, as well as the option of restricting RDT use to only those older than six years. Sensitivity analyses considered lower cost ACTs and RDTs and different population age distributions. RESULTS: Compared to treating patients on the basis of clinical diagnosis, the use of RDTs in all clinically diagnosed malaria cases results in cost savings only when 29% and 52% or less of all suspected malaria cases test positive for malaria and are treated with AS+SP and AL, respectively. These cut-off points increase to 41.5% (for AS+SP) and to 74% (for AL) when the use of RDTs is restricted to only those older than six years of age. When 25% of clinically diagnosed patients are RDT positive and treated using AL, there are cost savings per malaria positive patient treated of up to $2.12. When more than 29% of clinically diagnosed cases are malaria test positive, the incremental cost per malaria positive patient treated is less than US$ 1. When relatively less expensive ACTs are introduced (e.g. current WHO preferential price for AL of $1.44 per adult treatment), the RDT price to the healthcare provider should be $0.65 or lower for RDTs to be cost saving in populations with between 30 and 52% of clinically diagnosed malaria cases being malaria test positive. CONCLUSION: While the use of RDTs in all suspected cases has been shown to be cost-saving when parasite prevalence among clinically diagnosed malaria cases is low to moderate, findings show that targeting RDTs at the group older than six years and treating children less than six years on the basis of clinical diagnosis is even more cost-saving. In semi-immune populations, young children carry the highest risk of severe malaria and many healthcare providers would find it harder to deny antimalarials to those who test negative in this age group.
Open Access
Therapeutic efficacy of sulfadoxine-pyrimethamine for plasmodium falciparum malaria
(2005) Mabuza, Aaron; Govere, John; La Grange, Kobus; Mngomezulu, Nicros; Allen, Elizabeth; Zitha, Alpheus; Mbokazi, Frans; Durrheim, David; Barnes, Karen
Objectives. To assess the therapeutic efficacy of sulfadoxinepyrimethamine (SP) after 5 years of use as first-line treatment of uncomplicated Plasmodium falciparum malaria, and thus guide the selection of artemisinin-based combination therapy in Mpumalanga, South Africa. Design. An open-label, in vivo therapeutic efficacy study of patients with uncomplicated P. falciparum malaria treated with a single oral dose of SP, with response to treatment monitored clinically and parasitologically on days 1, 2, 3, 7, 14, 21, 28 and 42. Setting. Mangweni and Naas public health care clinics, Tonga district in rural Mpumalanga. Subjects, outcome measures and results. Of 152 patients recruited sequentially, 149 (98%) were successfully followed up for 42 days. One hundred and thirty-four patients (90%) demonstrated adequate clinical and parasitological response. Of the 15 patients (10%) who failed treatment, 2 (1.3%) had an early treatment failure, and polymerase chain reaction confirmed recrudescent infection in all 13 patients (8.7%) who had late parasitological (N = 11) or clinical (N = 2) failure. Gametocyte carriage was prevalent following SP treatment (84/152) and this has increased significantly since implementation in 1998 (relative risk 2.77 (confidence interval 1.65 - 4.66); p = 0.00004). Conclusion. Asexual P. falciparum parasites in Mpumalanga remain sensitive to SP, with no significant difference between the baseline cure rate (94.5%) at introduction in 1998, and the present 90% cure rate (p = 0.14). However, since gametocyte carriage has increased significantly we recommend that SP be combined with artesunate in Mpumalanga to reduce gametocyte carriage and thus decrease malaria transmission and potentially delay antimalarial resistance. S Afr Med J 2005; 95: 346-349.
Open Access
Treating AIDS-associated cerebral toxoplasmosis - pyrimethamine plus sulfadiazine compared with cotrimoxazole, and outcome with adjunctive glucocorticoids
(2007) Arens, James; Barnes, Karen; Crowley, Nicola; Maartens, Gary
We conducted a retrospective study of AIDS-associated cerebral toxoplasmosis. Eighteen patients received pyrimethamine plus sulfadiazine and 25 co-trimoxazole, with comparable baseline characteristics. There were no differences in clinical outcomes, but co-trimoxazole was better tolerated (p = 0.066). There was also a trend towards more deaths among patients who received glucocorticoids.
Open Access
World Antimalarial Resistance Network (WARN) IV: Clinical pharmacology
(BioMed Central Ltd, 2007) Barnes, Karen; Lindegardh, Niklas; Ogundahunsi, Olumide; Olliaro, Piero; Plowe, Christopher; Randrianarivelojosia, Milijaona; Gbotosho, Grace; Watkins, William; Sibley, Carol; White, Nicholas
A World Antimalarial Resistance Network (WARN) database has the potential to improve the treatment of malaria, through informing current drug selection and use and providing a prompt warning of when treatment policies need changing. This manuscript outlines the contribution and structure of the clinical pharmacology component of this database. The determinants of treatment response are multi-factorial, but clearly providing adequate blood concentrations is pivotal to curing malaria. The ability of available antimalarial pharmacokinetic data to inform optimal dosing is constrained by the small number of patients studied, with even fewer (if any) studies conducted in the most vulnerable populations. There are even less data relating blood concentration data to the therapeutic response (pharmacodynamics). By pooling all available pharmacokinetic data, while paying careful attention to the analytical methodologies used, the limitations of small (and thus underpowered) individual studies may be overcome and factors that contribute to inter-individual variability in pharmacokinetic parameters defined. Key variables for pharmacokinetic studies are defined in terms of patient (or study subject) characteristics, the formulation and route of administration of the antimalarial studied, the sampling and assay methodology, and the approach taken to data analysis. Better defining these information needs and criteria of acceptability of pharmacokinetic-pharmacodynamic (PK-PD) studies should contribute to improving the quantity, relevance and quality of these studies. A better understanding of the pharmacokinetic properties of antimalarials and a more clear definition of what constitutes "therapeutic drug levels" would allow more precise use of the term "antimalarial resistance", as it would indicate when treatment failure is not caused by intrinsic parasite resistance but is instead the result of inadequate drug levels. The clinical pharmacology component of the WARN database can play a pivotal role in monitoring accurately for true antimalarial drug resistance and promptly correcting sub-optimal dosage regimens to prevent these contributing to the emergence and spread of antimalarial resistance.