Browsing by Subject "Malaria"
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- ItemOpen AccessAbsence of kelch13 artemisinin resistance markers but strong selection for lumefantrine-tolerance molecular markers following 18 years of artemisinin-based combination therapy use in Mpumalanga Province, South Africa (2001–2018)(2019-08-22) Raman, Jaishree; Kagoro, Frank M; Mabuza, Aaron; Malatje, Gillian; Reid, Anthony; Frean, John; Barnes, Karen IAbstract Background The ability of Plasmodium falciparum parasites to develop resistance to widely used anti-malarials threatens malaria control and elimination efforts. Regular drug efficacy monitoring is essential for ensuring effective treatment policies. In low transmission settings where therapeutic efficacy studies are often not feasible, routine surveillance for molecular markers associated with anti-malarial resistance provides an alternative for the early detection of emerging resistance. Such a longitudinal survey of changes in the prevalence of selected molecular markers of resistance was conducted in the malaria-endemic regions of Mpumalanga Province, South Africa, where malaria elimination at a district-level is being pursued. Methods Molecular analyses to determine the prevalence of alleles associated with resistance to lumefantrine (mdr86N, crt76K and mdr1 copy number variation) and sulfadoxine–pyrimethamine (dhfr triple, dhps double, SP quintuple) were conducted between 2001 and 2018, while artemisinin resistance markers (kelch13 mutations) were assessed only in 2018. Results Parasite DNA was successfully amplified from 1667/2393 (70%) of malaria-positive rapid diagnostic tests routinely collected at primary health care facilities. No artemisinin resistance-associated kelch13 mutations nor amplification of the mdr1 gene copy number associated with lumefantrine resistance were observed. However, prevalence of both the mdr86N and crt76K alleles increased markedly over the study period, with all isolates collected in 2018 carrying these markers. SP quintuple mutation prevalence increased steadily from 14% in 2001 to 96% in 2018. Mixed alleles at any of the codons assessed were rare by 2018. Conclusion No kelch13 mutations confirmed or suspected to be associated with artemisinin resistance were identified in 2018. Although parasites carrying the mdr86N and crt76K alleles associated with reduced lumefantrine susceptibility were strongly selected for over the study period, nearing fixation by 2018, the marker for lumefantrine resistance, namely increased mdr1 copy number, was not observed in this study. The increase in mdr86N and crt76K allele prevalence together with intense regional artemether–lumefantrine drug pressure, raises concern regarding the sustained artemether–lumefantrine efficacy. Regular, rigorous anti-malarial resistance marker surveillance across all three South African malaria-endemic provinces to inform case management is recommended.
- ItemOpen AccessAnticancer properties of distinct antimalarial drug classes(Public Library of Science, 2013) Hooft van Huijsduijnen, Rob; Guy, R Kiplin; Chibale, Kelly; Haynes, Richard K; Peitz, Ingmar; Kelter, Gerhard; Phillips, Margaret A; Vennerstrom, Jonathan L; Yuthavong, Yongyuth; Wells, Timothy N CWe have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase) inhibitors effected potent inhibition of proliferation with IC 50 s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase) and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor), emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC 50 s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings.
- ItemOpen AccessAntiplasmodial activity, in vivo pharmacokinetics and anti-malarial efficacy evaluation of hydroxypyridinone hybrids in a mouse model(2015) Dambuza, Ntokozo S; Smith, Peter; Evans, Alicia; Norman, Jennifer; Taylor, Dale; Andayi, Andrew; Egan, Timothy; Chibale, Kelly; Wiesner, LubbeBackgroundDuring the erythrocytic stage in humans, malaria parasites digest haemoglobin of the host cell, and the toxic haem moiety crystallizes into haemozoin. Chloroquine acts by forming toxic complexes with haem molecules and interfering with their crystallization. In chloroquine-resistant strains, the drug is excluded from the site of action, which causes the parasites to accumulate less chloroquine in their acid food vacuoles than chloroquine-sensitive parasites. 