Background: Even with newer and repurposed anti-TB drugs almost a third of patients with XDR-TB have unfavourable outcomes. In patients with localised disease and adequate pulmonary reserve, surgery is an important adjunctive treatment. However, there are no outcome data from TB endemic countries, and the prognostic significance of pre-operative PET-CT findings remains unknown. Objectives: To report outcomes for resectional surgery in our setting, and to study whether PET activity outside of the resection influences treatment outcomes. Methods: A retrospective study of all XDR-TB patients undergoing surgery at Groote Schuur Hospital (GSH) between July 2010 and December 2016 was performed. PET-CT was performed in a subgroup. Patients were followed up to determine treatment outcomes at 24-months post- surgery. Treatment success and failure, including all-cause mortality, was determined. Results: In total, 35 patients underwent surgery. The mean age was 36, 49% were male and 26% were HIV-infected. Pneumonectomy was the most common procedure (57%). Three patients (9%) were lost to follow up by 24 months. Total all-cause mortality was 34%. Treatment success was achieved in 15/35 (43%). In patients who underwent pre-operative PET-CT, there were no overall radiological features or PET parameters that were found to be prognostic for treatment failure. Conclusion: Resectional surgery for DR-TB in combination with chemotherapy resulted in cure in less than half of patients. Our data do not support the use of PET-CT to preselect patients or prognosticate about their outcome. These data inform clinical practice and underscore the need to support antibiotic stewardship strategies in TB-endemic settings.

Magister Public Health - MPH / Ototoxic induced hearing loss is a common adverse event related to aminoglycosides used in Multi Drug Resistant -Tuberculosis treatment. Exposure to ototoxic drugs damages the structures of the inner ear. Symptomatic hearing loss presents as tinnitus, decreased hearing, a blocked sensation, difficulty understanding speech, and perception of fluctuating hearing, dizziness and hyperacusis/recruitment. The World Health Organization (1995) indicated that most cases of ototoxic hearing loss globally could be attributed to treatment with aminoglycosides. The aim of the study was to determine the proportion of DR-TB patients initiated on treatment at three decentralized sites during a defined period (1st October to 31st December 2015) who developed ototoxic induced hearing loss and the corresponding risk factors, whilst receiving audiological monitoring with an extended high frequency audiometer (KUDUwave). A retrospective cross-sectional study was conducted. Cumulatively across the three decentralized sites, 69 patient records were reviewed that met the inclusion criteria of the study. The mean age of the patients was 36.1, with a standard deviation (SD) of 10.7 years; more than half (37) were female. Ototoxicity , a threshold shift, placing patients at risk of developing a hearing loss was detected in 56.5% (n=39)of patients and not detected in 30.4%(n=21).The remaining 13,1% (n=9)is missing data. As a result, the regimen was adjusted in 36.2% of patients. . From the 53 patients who were tested for hearing loss post completion of the injectable phase of treatment, 22.6% (n=12) had normal hearing, 17.0 % (n=9) had unilateral hearing loss, and 60.4% (n=32) had bilateral hearing loss. Therefore, a total of 41 patients had a degree of hearing loss: over 30% (n=22)had mild to moderate hearing loss, and only about 15% (n=11)had severe to profound hearing loss. Analysis of risk factors showed that having ototoxicity detected and not adjusting regimen significantly increases the risk of patients developing a hearing loss. The key findings of the study have shown that a significant proportion of DR-TB patients receiving an aminoglycoside based regimen are at risk of developing ototoxic induced hearing loss, despite receiving audiological monitoring with an extended high frequency audiometer that allows for early detection of ototoxicity (threshold shift).

Multidrug-resistant Mycobacterium tuberculosis (MDR-TB) is a leading cause of morbidity and mortality in the Philippines. The purpose of this study was to gain knowledge about the relationship between potential risk factors and MDR-TB. Risk factors (the independent variables) for MDR-TB (the dependent variable) include previous TB treatment, infection with HIV, exposure to patients with drug-susceptible TB/MDR-TB, delays in diagnosis and treatment, employment status, smoking, imprisonment, alcohol abuse, and poor compliance with TB treatment regimens. The study was based on the epidemiological approach to causal inference work. A case-control study design was used wherein a quantitative method was applied in data analysis to assess the strength of the pre-identified possible risk factor(s) association to MDR-TB infection. Data were collected using survey questionnaires that were administered to patients (N = 172) from health centers in Leyte, San Mateo Rizal, and San Lazaro. Hypotheses were tested using chi-square analysis, Fisher's exact test, and an odd ratio. Drug-susceptible TB respondents who smoked on a daily basis were three times more likely (95% CI 1.021-13.341, OR 3.69) to develop an MDR-TB infection than were other respondents. Respondents who did not comply with the anti-TB treatment regimen were nine times more likely (95% CI 2.104-43.059, OR 9.519) to develop an MDR-TB infection than other respondents. Health care providers may be able to use study findings to develop programs to help drug-susceptible TB patients stop smoking and better comply with treatment regimens designed to prevent MDR-TB infection, resulting, potentially, in improved public health outcomes for patients.

