Malaria In sub-Saharan Africa Research Articles

The threat of antimalarial drug resistance

Abstract: History has shown us that wherever antimalarial drugs are deployed antimalarial drug resistance will follow. A pattern has emerged with the drugs falling to resistance first in South East Asia and subsequently in India, Latin America and Africa. The decline in chloroquine efficacy led to millions of avoidable deaths from malaria in sub-Saharan Africa throughout the 1980s and ‘90s. Artemisinin based combination treatments (ACTs) are the recommended first line treatments for falciparum malaria worldwide. The unique properties of the artemisinin derivatives, in particular their ability to reduce peripheral blood parasitaemia rapidly, make them the most potent antimalarial drug class ever used. They are partnered with slower acting antimalarial drugs and given over 3 days. Resistance to both the artemisinin derivatives and their partner drugs (mefloquine and piperaquine) has emerged in South East Asia over the last decade. Now failure rates of the combinations exceed 30% at some locations. Alarmingly, malaria is on the rise again in western Cambodia where incidence rates had reduced dramatically over the last decade. Genetic studies have identified several mutations in a gene encoding for a plasmodial kelch protein associated with artemisinin resistance. Sampling from several sites throughout Asia has suggested resistance may have emerged multiple times at different locations. This is unlike chloroquine resistance which is thought to have emerged only twice and then spread globally. This finding has implications for global surveillance and containment strategies. Newer antimalarial drug compounds are in development but are still several years away from registration. The most practical solution to contain the threat of antimalarial drug resistance before the death toll from malaria rises is to intensify our efforts to eliminate falciparum malaria.

Analysis of esterase enzyme activity in adults of the major malaria vector Anopheles funestus.

BackgroundAnopheles funestus is a major vector of malaria in sub-Saharan Africa. In order to apply effective control measures against this vector, it is necessary to understand the underlying physiological factors that play a critical role in its development, reproduction, fertility and susceptibility to insecticides. One enzyme family involved in the above mentioned biological pathways is the esterases. The aim of this study was to analyse esterase activity levels at different ages during the life-span of adult Anopheles funestus Giles in order to better understand the complex biological processes in this species.MethodsIsoenzyme electrophoresis (IEE) was used to examine the esterase activity in laboratory colonised An. funestus adults aged between 2 h (h) and 30 days post eclosion as well as in wild An. funestus adults aged between 2 h and 15 days post eclosion. Esterase activity was quantified by densitometry analysis of the IEE gels. Esterases were classified according to their activity inhibition by organic phosphates, eserine sulphate and sulphydryl reagents.ResultsNine esterases IEE profiles were common to both the laboratory colonised and wild An. funestus adults. These esterases were further divided into acetylesterases, arylesterases, carboxylesterases and acetylcholinesterase. The activity level of certain specific esterases was primarily influenced by age and/or gender.ConclusionsThe information from this study contributes towards the general understanding of esterase enzyme activity variation in adults of a major malaria vector An. funestus. This variation likely carries physiological and adaptive significance and may influence specific characteristics, such as reproductive fitness and insecticide resistance that are epidemiologically important.

Gene drive through a landscape: Reaction–diffusion models of population suppression and elimination by a sex ratio distorter

Some genes or gene complexes are transmitted from parents to offspring at a greater-than-Mendelian rate, and can spread and persist in populations even if they cause some harm to the individuals carrying them. Such genes may be useful for controlling populations or species that are harmful. Driving-Y chromosomes may be particularly potent in this regard, as they produce a male-biased sex ratio that, if sufficiently extreme, can lead to population elimination. To better understand the potential of such genes to spread over a landscape, we have developed a series of reaction–diffusion models of a driving-Y chromosome in 1-D and radially-symmetric 2-D unbounded domains. The wild-type system at carrying capacity is found to be unstable to the introduction of driving-Y males for all models investigated. Numerical solutions exhibit travelling wave pulses and fronts, and analytical and semi-analytical solutions for the asymptotic wave speed under bounded initial conditions are derived. The driving-Y male invades the wild-type equilibrium state at the front of the wave and completely replaces the wild-type males, leaving behind, at the tail of the wave, a reduced- or zero-population state of females and driving-Y males only. In our simplest model of a population with one life stage and density-dependent mortality, wave speed depends on the strength of drive and the diffusion rate of Y-drive males, and is independent of the population dynamic consequences (suppression or elimination). Incorporating an immobile juvenile stage of fixed duration into the model reduces wave speed approximately in proportion to the relative time spent as a juvenile. If females mate just once in their life, storing sperm for subsequent reproduction, then wave speed depends on the movement of mated females as well as Y-drive males, and may be faster or slower than in the multiple-mating model, depending on the relative duration of juvenile and adult life stages. Numerical solutions are shown for parameter values that may in part be representative for Anopheles gambiae, the primary vector of malaria in sub-Saharan Africa.