3-Hydroxylpyridin-4-ones are known to chelate iron; hydroxypyridone-chloroquine (HPO-CQ) hybrids were synthesized in order to determine whether they can inhibit parasites proliferation in the parasitic digestive vacuole by withholding iron from plasmodial parasite metabolic pathway.MethodsTwo HPO-CQ hybrids were tested against Plasmodium falciparum chloroquine-sensitive (D10 and 3D7) and -resistant strains (Dd2 and K1). The pharmacokinetic properties of active compounds were determined using a mouse model and blood samples were collected at different time intervals and analysed using LC–MS/MS. For in vivo efficacy the mice were infected with Plasmodium berghei in a 4-day Peters’ test. The parasitaemia was determined from day 3 and the course of the infection was followed by microscopic examination of stained blood films every 2–3days until a rise in parasitaemia was observed in all test subjects.ResultsIC50 values of the two compounds for sensitive and resistant strains were 0.064 and 0.047µM (compound 1), 0.041 and 0.122µM (compound 2) and 0.505 and 0.463µM (compound 1), 0.089 and 0.076µM (compound 2), respectively. Pharmacokinetic evaluation of these compounds showed low oral bioavailability and this affected in vivo efficacy when compounds were dosed orally. However, when dosed intravenously compound 1 showed a clearance rate of 28ml/min/kg, an apparent volume of distribution of 20l/kg and a half-life of 4.3h. A reduction in parasitaemia was observed when compound 1 was dosed intravenously for four consecutive days in P. berghei-infected mice. However, a rise in parasitaemia levels was observed on day 6 and on day 9 for chloroquine-treated mice.ConclusionThe hybrid compounds that were tested were able to reduce parasitaemia levels in P. berghei-infected mice when dosed intravenously, but parasites recrudesced 24h after the administration of the least dose. Despite low oral bioavailability, the IV data obtained suggests that further structural modifications may lead to the identification of more HPO-CQ hybrids with improved pharmacokinetic properties and in vivo efficacy.
- ItemOpen AccessCase management of malaria: Treatment and chemoprophylaxis(2013) Ukpe, I S; Moonasar, D; Raman, J; Barnes, K I; Baker, L; Blumberg, LMalaria case management is a vital component of programmatic strategies for malaria control and elimination. Malaria case management encompasses prompt and effective treatment to minimise morbidity and mortality, reduce transmission and prevent the emergence and spread of antimalarial drug resistance. Malaria is an acute illness that may progress rapidly to severe disease and death, especially in non-immune populations, if not diagnosed early and promptly treated with effective drugs. In this article, the focus is on malaria case management, addressing treatment, monitoring for parasite drug resistance, and the impact of drug resistance on treatment policies; it concludes with chemoprophylaxis and treatment strategies for malaria elimination in South Africa.
- ItemOpen AccessThe co-inheritance of alpha-thalassemia and sickle cell anemia is associated with better hematological indices and lower consultations rate in Cameroonian patients and could improve their survival(Public Library of Science, 2014) Rumaney, Maryam Bibi; Bitoungui, Valentina Josiane Ngo; Vorster, Anna Alvera; Ramesar, Raj; Kengne, Andre Pascal; Ngogang, Jeanne; Wonkam, AmbroiseBACKGROUND: Co-inheritance of α-thalassemia was reported to be associated with a delayed age of disease onset among Cameroonian Sickle Cell Anemia (SCA) patients. The present study aimed to explore the correlation between α-thalassemia, hematological indices, and clinical events in these patients. Methods and FINDINGS: We studied 161 Cameroonian SCA patients and 103 controls (59.1% HbAA) with median ages of 17.5 and 23 years. RFLP-PCR was used to confirm SCA genotype and to describe haplotypes in the HBB-like genes cluster. Multiplex Gap-PCR was performed to investigate the 3.7 kb α-globin gene deletions. SNaPshot PCR, capillary electrophoresis and cycle sequencing were used for the genotyping of 10 SNPs in BCL11A , HMIP1/2 , OR51B5/6 and HBG loci, known to influence HbF levels. Generalised linear regression models adjusted for age, sex and SNPs genotypes was used to investigate effects of α-thalassemia on clinical and hematological indices. The median rate of vaso-occlusive painful crisis and hospitalisations was two and one per year, respectively. Stroke was reported in eight cases (7.4%). Benin haplotype was the most prevalent (66.3%; n = 208 chromosomes). Among patients, 37.3% ( n = 60) had at least one 3.7 kb deletion, compared to 10.9% ( n = 6) among HbAA controls (p<0.001). Among patients, the median RBC count increased with the number of 3.7 kb deletions [2.6, 3.0 and 3.4 million/dl, with no, one and two deletions (p = 0.01)]. The median MCV decreased with the number of 3.7 kb deletion [86, 80, and 68fl, with no, one and two deletions (p<0.0001)], as well as median WBC counts [13.2, 10.5 and 9.8×10 9 /L (p<0.0001. The co-inheritance of α-thalassemia was associated with lower consultations rate (p = 0.038). CONCLUSION: The co-inheritance of α-thalassemia and SCA is associated with improved hematological indices, and lower consultations rate in this group of patients. This could possibly improve their survival and explain the higher proportion of α-thalassemia among patients than controls.