Doctor Educationis / Ototoxic induced hearing loss is a common adverse event related to aminoglycosides used in Multi Drug Resistant -Tuberculosis treatment. Exposure to ototoxic drugs damages the structures of the inner ear. Symptomatic hearing loss presents as tinnitus, decreased hearing, a blocked sensation, difficulty understanding speech, and perception of fluctuating hearing, dizziness and hyperacusis/recruitment. The World Health Organization (1995) indicated that most cases of ototoxic hearing loss globally could be attributed to treatment with aminoglycosides. The aim of the study was to determine the proportion of DR-TB patients initiated on treatment at three decentralized sites during a defined period (1st October to 31st December 2015) who developed ototoxic induced hearing loss and the corresponding risk factors, whilst receiving audiological monitoring with an extended high frequency audiometer (KUDUwave). A retrospective cross-sectional study was conducted. Cumulatively across the three decentralized sites, 69 patient records were reviewed that met the inclusion criteria of the study. The mean age of the patients was 36.1, with a standard deviation (SD) of 10.7 years; more than half (37) were female. Ototoxicity , a threshold shift, placing patients at risk of developing a hearing loss was detected in 56.5% (n=39)of patients and not detected in 30.4%(n=21).The remaining 13,1% (n=9)is missing data. As a result, the regimen was adjusted in 36.2% of patients. . From the 53 patients who were tested for hearing loss post completion of the injectable phase of treatment, 22.6% (n=12) had normal hearing, 17.0 % (n=9) had unilateral hearing loss, and 60.4% (n=32) had bilateral hearing loss. Therefore, a total of 41 patients had a degree of hearing loss: over 30% (n=22)had mild to moderate hearing loss, and only about 15% (n=11)had severe to profound hearing loss. Analysis of risk factors showed that having ototoxicity detected and not adjusting regimen significantly increases the risk of patients developing a hearing loss. The key findings of the study have shown that a significant proportion of DR-TB patients receiving an aminoglycoside based regimen are at risk of developing ototoxic induced hearing loss, despite receiving audiological monitoring with an extended high frequency audiometer that allows for early detection of ototoxicity (threshold shift).

South Africa has one of the world’s highest burdens of TB, HIV/TB co-infection, and drug-resistant TB. Second-line TB treatment is less effective, more expensive, and more toxic than treatment for drug-sensitive TB. Nearly 1 in every 5 persons who starts treatment for drug-resistant TB in South Africa will die; 1 in every 3 persons who survives treatments experiences permanent, profound hearing loss. For decades there was little progress in TB research, however, and so treatment with old regimens continued despite safety concerns. In 2012 the US and European regulatory authorities approved a new drug, bedaquiline, but only for treatment in cases with no other options. In 2015, the South African Medicines Control Council approved bedaquiline for drug-resistant TB, but only a limited number of doses were approved in the 2016/2017 annual budget and the focus, again, was only for the patients who had no other options. In order to inform policy makers in planning and budgeting for drug-resistant TB treatment, the aim of this thesis was to determine whether the simple calculation that bedaquiline was too expensive relative to standard regimens using kanamycin was too simple. Particularly, given the high burden of adverse drug reactions (ADR) associated with kanamycin, would the inclusion of the cost and burden of ADR affect the incremental cost effectiveness ratio of a new treatment regimen where bedaquiline replaces kanamycin? Analysis of the national drug-resistant TB case register showed that mortality during second-line treatment was early, primarily in the first 6 months of treatment, even when patients do not have extensive drug resistance. HIV-positive patients not on anti-retroviral therapy (ART) at initiation of drug-resistant TB treatment have the highest risk of mortality. The high early mortality is a real risk that clinicians have to balance when deciding to initiate ART and effective second-line TB treatment both as quickly as possible. Daily injections coupled with taking more than 10 pills each day are a heavy burden for patient compliance, but also pose concerns in terms of overlapping and compounding toxicities; this burden was confirmed through a meta-analysis of the pooled frequency of adverse events among cohorts with at least 25% of the patients HIV-positive. A competing risk analysis of a cohort of drug-resistant TB patients from Johannesburg – addressing the reality that patients may not have experienced an ADR because they died rather than because they were at lower risk – indicated that HIV-infected patients who are not yet stable on ART and second-line TB treatment are at the highest risk of ADR. A Markov model built and parameterized using the data from the South African national TB programme indicates that bedaquiline for all drug-resistant TB led to a small gain in effectiveness at a cost that was under the costs of the drug itself, due to savings from daily injection visits. While cost-effective, it was not clear that South African policy makers needed to move beyond the offer of bedaquiline for patients with extensive drug resistance. However, the calculation, and the decision point, were different once the costs and disability associated with ADRs was included in the analysis. Bedaquiline-based regimens offer a cost-saving and more effective alternative to an injection-based regimen for drug-resistant TB patients treated in the public sector in South Africa.