Plasmodium vivax Transmission in Africa.

Malaria in sub-Saharan Africa has historically been almost exclusively attributed to Plasmodium falciparum (Pf). Current diagnostic and surveillance systems in much of sub-Saharan Africa are not designed to identify or report non-Pf human malaria infections accurately, resulting in a dearth of routine epidemiological data about their significance. The high prevalence of Duffy negativity provided a rationale for excluding the possibility of Plasmodium vivax (Pv) transmission. However, review of varied evidence sources including traveller infections, community prevalence surveys, local clinical case reports, entomological and serological studies contradicts this viewpoint. Here, these data reports are weighted in a unified framework to reflect the strength of evidence of indigenous Pv transmission in terms of diagnostic specificity, size of individual reports and corroboration between evidence sources. Direct evidence was reported from 21 of the 47 malaria-endemic countries studied, while 42 countries were attributed with infections of visiting travellers. Overall, moderate to conclusive evidence of transmission was available from 18 countries, distributed across all parts of the continent. Approximately 86.6 million Duffy positive hosts were at risk of infection in Africa in 2015. Analysis of the mechanisms sustaining Pv transmission across this continent of low frequency of susceptible hosts found that reports of Pv prevalence were consistent with transmission being potentially limited to Duffy positive populations. Finally, reports of apparent Duffy-independent transmission are discussed. While Pv is evidently not a major malaria parasite across most of sub-Saharan Africa, the evidence presented here highlights its widespread low-level endemicity. An increased awareness of Pv as a potential malaria parasite, coupled with policy shifts towards species-specific diagnostics and reporting, will allow a robust assessment of the public health significance of Pv, as well as the other neglected non-Pf parasites, which are currently invisible to most public health authorities in Africa, but which can cause severe clinical illness and require specific control interventions.

Malaria eradication and economic outcomes in sub-Saharan Africa: Evidence from Uganda

This study evaluates the economic consequences of a 1959–1960 malaria eradication campaign in southwestern Uganda. The effort constitutes a rare, large-scale, and well-documented attempt to eliminate malaria in sub-Saharan Africa and produced an immediate disease reduction. We use this quasi-experimental health shock to identify long-term changes in educational and economic outcomes. Comparing the treatment district to a similar synthetic control, we find malaria eradication raised educational attainment by about a half year for both males and females, increased primary school completion among females and generated an almost 40% rise in the likelihood of male wage employment.

The AvecNet Trial to assess whether addition of pyriproxyfen, an insect juvenile hormone mimic, to long-lasting insecticidal mosquito nets provides additional protection against clinical malaria over current best practice in an area with pyrethroid-resistant vectors in rural Burkina Faso: study protocol for a randomised controlled trial.

BackgroundRecent reductions in malaria in sub-Saharan Africa have been associated with increased coverage with long-lasting insecticidal nets (LLINs). Pyrethroids are currently the only insecticide class used for treating nets, and the rapid increase in resistance to pyrethroids in vector mosquitoes may jeopardise future vector control. Nets containing a novel combination of permethrin, a pyrethroid, and pyriproxyfen, an insect juvenile hormone mimic, (PPF-LLIN) may enhance malaria control, as well as reducing the spread of pyrethroid-resistant mosquitoes. This trial will determine whether PPF-LLINs provide incremental protection against malaria over current best practice of LLINs and prompt treatment in an area with pyrethroid-resistant vectors.MethodsA 2 armed cluster-randomised controlled trial will be conducted in Burkina Faso to assess whether PPF-LLIN (containing 2% permethrin and 1% pyriproxyfen w/w) provide better protection against clinical malaria in children than 2% permethrin-treated LLINs. Study subjects will be recruited and provided with LLINs at the start of the study. The LLINs will be exchanged for PPF-LLIN by cluster in a step-wedge fashion so 3 months before the end of the 2 year trial all participants will have a PPF-LLIN. The primary endpoint will be clinical malaria incidence measured by passive case detection in a cohort of children, aged 6 months to 5 years. Anaemia and parasite prevalence will also be measured in children during cross-sectional surveys. Exposure to malaria parasites will be assessed using light traps followed by identification of common vector species and their sporozoite infection rates. Safety evaluation will include recording of adverse events and pregnancy outcomes. The main endpoint analysis will include adjusting for distance between village clusters with different types of nets, as the impact of PPF-LLIN is likely to increase as larger areas are dominated by PPF-LLIN, reducing the spill over of mosquitoes from villages with LLINs.DiscussionThe step-wedge design is to measure the impact of an incrementally delivered environmental intervention where we expect the degree of control to be improved as more people use PPF-LLIN over a larger area. Trial findings will help inform policy makers on the effectiveness of PPF-LLIN nets for malaria control in areas of pyrethroid resistance.Trial registrationISRCTN21853394 – AvecNet, registered on 3 April 2013.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-015-0606-4) contains supplementary material, which is available to authorized users.