- ItemOpen AccessComplex interactions between malaria and malnutrition: a systematic literature review(BioMed Central, 2018-10-29) Das, D; Grais, R F; Okiro, E A; Stepniewska, K; Mansoor, R; van der Kam, S; Terlouw, D J; Tarning, J; Barnes, K I; Guerin, P JAbstract Background Despite substantial improvement in the control of malaria and decreased prevalence of malnutrition over the past two decades, both conditions remain heavy burdens that cause hundreds of thousands of deaths in children in resource-poor countries every year. Better understanding of the complex interactions between malaria and malnutrition is crucial for optimally targeting interventions where both conditions co-exist. This systematic review aimed to assess the evidence of the interplay between malaria and malnutrition. Methods Database searches were conducted in PubMed, Global Health and Cochrane Libraries and articles published in English, French or Spanish between Jan 1980 and Feb 2018 were accessed and screened. The methodological quality of the included studies was assessed using the Newcastle-Ottawa Scale and the risk of bias across studies was assessed using the GRADE approach. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) guideline were followed. Results Of 2945 articles screened from databases, a total of 33 articles were identified looking at the association between malnutrition and risk of malaria and/or the impact of malnutrition in antimalarial treatment efficacy. Large methodological heterogeneity of studies precluded conducting meaningful aggregated data meta-analysis. Divergent results were reported on the effect of malnutrition on malaria risk. While no consistent association between risk of malaria and acute malnutrition was found, chronic malnutrition was relatively consistently associated with severity of malaria such as high-density parasitemia and anaemia. Furthermore, there is little information on the effect of malnutrition on therapeutic responses to artemisinin combination therapies (ACTs) and their pharmacokinetic properties in malnourished children in published literature. Conclusions The evidence on the effect of malnutrition on malaria risk remains inconclusive. Further analyses using individual patient data could provide an important opportunity to better understand the variability observed in publications by standardising both malaria and nutritional metrics. Our findings highlight the need to improve our understanding of the pharmacodynamics and pharmacokinetics of ACTs in malnourished children. Further clarification on malaria-malnutrition interactions would also serve as a basis for designing future trials and provide an opportunity to optimise antimalarial treatment for this large, vulnerable and neglected population. Trial registration PROSPERO CRD42017056934 .
- ItemOpen AccessCost-effectiveness analysis of the available strategies for diagnosing malaria in outpatient clinics in Zambia(BioMed Central Ltd, 2009) Chanda, Pascalina; Castillo-Riquelme, Marianela; Masiye, FelixBACKGROUND:Malaria in Zambia accounts for about 4 million clinical cases and 8 000 deaths annually. Artemether-lumefantrine (ACT), a relatively expensive drug, is being used as first line treatment of uncomplicated malaria. However, diagnostic capacity in Zambia is low, leading to potentially avoidable wastage of drugs due to unnecessary anti malarial treatment. METHODS: A cost-effectiveness evaluation of the three current alternatives to malaria diagnosis (clinical, microscopy and Rapid Diagnostic Tests- RDT) was conducted in 12 facilities from 4 districts in Zambia. The analysis was conducted along an observational study, thus reflecting practice in health facilities under routine conditions. Average and incremental cost effectiveness ratios were estimated from the providers' perspective. Effectiveness was measured in relation to malaria cases correctly diagnosed by each strategy. RESULTS: Average cost-effectiveness ratios show that RDTs were more efficient (US$ 6.5) than either microscopy (US$ 11.9) or clinical diagnosis (US$ 17.1) for malaria case correctly diagnosed. In relation to clinical diagnoses the incremental cost per case correctly diagnosed and treated was US$ 2.6 and US$ 9.6 for RDT and microscopy respectively. RDTs would be much cheaper to scale up than microscopy. The findings were robust to changes in assumptions and various parameters. CONCLUSION: RDTs were the most cost effective method at correctly diagnosing malaria in primary health facilities in Zambia when compared to clinical and microscopy strategies. However, the treatment prescription practices of the health workers can impact on the potential that a diagnostic test has to lead to savings on antimalarials. The results of this study will serve to inform policy makers on which alternatives will be most efficient in reducing malaria misdiagnosis by taking into account both the costs and effects of each strategy.