Multidrug-resistant tuberculosis (MDR-TB) is a public health problem in several countries such as Angola, India, China, Kenya, and Nigeria. Due to the increasing high burden of MDR-TB, most of these countries do not have adequate capacities to manage MDR-TB patients effectively. This study investigated the effect of model of care; human immunodeficiency virus comorbidity; and demographic factors such as age, gender, and marital status on the treatment outcomes of MDR-TB patients in Nigeria. The study was based on the analysis of secondary data of 402 MDR-TB patients accessed from the data systems of the National Tuberculosis, Buruli Ulcer, and Leprosy Control Program. The theoretical framework for this study was the health belief model. The results of the study showed that treatment outcomes were similar for hospital and community-based models of care. Age was the only factor found to be significantly associated with treatment outcomes; age > than 40 years was a predictor of unsuccessful treatment outcomes among MDR-TB patients at a p-value of 0.026. In the multivariate logistics regression analysis, age and model of care were found to be significantly associated with treatment outcomes at p-values of 0.043 and 0.048, respectively. Marital status, gender, and HIV comorbidity were not significantly associated with treatment outcomes. Implications of the findings of this study for social change in a health care program include opportunities to help reduce the number of patients on waiting lists for MDR-TB treatment. These strategies may ultimately help to reduce the spread of MDR-TB infection as well as the mortality associated with late treatment.

Migrant workers in the Deciduous Fruit Industry are part of the marginalised communities in South Africa. They are often voiceless in the communities they find themselves. They are historically displaced, often prone to xenophobia and very vulnerable in terms of HIV. Not only do they have a high infection rate but they also struggle in isolation to carry the burden of HIV and AIDS affection or infection. They will face double jeopardy when a partner becomes ill, in the homeland and they have to continue with employment. The main aim of this research was to reach a holistic understanding through interdisciplinary investigation. The important question that I aim to answer is; “What is the experience of God in the lives of persons affected or infected by HIV and AIDS.” I have looked at Postfoundationalism and the Seven Movements as proposed by Muller to present the research undertaken among migrant workers with HIV and AIDS. The Practical Theology, which I explore, develops out of a very specific praxis, HIV and AIDS. I have also made used of Transversal Rationality as a practical way of doing interdisciplinary work with the stories of my co-researchers affected with HIV AIDS as a case study. I understand that Christian belief has its own integrity, which is exclusive, but if valid, is vital to be able to incorporate the different dimensions of our modern practise to give it the maximum level of meaning and significance. I hope to demonstrate this possibility through my thesis. / Thesis (PhD)--University of Pretoria, 2010. / Practical Theology / unrestricted

Philosophiae Doctor - PhD / Tuberculosis is a bacterial infection which is a major cause of death worldwide. TB is a curable disease, however the bacterium can become resistant to the first line treatment against the disease. This leads to a disease called drug resistant TB that is difficult and expensive to treat. It is well-known that TB disease thrives in communities in overcrowded environments with poor ventilation, weak nutrition, inadequate or inaccessible medical care, etc, such as in some prisons or some refugee camps. In particular, the World Health Organization discovered that a number of prisoners come from socio-economic disadvantaged population where the burden of TB disease may be already high and access to medical care may be limited. In this dissertation we propose compartmental models of systems of differential equations to describe the population dynamics of TB disease under conditions of crowding. Such models can be used to make quantitative projections of TB prevalence and to measure the effect of interventions. Indeed we apply these models to specific regions and for specific purposes. The models are more widely applicable, however in this dissertation we calibrate and apply the models to prison populations.