The Long Struggle against Malaria in Tropical Africa by James L. A. Webb Jr.

Reviewed by: The Long Struggle against Malaria in Tropical Africa by James L. A. Webb Jr. Urmi Engineer The Long Struggle against Malaria in Tropical Africa. By james l. a. webb jr. New York: Cambridge University Press, 2014. 219 pp. $94.95 (cloth); $72.00 (ebook). James L. A. Webb’s The Long Struggle against Malaria in Tropical Africa is an interdisciplinary historical study of the successes and failures of twentieth-century efforts to control malaria in tropical Africa. The book is a critical contribution to the study of world history and the growing literature on histories of disease, ecology, and global health, as well as the emergent subfield of historical epidemiology, of which Webb is a pioneer. Historical epidemiology brings a historical perspective to the study of contemporary disease challenges, which can be used to evaluate the strengths and limitations of current practices (p. xi). This book [End Page 655] serves as a sequel to and elaboration of arguments that Webb presented in Humanity’s Burden: A Global History of Malaria, which detailed the complex ecological history of humans and malarial parasites.9 The Long Struggle against Malaria in Tropical Africa begins with an introduction to the history of malaria, which lays the groundwork for understanding the author’s critical arguments about acquired immunity and the severe consequences of lapses in malaria control policy, a core theme that Webb reiterates throughout the text. Gaps in malaria control efforts enabled the resurgence of malaria and caused impacts that were more devastating to adult African populations than prior outbreaks, since they were not exposed to malaria as children and did not acquire immunity. The first two chapters, “European Vulnerability” and “African Immunity,” outline European and African experiences with malaria in the early twentieth century. Chapter 1 discusses the history of European efforts to avoid malaria, which included the use of quinine, residential segregation, and mosquito control. Chapter 2 focuses on African responses to malaria and outlines indigenous strategies for treating malarial symptoms and repelling mosquitoes, including burning smoky fires, applying plant ointments, and using mosquito traps. These chapters also demonstrate how European settlement, agricultural development, and urban growth resulted in new patterns of malaria transmission in rural highlands and lowlands in tropical East Africa. Chapter 3 focuses on the postwar global malaria eradication campaign (1950–1965) led by the World Health Organization (WHO) and elucidates the consequences of the closure of WHO pilot projects. The WHO campaign operated by spraying synthetic insecticides and administering synthetic antimalarial drugs. The success of eradication campaigns in the United States, Mexico, Italy, Greece, Corsica, Venezuela, Ceylon, and elsewhere led to optimism among global public health policymakers. Webb argues that these campaigns ultimately failed in tropical Africa due to the development of resistance to insecticides among mosquitoes and the lack of cooperation with African populations in malarial zones. Further, the loss of acquired immunities among local populations eventually enabled the resurgence of malaria, with higher mortality and morbidity rates among African adults than ever before. The book’s discussion of African responses to public health programs raises questions about the necessity and motivations of early eradication [End Page 656] campaigns. During the colonial period, European states were primarily concerned with protecting nonimmune Europeans from malaria; however by the World War II era, they became increasingly interested in eradicating the disease in African environments. Cultural perceptions of the seriousness of malaria shaped African and European ideas about the necessity of antimalarial campaigns, as most African adults saw malaria as “an annoyance, an unpleasant reality of life like the seasonal flu, rather than a problem to be tacked with scarce resources” (p. 94). Chapter 4, entitled “Positive Turbulence,” focuses on responses to malaria among new independent African governments between 1965 and 1980. Webb argues that resistance to WHO campaigns was political as well as ecological; new African governments expressed ideological resistance to colonial models of public health administration, and parasites and mosquitoes developed genetic resistance to antimalarials and insecticides. However, African states did facilitate the distribution of chloroquine, which was generally accepted among Africans and led to a general decline of malaria in sub-Saharan Africa. Despite the promise of chloroquine, “serious trouble lay ahead,” as chloroquine resistance...

Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013

The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occured since the Millennium Declaration. To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010-13) of incidence, drug resistance, and coverage of insecticide-treated bednets. Globally in 2013, there were 1·8 million new HIV infections (95% uncertainty interval 1·7 million to 2·1 million), 29·2 million prevalent HIV cases (28·1 to 31·7), and 1·3 million HIV deaths (1·3 to 1·5). At the peak of the epidemic in 2005, HIV caused 1·7 million deaths (1·6 million to 1·9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19·1 million life-years (16·6 million to 21·5 million) have been saved, 70·3% (65·4 to 76·1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7·5 million (7·4 million to 7·7 million), prevalence was 11·9 million (11·6 million to 12·2 million), and number of deaths was 1·4 million (1·3 million to 1·5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7·1 million (6·9 million to 7·3 million), prevalence was 11·2 million (10·8 million to 11·6 million), and number of deaths was 1·3 million (1·2 million to 1·4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64·0% of cases (63·6 to 64·3) and 64·7% of deaths (60·8 to 70·3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1·2 million deaths (1·1 million to 1·4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31·5% (15·7 to 44·1). Outside of Africa, malaria mortality has been steadily decreasing since 1990. Our estimates of the number of people living with HIV are 18·7% smaller than UNAIDS's estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action. Bill & Melinda Gates Foundation.

Multigene Phylogenetics Reveals Temporal Diversification of Major African Malaria Vectors

The major vectors of malaria in sub-Saharan Africa belong to subgenus Cellia. Yet, phylogenetic relationships and temporal diversification among African mosquito species have not been unambiguously determined. Knowledge about vector evolutionary history is crucial for correct interpretation of genetic changes identified through comparative genomics analyses. In this study, we estimated a molecular phylogeny using 49 gene sequences for the African malaria vectors An. gambiae, An. funestus, An. nili, the Asian malaria mosquito An. stephensi, and the outgroup species Culex quinquefasciatus and Aedes aegypti. To infer the phylogeny, we identified orthologous sequences uniformly distributed approximately every 5 Mb in the five chromosomal arms. The sequences were aligned and the phylogenetic trees were inferred using maximum likelihood and neighbor-joining methods. Bayesian molecular dating using a relaxed log normal model was used to infer divergence times. Trees from individual genes agreed with each other, placing An. nili as a basal clade that diversified from the studied malaria mosquito species 47.6 million years ago (mya). Other African malaria vectors originated more recently, and independently acquired traits related to vectorial capacity. The lineage leading to An. gambiae diverged 30.4 mya, while the African vector An. funestus and the Asian vector An. stephensi were the most closely related sister taxa that split 20.8 mya. These results were supported by consistently high bootstrap values in concatenated phylogenetic trees generated individually for each chromosomal arm. Genome-wide multigene phylogenetic analysis is a useful approach for discerning historic relationships among malaria vectors, providing a framework for the correct interpretation of genomic changes across species, and comprehending the evolutionary origins of this ubiquitous and deadly insect-borne disease.

Artesunate plus pyronaridine for treating uncomplicated Plasmodium falciparum malaria.

