Outcomes and cost-effectiveness of different models of delivery of antiretroviral therapy

Background: HIV remains a major contributor to the burden of disease in the Eastern and Southern African region, where around half of those with HIV/AIDS reside, according to the 2016 UNAIDS estimates. Data on the direct costs and outcomes of providing health care are important due to competing health needs and limited budgets in resource-limited settings, especially if we are to reach the UNAIDS 90-90-90 goals. This thesis presents a series of studies, which together represent the typical journey followed within an economic evaluation, starting with the establishment of a cohort, then onto cost and outcome analyses and, finally, the development of a Markov model for the purpose of establishing the cost-effectiveness of a particular intervention. Methods: Data for this thesis come from several cohorts within South Africa, with patients commencing ART between 1998 and 2014, and with care provided within a number of different models: private (Aid for AIDS), public-private partnerships or PPP (BroadReach), and public sector (Khayelitsha). The study design for all were retrospective cohort analyses. These cohorts had important strengths in their data: adherence measures (private, PPP); initiating ART at CD4 counts > 200 cells/µL (private); detailed cost data (private); long duration of follow-up with a larger proportion on second-line ART (private); ability to assess health care utilization pre-ART and in patient loss to ART follow-up (private); and availability of national identity numbers, allowing us to confirm mortality from national death register data (private, PPP). Results: The results sections of this thesis are presented in the form of published papers and chapters. In the first analysis (Chapter 4), we present a cohort profile for Aid for AIDS, where we describe the history of the programme and contrast it with the public sector programme in South Africa. In the second analysis (Chapter 5), we present a paper highlighting the profile and determinants of costs on ART over time in the private cohort. We draw attention to the impact of baseline stage and adherence to ART on early and late costs respectively. In the third analysis (Chapter 6), we explore different models of HIV care: GP versus clinic for public sector patients and courier versus collect pharmacy for private sector patients. In the third analysis (Chapter 7), we present a paper which reviews cost-effectiveness studies in LMICs and explores the relative impact of various factors on costs and mortality in preparation for the final analysis (Chapter 8), which required the development of a novel HIV Markov model. Conclusion: Interventions, such as public-private partnerships with GPs or home-refill by courier, which we have found to be associated with lower costs and improved outcomes respectively, should be considered for implementation in South Africa, especially in light of the proposed National Health Insurance. The focus of this thesis on models of ART delivery and the inclusion of under-represented or novel models are significant strengths

The impact of male overweight on semen quality and outcome of assisted reproduction

The impact of obesity on male reproductive health remains a contested topic as evidence is inconclusive and inconsistent. Even more debatable is the effect of male obesity in assisted reproduction. In the manuscript, “the impact of male overweight on semen quality and outcome of assisted reproduction” published in Asian Journal of Andrology, Thomsen et al. investigated the effect of male obesity on fertilization outcomes in intrauterine insemination, in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) programs further contributes to the increasing body of evidence in this field.Web of Scienc

Study into the feasibility and design of a renewable energy portfolio for the Klein Constantia Wine

Includes bibliographical references.The South African wine industry has seen a growing interest in the field of renewable energy in recent years. This has been due, in part, to rising energy costs a long with increased public and consumer awareness around the issues of global warming and sustainability. This project was conceived in the light of these developments, and centres on an investigation into the feasibility and design of a renewable - energy portfolio for the Klein Constantia Wine Estate, located in the Western Cape. A literature survey was undertaken, shedding light on the common uses of energy on wine farms, renewable energy initiatives within the industry and the technologies available. A case study was then conducted using Klein Constanta Wine Estate as the subject. Physical measurements were taken where possible and, along with a combination of topographical, satellite and local climate data , were used to develop estimates f or the energy - generation potential of the farm's renewable resources and the cost implications thereof. Following this, a qualitative and quantitative analysis was conducted to determine the most favourable technologies from a portfolio design perspective. From these findings, three potential portfolio designs were developed, each covering varying degrees of the farm's energy consumption. Based on the se final designs, it was concluded that there was indeed significant potential for investment in renewable energy at Klein Constantia; and that the farm could more than cover its energy requirements. While the financial returns would be minimal, with relatively long payback - periods, the secondary benefits to the farm were considered to be sufficient to justify the investments. The final decision, however, would likely rest on the weight given to the secondary benefits by the farm owners. It was also determined that, in the case of Klein Constantia, the larger the investment the less secure it would be. This was primarily due to the need for higher - risk and more expensive technology options being required when the energy target was raised. With this in mind a renewable energy portfolio, covering only the farm's electricity use, was found to be the most favourable option available to the farm