- ItemOpen AccessCRIMALDDI: platform technologies and novel anti-malarial drug targets(BioMed Central Ltd, 2013) Vial, Henri; Taramelli, Donatella; Boulton, Ian; Ward, Steve; Doerig, Christian; Chibale, KellyThe Coordination, Rationalization, and Integration of antiMALarial drug Discovery & Development Initiatives (CRIMALDDI) Consortium, funded by the EU Framework Seven Programme, has attempted, through a series of interactive and facilitated workshops, to develop priorities for research to expedite the discovery of new anti-malarials. This paper outlines the recommendations for the development of enabling technologies and the identification of novel targets.Screening systems must be robust, validated, reproducible, and represent human malaria. They also need to be cost-effective. While such systems exist to screen for activity against blood stage Plasmodium falciparum, they are lacking for other Plasmodium spp. and other stages of the parasite's life cycle. Priority needs to be given to developing high-throughput screens that can identify activity against the liver and sexual stages. This in turn requires other enabling technologies to be developed to allow the study of these stages and to allow for the culture of liver cells and the parasite at all stages of its life cycle.As these enabling technologies become available, they will allow novel drug targets to be studied. Currently anti-malarials are mostly targeting the asexual blood stage of the parasite's life cycle. There are many other attractive targets that need to be investigated. The liver stages and the sexual stages will become more important as malaria control moves towards malaria elimination. Sexual development is a process offering multiple targets, even though the mechanisms of differentiation are still not fully understood. However, designing a drug whose effect is not curative but would be used in asymptomatic patients is difficult given current safety thresholds. Compounds active against the liver schizont would have a prophylactic effect and Plasmodium vivax elimination requires effectors against the dormant liver hypnozoites. It may be that drugs to be used in elimination campaigns will also need to have utility in the control phase. Compounds with activity against blood stages need to be screened for activity against other stages.Natural products should also be a valuable source of new compounds. They often occupy non-Lipinski chemical space and so may reveal valuable new chemotypes.
- ItemRestrictedThe crystal structure of halofantrine–ferriprotoporphyrin IX and the mechanism of action of arylmethanol antimalarials.(Elsevier, 2008) de Villiers, Katherine A; Marques, Helder; Egan, Timothy JThe crystal structure of the complex formed between the antimalarial drug halofantrine and ferriprotoporphyrin IX (Fe(III)PPIX) has been determined by single crystal X-ray diffraction. The structure shows that halofantrine coordinates to the Fe(III) center through its alcohol functionality in addition to p-stacking of the phenanthrene ring over the porphyrin. The length of the Fe(III)–O bond is consistent with an alkoxide and not an alcohol coordinating group. The iron porphyrin is five coordinate and monomeric. Changes in the electronic spectrum of Fe(III)PPIX upon addition of halofantrine base in acetonitrile solution are almost identical to those observed upon addition of quinidine free base in the same solvent. This suggests homologous binding. Molecular mechanics modeling of Fe(III)PPIX complexes of quinidine, quinine, 9-epiquinine and 9-epiquinidine based on this homology suggests that the antimalarially active quinidine and quinine can readily adopt conformations that permit formation of an intramolecular salt bridge between the protonated quinuclidine tertiary amino group and unprotonated heme propionate group, while the inactive epimers 9-epiquinidine and 9-epiquinine have to adopt high energy conformations in order to accommodate such salt bridge formation. We propose that salt bridge formation may interrupt formation of the hemozoin precursor dimer formed during the heme detoxification pathway and so account for the strong activity of the two active isomers.
- ItemOpen AccessEffect of artemether-lumefantrine policy and improved vector control on malaria burden in KwaZulu-Natal, South Africa(Public Library of Science, 2005) Barnes, Karen I; Durrheim, David N; Little, Francesca; Jackson, Amanda; Mehta, Ushma; Allen, Elizabeth; Dlamini, Sicelo S; Tsoka, Joyce; Bredenkamp, Barry; Mthembu, D JothamIn KwaZulu-Natal strengthening of vector control and a change in antimalarial treatment policy to use of artemether-lumefantrine has been associated with a decrease in malaria cases, admissions, and deaths.