The World Health Organization (WHO) recommends that people with uncomplicated Plasmodium falciparum malaria are treated using Artemisinin-based Combination Therapy (ACT). ACT combines three-days of a short-acting artemisinin derivative with a longer-acting antimalarial which has a different mode of action. Pyronaridine has been reported as an effective antimalarial over two decades of use in parts of Asia, and is currently being evaluated as a partner drug for artesunate. To evaluate the efficacy and safety of artesunate-pyronaridine compared to alternative ACTs for treating people with uncomplicated P. falciparum malaria. We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; LILACS; ClinicalTrials.gov; the metaRegister of Controlled Trials (mRCT); and the WHO International Clinical Trials Search Portal up to 16 January 2014. We searched reference lists and conference abstracts, and contacted experts for information about ongoing and unpublished trials. Randomized controlled trials of artesunate-pyronaridine versus other ACTs in adults and children with uncomplicated P. falciparum malaria.For the safety analysis, we also included adverse events data from trials comparing any treatment regimen containing pyronaridine with regimens not containing pyronaridine. Two authors independently assessed trial eligibility and risk of bias, and extracted data. We combined dichotomous data using risk ratios (RR) and continuous data using mean differences (MD), and presented all results with a 95% confidence interval (CI). We used the GRADE approach to assess the quality of evidence. We included six randomized controlled trials enrolling 3718 children and adults. Artesunate-pyronaridine versus artemether-lumefantrineIn two multicentre trials, enrolling mainly older children and adults from west and south-central Africa, both artesunate-pyronaridine and artemether-lumefantrine had fewer than 5% PCR adjusted treatment failures during 42 days of follow-up, with no differences between groups (two trials, 1472 participants, low quality evidence). There were fewer new infections during the first 28 days in those given artesunate-pyronaridine (PCR-unadjusted treatment failure: RR 0.60, 95% CI 0.40 to 0.90, two trials, 1720 participants, moderate quality evidence), but no difference was detected over the whole 42 day follow-up (two trials, 1691 participants, moderate quality evidence). Artesunate-pyronaridine versus artesunate plus mefloquineIn one multicentre trial, enrolling mainly older children and adults from South East Asia, both artesunate-pyronaridine and artesunate plus mefloquine had fewer than 5% PCR adjusted treatment failures during 28 days follow-up (one trial, 1187 participants, moderate quality evidence). PCR-adjusted treatment failures were 6% by day 42 for these treated with artesunate-pyronaridine, and 4% for those with artesunate-mefloquine (RR 1.64, 95% CI 0.89 to 3.00, one trial, 1116 participants, low quality evidence). Again, there were fewer new infections during the first 28 days in those given artesunate-pyronaridine (PCR-unadjusted treatment failure: RR 0.35, 95% CI 0.17 to 0.73, one trial, 1720 participants, moderate quality evidence), but no differences were detected over the whole 42 days (one trial, 1146 participants, low quality evidence). Adverse effectsSerious adverse events were uncommon in these trials, with no difference detected between artesunate-pyronaridine and comparator ACTs. The analysis of liver function tests showed biochemical elevation were four times more frequent with artesunate-pyronaridine than with the other antimalarials (RR 4.17, 95% CI 1.38 to 12.62, four trials, 3523 participants, moderate quality evidence). Artesunate-pyronaridine performed well in these trials compared to artemether-lumefantrine and artesunate plus mefloquine, with PCR-adjusted treatment failure at day 28 below the 5% standard set by the WHO. Further efficacy and safety studies in African and Asian children are required to clarify whether this combination is an option for first-line treatment.

Estimates of the changing age-burden of Plasmodium falciparum malaria disease in sub-Saharan Africa

Estimating the changing burden of malaria disease remains difficult owing to limitations in health reporting systems. Here, we use a transmission model incorporating acquisition and loss of immunity to capture age-specific patterns of disease at different transmission intensities. The model is fitted to age-stratified data from 23 sites in Africa, and we then produce maps and estimates of disease burden. We estimate that in 2010 there were 252 (95% credible interval: 171–353) million cases of malaria in sub-Saharan Africa that active case finding would detect. However, only 34% (12–86%) of these cases would be observed through passive case detection. We estimate that the proportion of all cases of clinical malaria that are in under-fives varies from above 60% at high transmission to below 20% at low transmission. The focus of some interventions towards young children may need to be reconsidered, and should be informed by the current local transmission intensity.

Population pharmacokinetics of azithromycin and chloroquine in healthy adults and paediatric malaria subjects following oral administration of fixed-dose azithromycin and chloroquine combination tablets