Molecular diagnosis of cystic fibrosis in South African populations

Cystic fibrosis (CF) is present in all South African population groups. In a significant proportion of patients a diagnosis of CF can be confirmed by DNAanalysis and the detection of two CF transmembrane conductance regulator (CFTR) mutations, using the panels of mutations developed in this study. The index of suspicion will also be raised in patients with a single CFTR mutation. DNAtesting is important, especially in region s without access to reliable sweat tests, and should be considered an aid to diagnosis. In addition to receiving appropriate treatment, patients and their families can receive more accurate genetic counselling, CF carrier testing and prenatal diagnosis

"Designer cytokines" targeting the tumor vasculature - think global and act local

Tumor necrosis factor (TNF) was discovered in 1975 as a lipopolysaccharide-induced serum factor that causes necrosis of tumors (Carswell et al, 1975). It was later found that TNF and cachectin, a factor causing wasting disease, were one and the same molecule (Beutler et al, 1985). Studies on the inflammatory activity of TNF have been translated into clinical success, namely blocking antibodies used to suppress autoimmune diseases. Research on TNF anti-tumor activity, in contrast, has not yet resulted in a therapeutic breakthrough. This may change, based on a study by Huyghe et al (2020) describing novel "designer cytokines" (TNF and interferon-γ) that increase local activity by targeting the CD13-positive tumor vasculature, while simultaneously lowering the binding affinity to the respective cytokine receptor, thereby reducing off-target effects on normal cells

The effect of insulin, leptin and inflammatory cytokines on reproductive health and hypogonadism in males diagnosed with the metabolic syndrome

Philosophiae Doctor - PhDThe metabolic syndrome (MetS) is a collection of various metabolic, hormonal and immunological risk factors that cluster together, closely related to poorly understood phenomena such a hyperinsulinaemia (insulin resistance), hyperleptinaemia (leptin resistance), a low grade, systemic and chronic inflammation and, in males, hypogonadism. Infertility is increasing globally, and male factor infertility accounts for a large percentage of couples who are not able to conceive. The relationship between components of MetS and male reproductive health is not clear, and requires further investigation, as does the impact of MetS on male reproductive health in a case controlled study. The impact of hyperinsulinaemia, hyperleptinaemia and inflammatory cytokines on the male reproductive tract also requires investigation. Furthermore, it is hypothesised that these phenomena negatively impact steroidogenesis cascades. In order to investigate this, a case controlled study and TM3 Leydig cell culture experiments were designed.Participants were recruited from public advertisements, and screened for strict exclusion criteria, including acute or chronic inflammation, hormonal treatments, vasectomy and leukocytospermia (> 106/ml). Following clinical diagnostics, 78 males were either placed into a control group (CG) or the MetS group, with numerous parameters compared between them. Serum was assayed for routine risk markers including HDL cholesterol, triglycerides, glucose and C-reactive protein (CRP). Saliva was assayed for free testosterone and progesterone. Semen samples underwent semen analysis for ejaculation volume, sperm concentration and motility, vitality, morphology and leukocyte concentration, in addition to mitochondrial membrane potential (MMP) and DNA fragmentation (DF). Both serum and seminal fluid were further assayed for insulin, leptin, tumour necrosis factor-alpha (TNF ) and interleukins 1-beta (IL1 ), 6 (IL6) and 8 (IL8). Glucose was also assayed in seminal fluid. Separately, hCG stimulated TM3 Leydig cells were exposed to varying concentrations of insulin (0.01, 0.1, 1 & 10 pg/ml), TNF , IL1 , IL6 and IL8 (0.1, 1, 10 & 100 pg/ml) for 48 hours at optimal cell culture conditions. TM3 cell viability, protein concentration and testosterone and progesterone concentrations were assessed.XXII Results indicated that males in the MetS group (n=34) had significantly increased body mass index, waist circumference, blood pressure, triglycerides, glucose, and Creactive protein (CRP) with decreased HDL cholesterol, as compared to the CG. Furthermore, ejaculation volume, sperm concentration, total sperm count, progressive and total motility were significantly decreased in the MetS group, and sperm with abnormal MMP and DF were increased in this group. No difference was found for morphology. Serum and seminal insulin, leptin, TNF , IL1 , IL6 and IL8 were all significantly increased in the MetS group. Both testosterone and progesterone were also significantly decreased in the MetS group. Insulin increased testosterone and decreased progesterone in the TM3 cells. TNF , IL1 and IL6 all decreased testosterone and progesterone concentrations and TM3 cell viability. IL8 increased TM3 cell viability and decreased progesterone, will no effect on testosterone. These results suggest MetS is associated with decreased fertility potential in males. Furthermore, a significant increase in seminal insulin, leptin, TNF , IL1 , IL6 and IL8 suggests local reproductive tract inflammation in the absence of leukocytospermia. Strong correlations between serum and seminal insulin, leptin, TNF , IL1 , IL6 and IL8, as well as serum CRP, imply that these systemic phenomenons are related to the reproductive tract changes observed. Therefore, the underlying pathophysiology of MetS negatively affects male reproduction, in addition to general health and wellbeing. A decrease in progesterone and testosterone suggests a collapse in steroidogenesis cascades. Additionally, inflammation, increased leptin and insulin resistance likely contribute to this collapse in steroidogenesis based on TM3 cell culture experiments. These results provide novel avenues for further investigations