- ItemOpen AccessEffect of malaria on productivity in a workplace: the case of a banana plantation in Zimbabwe(2019-12-03) Lukwa, Akim T; Mawoyo, Richard; Zablon, Karen N; Siya, Aggrey; Alaba, OlufunkeBackground Malaria is known to contribute to reduction in productivity through absenteeism as worker-hours are lost thus impacting company productivity and performance. This paper analysed the impact of malaria on productivity in a banana plantation through absenteeism. Methods This study was carried out at Matanuska farm in Burma Valley, Zimbabwe. Raw data on absenteeism was obtained in retrospect from the Farm Manager. Malaria infection was detected using malaria Rapid Diagnostic Test. Measures of absence from work place were determined and included; incidence of absence (number of absentees divided by the total workforce), absence frequency (number of malaria spells), frequency rate (number of spells divided by the number of absentees), estimated duration of spells (number of days lost due to malaria), severity rate (number of days lost divided by number of spells), incapacity rate (number of days lost divided by the number of absentees), number of absent days (number of spells times the severity rate), number of scheduled working days (actual working days in 5 months multiplied by total number of employees), absenteeism rate. Results A total of 143 employees were followed up over a 5-month period. Malaria positivity was 21%, 31.5%, 44.8%, 35.7% and 12.6% for January 2014 to May 2014, respectively. One spell of absence [194 (86.6%)] was common followed by 2 spells of absence [30 (13.4%)] for all employees. Duration of spells of absence due to malaria ranged from 1.5 to 4.1 working-days, with general workers being the most affected. Incidence of absence was 143/155 (93.3%), with total of spells of absence of over a 5-month period totalling 224. The frequency rate of absenteeism was 1.6 with severity rate of absence being 2.4. and incapacity rate was 3.7. Conclusion Malaria contributes significantly to worker absenteeism. Employers, therefore, ought to put measures that protect workers from malaria infections. Protecting workers can be done through malaria educative campaigns, providing mosquito nets, providing insecticide-treated work suits, providing repellents and partnering with different ministries to ensure protection of workers from mosquito bites.
- ItemOpen AccessEfficacy and pharmacokinetic evaluation of a novel anti-malarial compound (NP046) in a mouse model(BioMed Central Ltd, 2015) Abay, Efrem; van der Westuizen, Jan; Swart, Kenneth; Gibhard, Liezl; Lawrence, Nina; Dambuza, Ntokozo; Wilhelm, Anke; Pravin, Kendrekar; Wiesner, LubbeBACKGROUND: Even though malaria is a completely preventable and treatable disease, it remains a threat to human life and a burden to the global economy due to the emergence of multiple-drug resistant malaria parasites. According to the World Malaria Report 2013, in 2012 there were an estimated 207 million malaria cases and 627,000 deaths. Thus, the discovery and development of new, effective anti-malarial drugs are required. To achieve this goal, the Department of Chemistry at the University of the Free State has synthesized a number of novel amino-alkylated chalcones and analogues, which showed in vitro anti-malarial activity against both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains. The lead compound (NP046) was selected for a comprehensive pharmacokinetic (PK) and in vivo efficacy evaluation in a mouse model. METHODS: In vivo efficacy: Water solutions of NP046 were administered orally at 50 and 10mg/kg using oral gavage and IV at 5 and 1mg/kg via the dorsal penile vein to Plasmodium berghei (ANKA strain) infected male C57BL/6 mice (n=5), once a day for four days. Blood samples were collected via tail bleeding in tubes containing phosphate buffer saline (PBS) on day five to determine the % parasitaemia by flow cytometry.In vivo PK: NP046 solutions in water were administered orally (50 and 10mg/kg) and IV (5mg/kg) to male C57BL/6 mice (n=5). Blood samples were collected via tail bleeding into heparinized tubes and analysed using a validated LC-MS/MS assay. Data obtained from the concentration-time profile was evaluated using Summit PK software to determine the PK parameters of NP046. RESULTS: NP046 inhibited parasite growth for the oral and IV groups. Better parasite growth inhibition was observed for the IV group. The PK evaluation of NP046 showed low oral bioavailability (3.2% and 6% at 50mg/kg and 10mg/kg dose, respectively and a moderate mean half-life ranging from 3.1 to 4.4hours. CONCLUSION: Even though the oral bioavailability of NP046 is low, its percentage parasite growth inhibition is promising, but in order to improve the oral bioavailability, structure-activity-relationship (SAR) optimization studies are currently being conducted.