BackgroundPopulation pharmacokinetics (PK) of azithromycin (AZ) and chloroquine (CQ) following administration of fixed-dose combination tablet formulations of AZ and CQ (AZCQ) was evaluated using data from two studies: 1) in children with symptomatic uncomplicated falciparum malaria in sub-Saharan Africa; and 2) in healthy adults in the United States.MethodsStudy 1 included paediatric subjects randomized to either AZCQ or artemether-lumefantrine treatment in Cohort 1 (age 5–12 years) and Cohort 2 (age 6–59 months). Dosing of AZCQ was approximately 30 mg/kg AZ and 10 mg/kg CQ once daily for 3 days (for ≥20 kg weight: AZ/CQ 300/100 mg per tablet; 5 to <20 kg weight: AZ/CQ 150/50 mg per tablet). Study 2 included adults randomized to receive either two AZCQ tablets (AZ/CQ 250/155 mg per tablet) or individual commercial tablets of AZ 500 mg and CQ 300 mg. Serum AZ and plasma CQ concentrations from both studies were pooled. Population PK models were constructed using standard approaches to evaluate the concentration-time data for AZ and CQ and to identify any covariates predictive of PK behaviour.ResultsA three-compartment PK model with linear clearance and absorption adequately described AZ data, while a two-compartment model with linear clearance and absorption and an absorption lag adequately described CQ data. No overall bias or substantial model misspecification was evident using diagnostic plots and visual predictive checks. Body weight as an allometric function was the only covariate in the final AZ and CQ PK models. There were significantly lower AZ (0.488 vs 0.745 [mg•h/L]/[mg/kg], p < 0.00001) and CQ (0.836 vs 1.27 [mg•h/L]/[mg/kg], p < 0.00001) exposures (AUCinf) normalized by dose (mg/kg) in children compared with the adults.ConclusionsThe PK of AZ and CQ following administration of AZCQ was well described using a three- and two-compartment model, respectively. AZ and CQ exhibited linear absorption and clearance; the model for CQ included an absorption lag. Weight was predictive of exposure for both AZ and CQ. Assuming equivalent dosing (mg/kg), AZ and CQ exposure in children would be expected to be lower than that in adults, suggesting that children may require a higher dose (mg/kg) than adults to achieve the same AZ and CQ exposure.

Scale-up of Malaria Rapid Diagnostic Tests and Artemisinin-Based Combination Therapy: Challenges and Perspectives in Sub-Saharan Africa

Guido Bastiaens and colleagues describe barriers to achieving scale-up and appropriate use of rapid diagnostic tests and artemisinin-based combination therapy for malaria in sub-Saharan Africa. Please see later in the article for the Editors' Summary.

Editorial Commentary: Out of Africa: Links Between Invasive Nontyphoidal Salmonella Disease, Typhoid Fever, and Malaria

The report by Biggs et al in the current issue of Clinical Infectious Diseases provides important insight into relationships between the 2 main forms of invasive Salmonella disease and the major childhood infectious disease burden in sub-Saharan Africa—malaria. It is the latest in a series of carefully conducted clinical studies from Tanzania from the research groups of John Crump and Hugh Reyburn. The study combines blood culture and clinical data from 2 major hospitals located some 250 km apart in very different settings: the Kilimanjaro Christian Medical Centre (KCMC), at 890 m at the foot of Mount Kilimanjaro in Moshi, where malaria transmission is low and seasonal, and Teule Hospital, at 96 m near the coast in Muheza, where malaria transmission is intensive and perennial. Invasive Salmonella disease can be divided broadly into enteric fever, principally caused by Salmonella enterica serovars Typhi and Paratyphi A, and invasive nontyphoidal Salmonella (iNTS) disease, mainly caused by Salmonella Typhimurium and Enteritidis. Enteric fever is a particular problem in Southeast Asia [1], where iNTS disease is relatively uncommon. By contrast, iNTS disease is responsible for a much larger disease burden than enteric fever in sub-Saharan Africa, causing >100 000 deaths a year. In many African countries, nontyphoidal Salmonella (NTS) is the commonest cause of bacteremia [2], although in recent years, there has been a growing number of reports of invasive disease caused by S. Typhi in the region. It is currently uncertain what is driving the evolving epidemiology of invasive Salmonella disease in sub-Saharan Africa. The sites in Tanzania where this study was conducted represent 2 locations in Africa where both iNTS disease and typhoid can be studied. The authors investigated bacteremia among febrile children admitted to both hospitals. There was no difference in the isolation rates of Streptococcus pneumoniae and Escherichia coli, 2 commonly isolated bacterial pathogens, between the sites. However, bacteremia at Teule Hospital was twice as common as at KCMC and this difference is due to the higher incidence of iNTS disease at Teule. Half of all pathogenic isolates from that site were NTS, whereas only 1 case of NTS bacteremia was detected at KCMC. In contrast, S. Typhi accounted for 3% of culture isolates at Teule and a third at KCMC. These findings suggest the presence of a factor that exerts a strong influence on the 2 types of invasive Salmonella disease. Malaria is the obvious candidate. Malaria parasites were present in more than half of febrile children admitted at Teule, but only 2% at KCMC. Threequarters of iNTS disease cases at Teule were associated with malaria or recent malaria. By multivariate analysis, iNTS disease was significantly associated with younger age, recent malaria, acute severe

