NIHRDataInsights/HRCSData huggingface dataset:
Title: Pharmacological modelling and data analysis in decision support of antimalarial drug dosing regimens
Funder: Medical Research Council

Abstract: Antimalarial drug treatment failures have a complicated aetiology associated with a range of factors, including human pharmacokinetic variation, parasites variation in drug sensitivity, dosing regimens and adherence, and variability caused by dosing patients based on weight/age bands. It is increasingly recognized that models which incorporate these sources of variation have the potential to support and guide the drug implementation process through identification of a drug?s future therapeutic potential. Over the past two years, scientists at LSTM have made good progress in this area. As one of the partners of a large malaria modelling research consortium, dr Hastings has been developing and refining pharmacokinetic/ pharmacodynamic (PK/PD) models of antimalarial drug treatment to the state that they can now successfully capture the broad quantitative patterns noted in the field and clinic. Similarly, dr Terlouw has led the development of weight-for-age reference curves that are representative of patient populations in the endemic areas of Africa, Asia and Latin America, and has used this to identify optimal age-based dosing regimens, and the associated level of under and overdosing at population level. We propose to further refine, integrate and calibrate the two research agendas to generate a tool that can address operational questions surrounding deployment of the latest generation of antimalarial drugs, the artemisinin-combination therapies (ACTs). Specifically we propose: (i) We shall incorporate drug absorption and conversion phases; these are important determinants of peak, possible toxic, drug concentrations and occur on important timescales for short half-life artemisinins. (ii) Malaria parasites are insensitive to drugs in certain stages of their lifecycle, and may even enter ?dormant? stages that are unaffected by drugs; we shall develop a methodology to allow for these stages of insensitivity. (iii) We shall develop methodologies to optimise the design of age/height dosing bands. (iv) We shall explicitly calibrate PK/PD variation for the current generation of antimalarial drugs (the ACTs) to investigate the dynamics of drug resistance. Placing these factors in an explicit PK/PD framework s constitutes a significant advance on current modelling strategies for antimalarial drugs and has the potential to guide and optimise several key aspects of antimalarial deployment in resource-poor settings.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES);6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: A Randomised, Open-Label, Comparative Study of Itraconazole vs. Amphotericin B for the Induction Therapy of Penicilliosi
Funder: Medical Research Council

Abstract: Penicilliosis is emerging as one of the three most common HIV-associated opportunistic infections in Asia. Despite the rapid growing HIV epidemics in a region that houses one half of the worlds population, there has not been a single randomised controlled trial to evaluate the treatment of penicilliosis. The current recommendation of amphotericin B for 2 weeks followed by itraconazole for 10 weeks is based on one non-comparative study [1]. Amphotericin B has extremely limited availability, has significant side effects, needs to adminstered through a vein daily over 6 hours of infusion, and is prohibitively expensive in most areas of Asia. Itraconazole, on the other hand, is widely available in local pharmacies throughout Asia, can be given orally at a fraction of the price. Further, data from available case series suggest that itraconazole and amphotericin B have similar efficacies. We therefore propose to conduct a randomised, open-label, non-inferiority trial of the efficacy of itraconazole versus amphotericin B for penicilliosis. 440 adults from in and outpatient settings with culture-confirmed penicilliosis will be recruited, randomly allocated to either itraconazole or amphotericin B treatment, monitored daily in-hospital for 2 weeks, and at monthly intervals for a total of 6 months. Primary outcome is mortality at 2 weeks. Secondary outcomes include 6-month survival, clinical response, relapse, drug tolerability, and economic costs. Correlates of interests include admission prognostic factors, time-to-culture-sterilization, fungicidal activities, pharmacokinetic parameters, and serologic titres. These results will be available within five years and will either change or support current treatment guidelines for penicilliosis.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: A clinical trial of dexamethasone to reduce mortality in cryptococcal meningitis
Funder: Medical Research Council