- ItemOpen AccessEfficacy of sulphadoxine-pyrimethamine with or without artesunate for the treatment of uncomplicated Plasmodium falciparum malaria in southern Mozambique: a randomized controlled trial(BioMed Central Ltd, 2009) Allen, Elizabeth N; Little, Francesca; Camba, Tunisio; Cassam, Yasmin; Raman, Jaishree; Boulle, Andrew; Barnes, Karen IBACKGROUND: An artemisinin-based combination therapy, artesunate (AS) plus sulphadoxine-pyrimethamine (SP), was compared to SP monotherapy to provide evidence of further treatment options in southern Mozambique. METHODS: Between 2003 and 2005, 411 patients over one year and 10 kg with uncomplicated Plasmodium falciparum malaria were randomly allocated SP (25/1.25 mg per kg day 0) or AS/SP (as above plus 4 mg/kg artesunate days 0, 1 and 2). Allocation was concealed, but treatment was open-label except to microscopists. The primary objective was the relative risk of treatment failure, which was assessed using World Health Organization response definitions modified to a 42-day follow-up. RESULTS: Of the 411 subjects enrolled, 359 (87.3%) completed the follow up period (SP n = 175, AS/SP n = 184). A survival analysis including 408 subjects showed that the polymerase chain reaction-adjusted cure rates were 90.4% (95% confidence interval [CI] 84.9%-93.9%) and 98.0% (95% CI 94.8%-99.3%) for SP and AS/SP respectively. Multivariable analysis showed that treatment with AS/SP decreased the relative hazard of treatment failure by 80% compared to SP (hazard ratio [HR] 0.2; 95% CI 0.1-0.6) and age over seven years decreased the relative hazard of failure by 70% (HR 0.3; 95% CI 0.1-0.9), when compared to younger age. However, having a quintuple dhfr/dhps mutation increased the relative hazard of failure compared to fewer mutations (HR 3.2; 95% CI 1.3-7.5) and baseline axillary temperature increased the relative hazard of failure by 50% for each degreesC increase (HR 1.5; 95% CI 1.1-2.2). CONCLUSION: While both treatments were efficacious, AS plus SP significantly decreased the relative hazard of treatment failure compared to SP monotherapy Artesunate plus sulphadoxine-pyrimethamine, but not sulphadoxine-pyrimethamine monotherapy, met the current WHO criteria of >95% efficacy for policy implementation.TRIAL REGISTRATION:NCT00203736 and NCT00203814
- ItemOpen AccessEstimating the development assistance for health provided to faith-based organizations, 1990-2013(Public Library of Science, 2015) Haakenstad, Annie; Johnson, Elizabeth; Graves, Casey; Olivier, Jill; Duff, Jean; Dieleman, Joseph LBACKGROUND: Faith-based organizations (FBOs) have been active in the health sector for decades. Recently, the role of FBOs in global health has been of increased interest. However, little is known about the magnitude and trends in development assistance for health (DAH) channeled through these organizations. Material and METHODS: Data were collected from the 21 most recent editions of the Report of Voluntary Agencies. These reports provide information on the revenue and expenditure of organizations. Project-level data were also collected and reviewed from the Bill & Melinda Gates Foundation and the Global Fund to Fight AIDS, Tuberculosis and Malaria. More than 1,900 non-governmental organizations received funds from at least one of these three organizations. Background information on these organizations was examined by two independent reviewers to identify the amount of funding channeled through FBOs. RESULTS: In 2013, total spending by the FBOs identified in the VolAg amounted to US$1.53 billion. In 1990, FB0s spent 34.1% of total DAH provided by private voluntary organizations reported in the VolAg. In 2013, FBOs expended 31.0%. Funds provided by the Global Fund to FBOs have grown since 2002, amounting to $80.9 million in 2011, or 16.7% of the Global Fund's contributions to NGOs. In 2011, the Gates Foundation's contributions to FBOs amounted to $7.1 million, or 1.1% of the total provided to NGOs. CONCLUSION: Development assistance partners exhibit a range of preferences with respect to the amount of funds provided to FBOs. Overall, estimates show that FBOS have maintained a substantial and consistent share over time, in line with overall spending in global health on NGOs. These estimates provide the foundation for further research on the spending trends and effectiveness of FBOs in global health.