Impact of trehalose transporter knockdown onAnopheles gambiaestress adaptation and susceptibility toPlasmodium falciparuminfection

Anopheles gambiae is a major vector mosquito for Plasmodium falciparum, the deadly pathogen causing most human malaria in sub-Saharan Africa. Synthesized in the fat body, trehalose is the predominant sugar in mosquito hemolymph. It not only provides energy but also protects the mosquito against desiccation and heat stresses. Trehalose enters the mosquito hemolymph by the trehalose transporter AgTreT1. In adult female A. gambiae, AgTreT1 is predominantly expressed in the fat body. We found that AgTreT1 expression is induced by environmental stresses such as low humidity or elevated temperature. AgTreT1 RNA silencing reduces the hemolymph trehalose concentration by 40%, and the mosquitoes succumb sooner after exposure to desiccation or heat. After an infectious blood meal, AgTreT1 RNA silencing reduces the number of P. falciparum oocysts in the mosquito midgut by over 70% compared with mock-injected mosquitoes. These data reveal important roles for AgTreT1 in stress adaptation and malaria pathogen development in a major vector mosquito. Thus, AgTreT1 may be a potential target for malaria vector control.

Factoring Quality Laboratory Diagnosis into the Malaria Control Agenda for Sub-Saharan Africa

Recent progress in malaria control in sub-Saharan Africa has been achieved primarily through provision of insecticide-treated nets, indoor residual spraying, and antimalarial drugs. Although these interventions are important, proper case identification and accurate measurement of their impact depend on quality diagnostic testing. Current availability of diagnostic testing for malaria in sub-Saharan Africa is inadequate to support disease management, prevention programs, and surveillance needs. Challenges faced include a dearth of skilled workforce, inadequate health systems infrastructure, and lack of political will. A coordinated approach to providing pre-service clinical and laboratory training together with systems that support a scale-up of laboratory services could provide means not only for effective malaria case management but also, management of non-malaria febrile illnesses, disease surveillance, and accurate control program evaluation. A synthesis of the challenges faced in ensuring quality malaria testing and how to include this information in the malaria control and elimination agenda are presented.

The economic costs of malaria in children in three sub-Saharan countries: Ghana, Tanzania and Kenya.

BackgroundMalaria causes significant mortality and morbidity in sub-Saharan Africa (SSA), especially among children less than five years of age (U5 children). Although the economic burden of malaria in this region has been assessed previously, the extent and variation of this burden remains unclear. This study aimed to estimate the economic costs of malaria in U5 children in three countries (Ghana, Tanzania and Kenya).MethodsHealth system and household costs previously estimated were integrated with costs associated with co-morbidities, complications and productivity losses due to death. Several models were developed to estimate the expected treatment cost per episode per child, across different age groups, by level of severity and with or without controlling for treatment-seeking behaviour. Total annual costs (2009) were calculated by multiplying the treatment cost per episode according to severity by the number of episodes. Annual health system prevention costs were added to this estimate.ResultsHousehold and health system costs per malaria episode ranged from approximately US$ 5 for non-complicated malaria in Tanzania to US$ 288 for cerebral malaria with neurological sequelae in Kenya. On average, up to 55% of these costs in Ghana and Tanzania and 70% in Kenya were assumed by the household, and of these costs 46% in Ghana and 85% in Tanzania and Kenya were indirect costs. Expected values of potential future earnings (in thousands) lost due to premature death of children aged 0–1 and 1–4 years were US$ 11.8 and US$ 13.8 in Ghana, US$ 6.9 and US$ 8.1 in Tanzania, and US$ 7.6 and US$ 8.9 in Kenya, respectively. The expected treatment costs per episode per child ranged from a minimum of US$ 1.29 for children aged 2–11 months in Tanzania to a maximum of US$ 22.9 for children aged 0–24 months in Kenya. The total annual costs (in millions) were estimated at US$ 37.8, US$ 131.9 and US$ 109.0 nationwide in Ghana, Tanzania and Kenya and included average treatment costs per case of US$ 11.99, US$ 6.79 and US$ 20.54, respectively.ConclusionThis study provides important insight into the economic burden of malaria in SSA that may assist policy makers when designing future malaria control interventions.