Abstract: Cryptococcal meningitis is the leading cause of death in HIV patients in Asia and Africa with death rates between 55 and 70%. There are an estimated 625 000 deaths each year, most occurring in poorer countries and within 3 months of diagnosis. There has been no major advance in treatment since 1997 - no combination of antifungal drugs with greater sterilizing power than amphotericin and flucytosine has since been identified. In order to make a significant impact on mortality, alternative approaches need to be trialled. Adjuvant therapies are relatively untested in cryptococcal meningitis. Raised intracranial pressure, vasculitis with infarction and cerebral oedema are all complications of cryptococcal meningitis and are believed to contribute towards its high mortality. These pathologies are potentially modifiable with dexamethasone. Dexamethasone is a corticosteroid which is frequently used to treat intracranial pathology including vasculitides, raised pressure, and cerebral oedema. It is of proven benefit in reducing the death rate of tuberculous meningitis, a chronic meningitis that has some pathophysiological similarities to cryptococcal meningitis. Moreover, it has an excellent safety profile, is cheap and practicable. In addition, animal studies show that dexamethasone does not impair the action of antifungal drugs. Therefore, we propose a multicentre double blind randomised controlled trial of dexamethasone in HIV infected patients with cryptococcal meningitis. The study will be based in countries in Africa (Uganda, South Africa, Malawi) and Southeast Asia (Thailand, Laos, Vietnam, Indonesia) where this disease is a significant health burden, and in centres with track records of successful completion of large clinical trials and the subsequent translation of findings into national and international policy. The multi-centre nature of the trial, recruiting in African and Asian countries, ensures that the results of the trial will have generalizability and impact. The primary endpoint will be survival until 10 weeks after randomization. The study will have 80% power to detect a reduction in the death rate of 30% (Hazard Ratio 0.7), and will require 880 patients (allowing for 10% loss to follow up). The study will also have 80% power to detect a 40% reduction in death rate in each continent. Patients will receive optimised antifungal therapy and be randomised to receive dexamethasone or identical placebo. Secondary endpoints include disability, survival to 6 months, adverse event rates, opportunistic infection rates and the rate of fungal clearance.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: TB fast track: effect of a point-of-care TB test-and-treat algorithm on early mortality in people with HIV accessing ART
Funder: Medical Research Council

Abstract: Background: Early mortality remains high among adults with HIV accessing antiretroviral therapy (ART) in resource-constrained settings, with tuberculosis (TB) a leading cause of death. 20% people accessing ART in South Africa have undiagnosed TB. However, due to insensitivity of sputum microscopy, and a complex diagnostic pathway for smear-negative TB, the time to TB diagnosis is protracted, delaying both TB treatment (among those diagnosed with TB) and ART (among all investigated, whether or not TB is diagnosed). We hypothesise that a care pathway using point-of-care technology to rapidly identify individuals presenting for ART at high risk of TB and ensure they start TB treatment, then ART, will markedly reduce early mortality. Objective: To compare 6-month mortality among patients with HIV disease and CD4 150 cells/?l referred to start ART between intervention clinics implementing a point-of-care algorithm to identify individuals with a high probability of active TB, and facilitate rapid initiation of TB treatment, followed by ART; vs. control clinics delivering standard of care management according to South African TB/HIV care guidelines. Methods: This is a cluster-randomised trial, randomising 20 primary health clinics in Gauteng and Limpopo provinces, South Africa. ART-eligible patients (CD4 150, ambulant, no recent TB treatment) at intervention clinics will be assessed using simple point-of-care assays. Patients with any of: positive urine lipoarabinomannan (LAM), haemoglobin (Hb) 10, body mass index (BMI) 18.5 will be considered high probability TB, and start TB treatment immediately, then ART. Asymptomatic patients with negative LAM, Hb 10, BMI 18.5 will be low probability and will start ART. Others ( medium probability ) will be investigated for smear-negative TB as per South African guidelines with review after one week to re-categorise into high or low probability. In control clinics we will recruit similar patients and obtain permission for follow-up; management will be as per national guidelines. The primary outcome is mortality at 6 months after recruitment; secondary outcomes include severe morbidity, measured by duration of hospitalisation. Diagnostic cost per TB case detected, and cost per DALY, will be estimated. We estimate mortality conservatively at 25/100 person years in the control arm; with 10 clusters per arm, 175 patients per cluster, and 95% ascertainment of vital status at 6 months, using between-cluster coefficients of variation of 0.2 and 0.25, there will be 91% and 85% power to assess 40% reduction in mortality, respectively. Significance: This strategy may result in a major reduction in mortality for people with HIV.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Epidemiology, Ecology and Socio-Economics of Disease Emergence in Nairobi
Funder: Medical Research Council