- ItemOpen AccessEstimating the risk of declining funding for malaria in Ghana: the case for continued investment in the malaria response(2020-06-01) Shretta, Rima; Silal, Sheetal P; Malm, Keziah; Mohammed, Wahjib; Narh, Joel; Piccinini, Danielle; Bertram, Kathryn; Rockwood, Jessica; Lynch, MattBackground Ghana has made impressive progress against malaria, decreasing mortality and morbidity by over 50% between 2005 and 2015. These gains have been facilitated in part, due to increased financial commitment from government and donors. Total resources for malaria increased from less than USD 25 million in 2006 to over USD 100 million in 2011. However, the country still faces a high burden of disease and is at risk of declining external financing due to its strong economic growth and the consequential donor requirements for increased government contributions. The resulting financial gap will need to be met domestically. The purpose of this study was to provide economic evidence of the potential risks of withdrawing financing to shape an advocacy strategy for resource mobilization. Methods A compartmental transmission model was developed to estimate the impact of a range of malaria interventions on the transmission of Plasmodium falciparum malaria between 2018 and 2030. The model projected scenarios of common interventions that allowed the attainment of elimination and those that predicted transmission if interventions were withheld. The outputs of this model were used to generate costs and economic benefits of each option. Results Elimination was predicted using the package of interventions outlined in the national strategy, particularly increased net usage and improved case management. Malaria elimination in Ghana is predicted to cost USD 961 million between 2020 and 2029. Compared to the baseline, elimination is estimated to prevent 85.5 million cases, save 4468 lives, and avert USD 2.2 billion in health system expenditures. The economic gain was estimated at USD 32 billion in reduced health system expenditure, increased household prosperity and productivity gains. Through malaria elimination, Ghana can expect to see a 32-fold return on their investment. Reducing interventions, predicted an additional 38.2 clinical cases, 2500 deaths and additional economic losses of USD 14.1 billion. Conclusions Malaria elimination provides robust epidemiological and economic benefits, however, sustained financing is need to accelerate the gains in Ghana. Although government financing has increased in the past decade, the amount is less than 25% of the total malaria financing. The evidence generated by this study can be used to develop a robust domestic strategy to overcome the financial barriers to achieving malaria elimination in Ghana.
- ItemOpen AccessEvaluating 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, KarenBACKGROUND: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.
- ItemOpen AccessExploring the seasonality of reported treated malaria cases in Mpumalanga, South Africa(Public Library of Science, 2013) Silal, Sheetal Prakash; Barnes, Karen I; Kok, Gerdalize; Mabuza, Aaron; Little, FrancescaSouth Africa, having met the World Health Organisation's pre-elimination criteria, has set a goal to achieve malaria elimination by 2018. Mpumalanga, one of three provinces where malaria transmission still occurs, has a malaria season subject to unstable transmission that is prone to sporadic outbreaks. As South Africa prepares to intensify efforts towards malaria elimination, there is a need to understand patterns in malaria transmission so that efforts may be targeted appropriately. This paper describes the seasonality of transmission by exploring the relationship between malaria cases and three potential drivers: rainfall, geography (physical location) and the source of infection (local/imported). Seasonal decomposition of the time series by Locally estimated scatterplot smoothing is applied to the case data for the geographical and source of infection sub-groups. The relationship between cases and rainfall is assessed using a cross-correlation analysis. The malaria season was found to have a short period of no/low level of reported cases and a triple peak in reported cases between September and May; the three peaks occurring in October, January and May. The seasonal pattern of locally-sourced infection mimics the triple-peak characteristic of the total series while imported infections contribute mostly to the second and third peak of the season (Christmas and Easter respectively). Geographically, Bushbuckridge municipality, which exhibits a different pattern of cases, contributed mostly to the first and second peaks in cases while Maputo province (Mozambique) experienced a similar pattern in transmission to the imported cases. Though rainfall lagged at 4 weeks was significantly correlated with malaria cases, this effect was dampened due to the growing proportion of imported cases since 2006. These findings may be useful as they enhance the understanding of the current incidence pattern and may inform mathematical models that enable one to predict the impact changes in these drivers will have on malaria transmission.