New Insights into the Population Structure of Anopheles gambiae s.s. in the Gulf of Guinea Islands Revealed by Herves Transposable Elements

Transposable elements (TEs) are mobile portions of DNA that are able to replicate and spread in the genome of many organisms. TEs can be used as a means to insert transgenes in insects, being stably inherited throughout generations. Anopheles gambiae is the main vector of human malaria in Sub-Saharan Africa. Given the extraordinary burden this disease imposes, the mosquito became a choice target for genetic control approaches with the purpose of reducing malaria transmission. In this study, we investigated the abundance and distribution of Herves TE in An. gambiae s.s. from Cameroon and four islands in the Gulf of Guinea, in order to determine their genetic structure. We have detected a population subdivision between Equatorial Guinea islands and the islands of São Tomé, Príncipe and mainland. This partitioning associates more with political rather than geographic boundaries, possibly reflecting different mainland source populations colonizing the islands.

The effect of an anti-malarial subsidy programme on the quality of service provision of artemisinin-based combination therapy in Kenya: a cluster-randomized, controlled trial

BackgroundMany patients with suspected malaria in sub-Saharan Africa seek treatment from private providers, but this sector suffers from sub-standard medicine dispensing practices. To improve the quality of care received for presumptive malaria from the highly accessed private retail sector in western Kenya, subsidized pre-packaged artemether-lumefantrine (AL) was provided to private retailers, together with a one day training for retail staff on malaria diagnosis and treatment, job aids and community engagement activities.MethodsThe intervention was assessed using a cluster-randomized, controlled design. Provider and mystery-shopper cross-sectional surveys were conducted at baseline and eight months post-intervention to assess provider practices. Data were analysed based on cluster-level summaries, comparing control and intervention arms.ResultsOn average, 564 retail outlets were interviewed per year. At follow-up, 43% of respondents reported that at least one staff member had attended the training in the intervention arm. The intervention significantly increased the percentage of providers knowing the first line treatment for uncomplicated malaria by 24.2% points (confidence interval (CI): 14.8%, 33.6%; adjusted p=0.0001); the percentage of outlets stocking AL by 31.7% points (CI: 22.0%, 41.3%; adjusted p=0.0001); and the percentage of providers prescribing AL for presumptive malaria by 23.6% points (CI: 18.7%, 28.6%; adjusted p=0.0001). Generally outlets that received training and job aids performed better than those receiving one or none of these intervention components.ConclusionOverall, subsidizing ACT and retailer training can significantly increase the percentage of outlets stocking and selling AL for the presumptive treatment of malaria, but further research is needed on strategies to improve the provision of counselling advice to retail customers.

Prevalence of congenital malaria in high-risk Ghanaian newborns: a cross-sectional study

BackgroundCongenital malaria is defined as malaria parasitaemia in the first week of life. The reported prevalence of congenital malaria in sub-Saharan Africa is variable (0 - 46%). Even though the clinical significance of congenital malaria parasitaemia is uncertain, anti-malarial drugs are empirically prescribed for sick newborns by frontline health care workers. Data on prevalence of congenital malaria in high-risk newborns will inform appropriate drug use and timely referral of sick newborns.MethodsBlood samples of untreated newborns less than 1 week of age at the time of referral to Korle Bu Teaching hospital in Accra, Ghana during the peak malaria seasons (April to July) of 2008 and 2010 were examined for malaria parasites by, i) Giemsa-stained thick and thin blood smears for parasite count and species identification, ii) histidine-rich protein- and lactic dehydrogenase-based rapid diagnosis tests, or iii) polymerase chain reaction amplification of the merozoite surface protein 2 gene, for identification of sub-microscopic parasitaemia. Other investigations were also done as clinically indicated.ResultsIn 2008, nine cases of Plasmodium falciparum parasitaemia were diagnosed by microscopy in 405 (2.2%) newborns. All the nine newborns had low parasite densities (≤50 per microlitre). In 2010, there was no case of parasitaemia by either microscopy or rapid diagnosis tests in 522 newborns; however, 56/467 (12%) cases of P. falciparum were detected by polymerase chain reaction.ConclusionCongenital malaria is an uncommon cause of clinical illness in high-risk untreated newborns referred to a tertiary hospital in the first week of life. Empirical anti-malarial drug treatment for sick newborns without laboratory confirmation of parasitaemia is imprudent. Early referral of sick newborns to hospitals with resources and skills for appropriate care is recommended.