Abstract: Our overall objective is to understand the mechanisms leading to the introduction of pathogens into urban populations, and their subsequent spread. We focus on livestock as sources of these pathogens: emerging diseases are likely to be zoonotic in origin, and livestock pathogens, through the close interactions between livestock, their products and people, are at high of risk crossing the species barrier. It is often claimed that urbanization makes pathogen emergence more likely, but the underlying mechanisms are poorly understood. What is it, exactly, about urban environments that might predispose to an emergence event, and what is the contribution of livestock keeping to this process? We will investigate two key aspects of this. Firstly, does urban livestock keeping pre-dispose people to acquiring new or more diverse microbial flora? Is the risk compounded by poverty status or other social factors? How is the microbial flora influenced by the keeping of livestock in these areas? Secondly, we will investigate exposure to livestock products traded for food or other purposes. Do supply chains for these products bring people into contact with microbial diversity over and above what they would otherwise experience? Why do people source food from particular places, and what influences the microbial flora to which people are exposed through food? Why do supply chains exist in the way that they do, and how might they change as demand for products changes with urban growth, or as a consequence of legislation? We have created an interdisciplinary team of epidemiologists, microbiologists, urban planners, demographers, social scientists, geographers, public health specialists, ecologists and economists to address these questions, examining in detail the city of Nairobi, Kenya. We will focus on Escherichia coli, an exemplar of many potential emerging pathogens, which exists in a diversity of hosts, in the environment, on food, in waste. We will take a landscape genetics approach to understanding E. coli distribution and spread and how this is affected by environmental and socio-economic factors. Our approach, which builds on state-of-the-art methodologies across a range of disciplines, is likely to become a benchmark for future studies, and will be applicable to a wide range of situations where animals, people and the environment interact. The findings will inform development of policy on urban livestock keeping by improving knowledge of the public health risks and by putting those risks in a wider socio-economic context, including the risks associated with alternative sources of livestock products.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Defining the biomedical, environmental and social risk factors for human infection with Plasmodium knowlesi; opportuniti
Funder: Medical Research Council

Abstract: Background: Until recently, medical science has attributed malaria infections in humans to only four parasite species. However, molecular investigations during a malaria epidemic in Malaysian Borneo in 2004 confirmed the causative agent as Plasmodium knowlesi, a parasite formerly thought to only infect primates. Studies have since detected P. knowlesi in human populations in several other Southeast Asian countries. The primary hosts of P. knowlesi are macaque species that are widely distributed across Southeast Asia and in which infection is benign. P. knowlesi infections in humans however can cause severe and fatal disease. Moreover recent studies in Sabah, Malaysia, have suggested that transmission is not confined to adults or the forest fringe as previously described. We hypothesize that the change in land use patterns has lead to this apparent increase in cases and changing epidemiology. The appearance of other primate-associated pathogens within human populations has been linked with activities such as deforestation (eg Yellow fever) and hunting (eg Ebola). A common feature of these zoonoses is that community perceptions of disease risk strongly impact on the economic activities that drive exposure, and demonstrate the value of an integrated approach to prevention and control. Methods: We propose an interdisciplinary approach to examine the extent of infection with P.knowlesi at 2 study sites and to identify risk factors for infection that ultimately contribute to its control. A case control study, the first of its kind for P.knowlesi, will allow analysis of broad scale spatial and socio-behavioural factors associated with symptomatic infections. Alongside this we will conduct detailed entomological trapping experiments and primatology studies within habitats of potential epidemiological importance (closed canopy primary forest, secondary forest, etc.). These data together with mosquito and macaque infection rates will be incorporated into spatial and mathematical models to generate risk maps for P.knowlesi infection. We will use these maps to define areas in which to conduct cross sectional surveys to identify asymptomatic infections and exposure patterns with P.knowlesi. Outputs: We aim to identify the scale of public health threat posed by P. knowlesi, through characterisation of the biological, environmental and social factors responsible for triggering its emergence within human populations. By understanding these factors we will generate risk maps to define and focus appropriate control strategies. This will allow an understanding of the conditions that permit the parasite host switch from macaque to human, and predictions of the risk of further species crossover events may be possible.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Sources, Seasonality, Transmission and Control: Campylobacter and human behaviour in a changing environment
Funder: Medical Research Council

Abstract: Diarrhoeal disease is an important global killer that causes major health and economic problems Many organisms that cause it are zoonotic. They are widely distributed in the environment and there are several pathways to human disease. Research into diarrhoeal disease to date has been largely biomedical and focussed mainly on transmission through contaminated food or water. Fundamental gaps in our knowledge remain, namely the contributions of human behaviour and human-environment interactions influencing exposure to organisms and risk of disease. We propose a ground-breaking programme, bringing together scientists from a wide variety of disciplines in a ?one health? approach to tackle these fundamental knowledge gaps using Campylobacter spp. as an example. Important in its own right, Campylobacter is the most common bacterial cause of diarrhoeal disease in the developed world. It caused an estimated 700,000 cases in the UK in 2010 with ~200 deaths. Extreme outcomes include irritable bowel syndrome, arthritis and paralysis. The current, underestimated, annual UK cost of Campylobacter infection alone is #600m, exceeding that from Salmonella, Listeria and E. coli O157 combined. The transmission pathways for ~50% of human cases are unknown. Seasonal dynamics are central to the disease burden because ~40% of cases occur during the ?spring peak?, yet the relative roles of environmental and food pathways, and their interaction, in this seasonal emergence are poorly understood. To make major progress we face two important challenges. The first is to develop new methods that incorporate environmental and social systems to understand how they interact with Campylobacter. Secondly, since the behaviours of both humans and Campylobacter involve processes that play out over different temporal and spatial scales, the new methods we develop need to capture this. The challenge of analysing systems and data at different scales, whilst minimising loss of information in so doing, will be generally applicable to research on the interaction of social and ecological systems and zoonoses.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Exploitation of quorum sensing for the discovery of novel agents against staphylococci
Funder: Medical Research Council

