Although highly active antiretroviral regimen' (HAART) reduces HIV-related morbidity and mortality, it affects patients and induces HIV viral resistance which could lead to more complex therapeutic regimens. The present study evaluated and compared the cost-effectiveness of a protease inhibitor based highly active antiretroviral regimen' (PHAART) with a non nucleoside reverse transcriptase inhibitor based highly active antiretroviral regimen' (NHAART) in HIV-patients. The impact of initial HAART was investigated using retrospective cost analysis over a 10-year period and 6 months prospective HRQoL analysis of 150 patients (male 125, mean age 40 years) attending the Cardiff Royal Infirmary and the University Hospital of Wales. Data was collected on each patient's care resource utilization and their health-related quality of life (HRQoL) assessed using the Health Utility Index Mark III (HUI3) questionnaire. The effect of the HAART regimen, demographic attributes and clinical characteristics on costs and HRQoL were analyzed using a multilevel model of change. A Markov Monte Carlo model was then developed to simulate the impact, and evaluate the cost effectiveness, of both regimens beyond the study time horizon. The mean monthly outpatient cost for all patients was estimated to be 237.59. Patients receiving NHAART as the initial regimen cost significantly more (p 0.01, mean 262.19) than patients receiving PHAART (mean 234.98). Other factors associated with higher costs were being a non-British national, having a low CD4 count, a high viral load, and having AIDS. Patients receiving an initial NHAART regimen had a significantly better HRQoL (p 0.05). Factors associated with a higher HRQoL included being in employment and being in the asymptomatic stage of HIV. With respect to lifetime cost-effectiveness analysis, PHAART was found to be more cost-effective as an initial regimen since the incremental cost-effectiveness ratio of 8,871 per quality adjusted life years (QALY) gained, was below the UK threshold of 30,000 per QALY. The findings of this study indicate that patients receiving NHAART as their initial regimen had higher outpatient costs than those initiated on PHAART, but had a better HRQoL. In the long term, however, PHAART was estimated to be more cost- effective than NHAART as an initial regimen for HIV patients.

The current system in place to study safety of medicines after introduction on the market relies on spontaneous reporting. Adverse events occurring long after initiation or cessation of drug use are likely to be missed by this system. In this thesis we explore methods to identify signals of long-term, unexpected adverse events and methods to evaluate these signals. We utilised data from the UK General Practice Research Database (GPRD), a large primary care database. A systematic review investigating the validity of medical diagnoses recorded in this database illustrated that the GPRD is a powerful tool to study morbidity in primary care. However, intimate knowledge of the complexities of the database is needed to ensure the best use is made of the database. Pre-existing hypotheses of drug-induced systemic lupus erythematosus (SLE) were evaluated using the GPRD. Associations between risk of SLE and exposure to hydralazine, minocycline, and carbamazepine were confirmed using both a matched case-control design and the self controlled case series method. Spontaneous reports of drug-induced SLE recorded in the UK Yellow Card database indicated that symptoms of SLE often resolve after withdrawal of the suspected drug. Using the Smile Plot method to generate signals of drug-induced SLE, we were not able to identify known signals of drug-induced lupus. However, we did identify factors strongly associated with treatment of early symptoms of disease. These findings indicated a high specificity of the Smile Plot method. To improve sensitivity, better hierarchical coding systems for drugs are needed to ensure appropriate grouping. Lastly, we utilised the GPRD to provide an example of a systematically performed drug safety study. In a small subset of data, we generated hypotheses of drug-induced Hashimoto's disease. Associations were subsequently evaluated in a larger subset of data. No drugs were clearly associated with risk of Hashimoto's disease.