The Mechanisms and Management of Age-Related Oxidative Stress in Male Hypogonadism Associated with Non-communicable Chronic Disease

Androgens have diverse functions in muscle physiology, lean body mass, the regulation of adipose tissue, bone density, neurocognitive regulation, and spermatogenesis, the male repro- ductive and sexual function. Male hypogonadism, characterized by reduced testosterone, is com- monly seen in ageing males, and has a complex relationship as a risk factor and a comorbidity in age-related noncommunicable chronic diseases (NCDs), such as obesity, metabolic syndrome, type 2 diabetes, and malignancy. Oxidative stress, as a significant contributor to the ageing process, is a common feature between ageing and NCDs, and the related comorbidities, including hypertension, dyslipidemia, hyperglycemia, hyperinsulinemia, and chronic inflammation. Oxidative stress may also be a mediator of hypogonadism in males. Consequently, the management of oxidative stress may represent a novel therapeutic approach in this context. Therefore, this narrative review aims to discuss the mechanisms of age-related oxidative stress in male hypogonadism associated with NCDs and discusses current and potential approaches for the clinical management of these patients, which may include conventional hormone replacement therapy, nutrition and lifestyle changes, ad-herence to the optimal body mass index, and dietary antioxidant supplementation and/or phyto-medicines.O

Obesity is associated with increased seminal insulin and leptin alongside reduced fertility parameters in a controlled male cohort

Obesity appears to be associated with male reproductive dysfunction and infertility, although this has been inconsistent and inconclusive. Insulin and leptin are known mediators and modulators of the hypothalamus-pituitary-testes axis, contributing to the regulation of male reproductive potential and overall wellbeing. These hormones are also present in semen influencing sperm functions. Although abdominal obesity is closely associated with insulin resistance (hyperinsulinaemia), hyperleptinaemia and glucose dysfunction, changes in seminal plasma concentrations of insulin, leptin and glucose in obese males has not previously been investigated.Web of Scienc

Targeting human melanoma neoantigens by T cell receptor gene therapy

In successful cancer immunotherapy, T cell responses appear to be directed toward neoantigens created by somatic mutations; however, direct evidence that neoantigen-specific T cells cause regression of established cancer is lacking. Here, we generated T cells expressing a mutation-specific transgenic T cell receptor (TCR) to target different immunogenic mutations in cyclin-dependent kinase 4 (CDK4) that naturally occur in human melanoma. Two mutant CDK4 isoforms (R24C, R24L) similarly stimulated T cell responses in vitro and were analyzed as therapeutic targets for TCR gene therapy. In a syngeneic HLA-A2-transgenic mouse model of large established tumors, we found that both mutations differed dramatically as targets for TCR-modified T cells in vivo. While T cells expanded efficiently and produced IFN-γ in response to R24L, R24C failed to induce an effective antitumor response. Such differences in neoantigen quality might explain why cancer immunotherapy induces tumor regression in some individuals, while others do not respond, despite similar mutational load. We confirmed the validity of the in vivo model by showing that the melan-A-specific (MART-1-specific) TCR DMF5 induces rejection of tumors expressing analog, but not native, MART-1 epitopes. The described model allows identification of those neoantigens in human cancer that serve as suitable T cell targets and may help to predict clinical efficacy

Dosage adjustment in medical patients with renal impairment at Groote Schuur Hospital

BACKGROUND: Many drugs are eliminated by the kidneys and therefore may require dose adjustment in patients with renal impairment. The need for dose adjustment is frequently neglected by prescribers. METHODS: We reviewed folders of patients admitted to the Groote Schuur Hospital general medical wards between January and March 2008. Patients with renal impairment, defined as an estimated glomerular filtration rate (eGFR) or = 1 day after renal function tests were performed. We determined what proportion of these prescriptions required dose adjustment and whether drug doses were appropriately adjusted. RESULTS: We found renal impairment in 32% (97/301) of medical admissions. There were 615 prescription entries for the 97 patients with renal impairment. Dose adjustment was required in 19% (117/615) of prescription entries, and only 32% (37/117) of these prescription entries were correctly dose adjusted. Of 97 patients, 69 received one or more drugs that required dose adjustment (median 1, range 1 - 5). All drug doses were correctly adjusted in 12% (8/69) of patients. Importantly, in the majority of patients (59% (41/69)) no doses had been correctly adjusted. CONCLUSION: Consistent with international studies, drug dose adjustment in patients with renal impairment in a South African hospital was frequently neglected. Strategies to alert clinicians of the need for dose adjustment in renal impairment should be considered, including automated eGFR reporting and computerised aids to guide drug dosing, that account for renal impairment