- ItemOpen AccessFive years of antimalarial resistance marker surveillance in Gaza Province, Mozambique, following artemisinin-based combination therapy roll out(Public Library of Science, 2011) Raman, Jaishree; Mauff, Katya; Muianga, Pedro; Mussa, Abdul; Maharaj, Rajendra; Barnes, Karen IAntimalarial drug resistance is a major obstacle to malaria control and eventual elimination. The routine surveillance for molecular marker of resistance is an efficient way to assess drug efficacy, which remains feasible in areas where malaria control interventions have succeeded in substantially reducing malaria transmission. Community based asexual parasite prevalence surveys were conducted annually in sentinel sites in Gaza Province, Mozambique from 2006 until 2010, before, during and after antimalarial policy changes to artesunate plus sulfadoxine-pyrimethamine in 2006 and to artemether-lumefantrine in 2008. Genetic analysis of dhfr , dhps , crt , and mdr1 resistant genes was conducted on 3 331 (14.4%) Plasmodium falciparum PCR positive samples collected over the study period from 23 229 children aged 2 to 15 years. The quintuple dhfr/dhps mutation associated with sulfadoxine-pyrimethamine resistance increased from 56.2% at baseline to 75.8% by 2010. At baseline the crt 76T and mdr1 86Y mutants were approaching fixation, 96.1% and 74.7%, respectively. Following the deployment of artemisinin-based combination therapy, prevalence of both these chloroquine-resistance markers began declining, reaching 32.4% and 30.9%, respectively, by 2010. All samples analysed over the 5-year period possessed a single copy of the mdr1 gene. The high and increasing prevalence of the quintuple mutation supports the change in drug policy from artesunate plus sulfadoxine-pyrimethamine to artemether-lumefantrine in Mozambique. As chloroquine related drug pressure decreased in the region, so did the molecular markers associated with chloroquine resistance ( crt 76T and mdr1 86Y). However, this reversion to the wild-type mdr186N predisposes parasites towards developing lumefantrine resistance. Close monitoring of artemether-lumefantrine efficacy is therefore essential, particularly given the high drug pressure within the region where most countries now use artemether-lumefantrine as first line treatment.
- ItemOpen AccessGametocyte carriage in uncomplicated Plasmodium falciparum malaria following treatment with artemisinin combination therapy: a systematic review and meta-analysis of individual patient data(2016): Gametocytes are responsible for transmission of malaria from human to mosquito. Artemisinin combination therapy (ACT) reduces post-treatment gametocyte carriage, dependent upon host, parasite and pharmacodynamic factors. The gametocytocidal properties of antimalarial drugs are important for malaria elimination efforts. An individual patient clinical data meta-analysis was undertaken to identify the determinants of gametocyte carriage and the comparative effects of four ACTs: artemether-lumefantrine (AL), artesunate/amodiaquine (AS-AQ), artesunate/mefloquine (AS-MQ), and dihydroartemisinin-piperaquine (DP). : Factors associated with gametocytaemia prior to, and following, ACT treatment were identified in multivariable logistic or Cox regression analysis with random effects. All relevant studies were identified through a systematic review of PubMed. Risk of bias was evaluated based on study design, methodology, and missing data. : The systematic review identified 169 published and 9 unpublished studies, 126 of which were shared with the WorldWide Antimalarial Resistance Network (WWARN) and 121 trials including 48,840 patients were included in the analysis. Prevalence of gametocytaemia by microscopy at enrolment was 12.1 % (5887/48,589), and increased with decreasing age, decreasing asexual parasite density and decreasing haemoglobin concentration, and was higher in patients without fever at presentation. After ACT treatment, gametocytaemia appeared in 1.9 % (95 % CI, 1.7-2.1) of patients. The appearance of gametocytaemia was lowest after AS-MQ and AL and significantly higher after DP (adjusted hazard ratio (AHR), 2.03; 95 % CI, 1.24-3.12; P = 0.005 compared to AL) and AS-AQ fixed dose combination (FDC) (AHR, 4.01; 95 % CI, 2.40-6.72; P < 0.001 compared to AL). Among individuals who had gametocytaemia before treatment, gametocytaemia clearance was significantly faster with AS-MQ (AHR, 1.26; 95 % CI, 1.00-1.60; P = 0.054) and slower with DP (AHR, 0.74; 95 % CI, 0.63-0.88; P = 0.001) compared to AL. Both recrudescent (adjusted odds ratio (AOR), 9.05; 95 % CI, 3.74-21.90; P < 0.001) and new (AOR, 3.03; 95 % CI, 1.66-5.54; P < 0.001) infections with asexual-stage parasites were strongly associated with development of gametocytaemia after day 7. : AS-MQ and AL are more effective than DP and AS-AQ FDC in preventing gametocytaemia shortly after treatment, suggesting that the non-artemisinin partner drug or the timing of artemisinin dosing are important determinants of post-treatment gametocyte dynamics.
- ItemRestrictedHaemozoin formation(Elsevier, 2008) Egan, Timothy JFormation of malaria pigment or haemozoin is the major route of haem detoxification in the malaria parasite Plasmodium falciparum as well as several other species of haematophagous organisms, including other Plasmodium species, helminth worms such as Schistosoma mansoni and blood-sucking insects such as Rhodnius prolixus. Recent advances in our understanding of the formation of haemozoin, both from new observations that it is formed within lipid bodies in P. falciparum and S. mansoni and biomimetic studies on the formation of its synthetic counterpart -haematin are reviewed. The review also covers methods available for screening compounds for their ability to inhibit -haematin formation.