People living with HIV have up to a fourfold probability of developing type 2 diabetes (T2D), driven by HIV-related factors including the direct effect of certain HIV medicines, and general factors, notably obesity and age. This mixed-methods research, studying HIV patients in South London, aimed to characterise risk factors for T2D, and investigate the effectiveness and acceptability of a pilot lifestyle intervention. Data from a cross-sectional study (n=338) showed a T2D prevalence of 15.1%. Rather than HIV-specific factors the greater contribution to risk of prediabetes/T2D were the conventional risk factors hepatic steatosis and hypertension (odds ratios 7.3 and 2.6 respectively); modifiable factors made a greater contribution to prediabetes/T2D than fixed or historic factors. A pilot diet and activity intervention for people with HIV and prediabetes (n=33) demonstrated statistically significant improvements in 6-month change in glucose and insulin for both fasting levels (5.5% and 23.6% reductions respectively) and postprandial 3-hour incremental area under the curve (17.6% and 31.4% reductions respectively), and significant reductions in mean values for weight (4.7%), waist (6.2%), systolic blood pressure (7.7%) and fasting triglycerides (36.2%). Qualitative interviews (n=23) identified key themes of confidentiality and fear of disclosure of HIV status. Those who declined participation or achieved fewer intervention goals exhibited an external health locus of control, blaming diabetes risk on HIV medicines. Those who achieved more goals prioritised treating prediabetes. Enablers included a desire to avoid adding to pill or disease burden, and a strong support network. Deliberate weight loss leading to loss of cultural identity and disclosure of HIV status were significant barriers. T2D is highly prevalent in HIV. The effectiveness of the pilot intervention demonstrates the potential to prevent or delay T2D in HIV. However, people living with HIV present with unique barriers to change; future interventions must address these to improve effectiveness.

Introduction: The introduction of antiretroviral therapy has successfully transformed the Human Immunodeficiency Virus (HIV) into a long-term condition. However, nearly half of those living with HIV experience cognitive difficulties (HIV-associated Neurocognitive Disorders; HAND). The adverse effects of HIV on cognitive function have been well-documented. However, it has not been established whether individuals with HAND present with deficits in social cognition, specifically related to the ability to understand other people’s intentions and feelings (Theory of Mind; ToM). The present study aimed to address this gap in the research and explore whether individuals with HAND show deficits in cognitive and affective aspects of ToM, and whether these are related to general cognitive abilities. Method: Sixteen individuals with HAND between the ages of 26 and 60 (mean age = 46.81 years) were recruited from a rehabilitation centre for individuals living with HAND. Participants completed a neuropsychological test battery and two social cognition tests (verbal test of cognitive ToM and visual test of affective ToM). Data obtained using standardised measures was analysed quantitatively and descriptively. Results: The individual and group-level analyses indicate that individuals with HAND show impairments in social cognition, with greater deficits observed in the domain of mentalising (cognitive ToM) than affect recognition (affective ToM). Consistent with the correlational analyses, tentative links can be made between social cognition and processing speed, executive function and memory, although the manner in which these domains impact on social cognition requires further research. Implications: A key clinical implication is that social cognition should be routinely tested in individuals with HAND as part of a standard assessment of cognitive function. The findings further indicate that it might be useful to evaluate multiple domains of social cognition and interpret the results in the context of findings from other neuropsychological assessments.

HIV-associated neurocognitive disorder in HIV patients substantially reduces their quality of life. We hypothesised that the HIV matrix protein, p17, already linked to tumour promotion and aberrant angiogenesis could contribute to neurological decline and cellular dysfunction within the brain and aimed here to confirm this. The experimental design was formulated to test the direct neurodegenerative capacity of p17 protein on relevant brain cells, both in vitro and in vivo to ascertain the potential of p17 within the brain to encourage neurodegenerative processes and to confirm that p17 was present in the brain of infected individuals. In vitro cell culture experiments identified cellular signalling induced by p17 within brain cells. I characterised the effects of hippocampal CA1 injection of p17 on histological appearance of brain sections following the analysis of the animals by our collaborators- behaviour, cognitive function and memory. Histological expression of p17 in tissue from three HIV patients who died from stroke was determined. Cell signalling pathways potentially associated with neurodegenerative signalling or aberrant angiogenesis were studied by Western blotting. p17 increased phosphorylation of ERK1/2, IRS-1 and EGFR in endothelial cells, blocking cell signalling and angiogenesis via an inhibitor peptide of EGFR. In neurons, p17 induced the phosphorylation of ERK1/2, Tau, FAK and IRS-1. Cognitive function and behavioural deficiencies after p17 injection were mimicked by demonstration that it localised in ventricular tracts, cortical microvessels and neurons. p17 formed β-amyloid/prion-like protein fibrillar aggregates, suggesting a pathogenic direct capability similar to that of β-amyloid. P17 was also identified in macrophages, microvessels, neurons and amyloid-beta (Aβ)-positive plaques in HIV-infected human brain sections. This work supports the involvement of p17 in initiating/perpetuating neurodegenerative pathophysiology associated with cognitive decline. Key words: P17, HIV-associated neurocognitive decline, angiogenesis, fibrillary, signalling.

No description available.

This thesis aims to address a major knowledge gap in understanding the epidemiology of HIV infection among people who inject drugs (PWID) in the Middle East and North Africa (MENA) by 1) assessing HIV epidemic state, 2) estimating HIV epidemic potential using hepatitis C virus (HCV) prevalence, and 3) estimating HIV incidence and impact of interventions on incidence. Methods included systematic review and data synthesis, mathematical modelling, and ecological analysis of systematic review data. There was evidence of HIV epidemics among PWID in at least one-third of countries, most being emerging concentrated epidemics with HIV prevalence of about 10-15%. The overall high injecting risk environment suggests potential for further spread. Mathematical modelling indicated, across a range of HCV prevalence, overall acceptable precision in predicting endemic HIV prevalence among PWID. Ecological analysis on PWID MENA data also indicated a positive, statistically significant association between HCV and HIV endemic prevalence. Of nine MENA countries with data, five have high and three medium HIV epidemic potential, based on current HCV prevalence. The estimated HIV incidence rate among PWID ranged between 0.7% per person-year (ppy) and 7.8% ppy. Further, substantial number of HIV infections in the general population were estimated to be due to the dynamics of injecting drug use, namely among ex-PWID and sexual partners of current/ex-PWID. It was predicted that scale-up of antiretroviral therapy and harm reduction services could avert up to 90% and 70% of incident infections among PWID and their sexual partners, respectively. In conclusion, this thesis identified recent emerging HIV epidemics with high HIV incidence rates among PWID in multiple MENA countries. A novel method for estimating HIV epidemic potential using current HCV prevalence was demonstrated. In MENA, further HIV epidemic growth among PWID is predicted in most countries. Scale-up of HIV/drug interventions is needed to halt the growing epidemics.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell dysregulation and type 1 interferon (IFN) activity. Variants in the major histocompatibility complex (MHC) region confer the greatest genetic risk for SLE; however, the underlying causes of association remain elusive. One mechanism by which causal variants may drive genetic associations at the MHC is through regulating gene expression in a context-specific manner. This project investigates the effect of (i) SLE-associated MHC haplotypes, and (ii) IFN-α stimulation on gene regulation in ex vivo B cells, in order to further our understanding of how these factors contribute to disease risk. Expression quantitative trait loci (eQTLs) were investigated for variants tagging six SLE-risk or -protective haplotypes: DRB1*03:01 (rs2187668), DRB1*15:01 (rs3135391), DPB1 (rs3117213, rs2071351, rs2071349), and MSH5 (rs409558). eQTL analyses were conducted using publicly-available data sets. Additionally, gene expression data were generated from resting and IFN-α-stimulated ex vivo B cells. Several cis-eQTLs were identified and replicated in the publicly-available data sets. A novel trans-eQTL was identified for DRB1*03:01 haplotypes in the exon array data set, in both resting and IFN-α-stimulated cells, involving down-regulation of BTN3A2 (P < 2.63 × 10-6). These results suggest a regulatory role for disease-associated MHC haplotypes, and implicate BTN3A2 as a novel candidate gene on the DRB1*03:01 haplotype. The global effect of IFN-α stimulation on the B cell transcriptome was also explored. Several SLE susceptibility genes outside canonical type 1 IFN signalling pathways were differentially expressed in response to IFN-α. The direction of effect of IFN-α on the expression of SLE candidate genes paralleled the known functional consequences of SLE-associated polymorphisms in those genes. This suggests a previously unrecognised role for SLE candidate genes following activation of the type 1 IFN pathway, and sheds light into the role of IFN-α in the aetiopathogenesis of SLE.

This thesis sets out to examine how men who have sex with men (MSM) currently understand, evaluate and respond to HIV risk. The aims of the study were to explore key areas of HIV risk understanding, including how HIV risk was understood in a post-antiretroviral society and how masculinities affect this risk understanding. In addition, key aspects of the negotiation of sex used by those who were single and in (open) relationships were considered. An examination of a variety of mass media HIV prevention interventions was carried out to explore what viewing them tells us about risk perception and response. Of key interest to this research was how these understandings of HIV risk were evolving within the context of the shifting definitions of love, with the introduction of formalised relationship structures, and sex, caused by the impact of antiretrovirals in the MSM communities. This study unified the results from quantitative and qualitative data that emerged from an online mixed methods survey to unravel the experiences of a convenience sample of 557 UK-based MSM. This survey incorporated a mixture of both open and closed questions, vignette questions and made the use of visuals to allow nuanced responses to emerge. The findings reveal how these shifting definitions of sex and love are affecting how men understand HIV risk, the consequences for the negotiation of sex, and indicate various improvements that may need to be made to address these issues.

No description available.