Abstract: Staphylococcal infections are of major clinical importance. MRSA strains which exhibit multi-antibiotic resistance and cause invasive infections in healthy individuals constitute a serious health threat. While resistance has evolved against virtually every antibiotic deployed, the development of new classes of antibiotics has lagged far behind the urgent requirement for new drugs. Many major pharmaceutical companies have withdrawn from the antibiotic discovery field mainly because of the huge economic cost of developing drugs likely to become rapidly obsolete through resistance. Thus, there is an urgent need to identify novel antibacterial targets and develop new agents effective against multi-resistant bacteria. This in turn depends on a thorough understanding of the basic molecular biology and physiology of bacterial pathogens. In this context, the attenuation of virulence through the blockade of sophisticated global regulatory systems such as quorum sensing (QS) offers an attractive target. In S. aureus, the agr QS system, which is also shared by Gram positive pathogens including Listeria, Enterococcus and Clostridium, is central to virulence gene regulation, intracellular survival and biofilm development and dispersal. Here we propose to build on our previous work by employing a multidisciplinary research strategy combining chemical biology with bacterial physiology and in vivo studies to obtain detailed molecular insights into (a) the recognition of auto-inducing peptide (AIP) signal molecules by the histidine sensor kinase receptor, AgrC, and (b) the generation and export of AIPs via the transmembrane enzyme, AgrB. Unexpectedly, both growth and agr-dependent QS in S. aureus can be inhibited by Gram negative bacterial QS signal molecules and we have discovered analogues (tetramic and tetronic acids) which exhibit potent activity against staphylococci and other Gram positive bacteria including Clostridium difficile. In addition we have identified a class of thiol-reactive aryl quinones which inhibit agr potentially through the inactivation of SarA family proteins in S. aureus which regulate virulence via agr-dependent and -independent mechanisms We will therefore undertake extensive structure activity relationship, mechanistic and translational studies on the each compound class to elucidate their mechanisms of action and to develop agents with increased potency. The most promising compounds including novel AIP antagonists will be investigated for their activity against planktonic, biofilm and intracellular staphylococci in laboratory culture and for in vivo efficacy in experimental animal infection models. The work has broad implications for antibacterial agent discovery beyond S. aureus given the conservation of agr systems in Gram positive pathogens and two component systems in bacteria generally


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Over three years to improve immunogenicity and coverage of the next generation of meningococcal vaccines
Funder: Action Medical Research

Abstract: Background_x000D_ Meningococcal bacteria are the main cause of meningitis and septicaemia (bacterial infection of the blood) in children in the UK. The disease can strike healthy children rapidly and it can be difficult to establish an early diagnosis. Even with optimal treatment children can die and survivors are often left with long term disabilities such as loss of limbs and deafness. Although vaccines are available to protect children against some forms of meningococcal disease, none is currently available against the most common form, that caused by Neisseria meningitidis group B (also called meningococcus B or MenB) which accounts for over 80 per cent of cases in the UK. There are currently two vaccines for MenB in clinical development, but their coverage and efficacy remain uncertain. There remains an urgent need to develop effective vaccines to protect children against this serious disease._x000D_ The research project_x000D_ These researchers aim to develop next generation vaccines based on detailed knowledge of a key meningococcal protein called factor H binding protein (fHbp). MenB bacteria have this protein on their cell surface. Therefore, when injected, vaccines containing the protein will stimulate an immune response and cause the body to produce antibodies effective against MenB. However, there are three types of the protein and the vaccines currently in clinical trials contain only type 1 and/or type 3. This is likely to restrict how effective they are since meningococci with type 2 fHbp account for 30 per cent of meningococcal disease in the UK. This team will modify type 2 fHbp to make it more stable (and hence a more suitable vaccine) and add other important proteins from the cell surface of the bacterium to broaden the effect of the vaccine. The aim is to make a single protein-based vaccine which provides effective, broad-based immunity against disease caused by meningococcus B.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION