Master of Public Health - MPH / Adequate levels of adherence to treatment for tuberculosis (TB) and HIV at the same time poses a problem for public health in South Africa. TB/HIV co-infected patients face many potential barriers to adherence to treatment for both conditions. There is a need for more knowledge about factors influencing treatment adherence in co-infected patients on concomitant treatment. The aim of this study was to explore the barriers and facilitators to treatment adherence among people co-infected with TB/HIV living in the Alfred Nzo District, Eastern Cape, in order to identify the barriers and facilitators to adherence.

Philosophiae Doctor - PhD / This thesis was informed by what I perceived to be a tense relationship between Western biomedical science and, for example, “traditional” or “indigenous” ways of producing knowledge about medicinal plants used to manage a pervasive condition like Tuberculosis (TB) in South Africa. Hoping to reimagine this relationship and its possibilities, I follow medicinal plants collected from Genadendal through three research spaces with disparate but intertwined knowledge heritages to investigate these tensions but also to tease out how knowledge about locally used medicinal plants is generated and “done” in practice. The first space was at the South African Herbal Science and Medicines Institute (SAHMI) as part of an experiential science project led by scientists who were interested in studying medicinal plants which could potentially provide new sources of safe, affordable, and sustainable medicine for communicable conditions such as TB.

Background: Knowledge of the incidence of tuberculosis (TB) and hospitalization postpartum could reduce maternal morbidity and mortality. TB infections are prevalent in pregnant women living with Human immunodeficiency virus (HIV) compared to women not living with HIV in South Africa. Adherence to Antiretroviral Therapy (ART) is poor among pregnant and postpartum women living with HIV (WLHIV), thus making WLHIV at a higher risk of hospitalization postpartum, due to the increased risk of Cesarean delivery (CD) and obstetric conditions as a result of HIV. The prevalence of TB among pregnant and postpartum women is poorly defined including in high prevalence TB and HIV locations, indicating limited evidence. The aim is to explore the incidence of TB and hospitalization within four years postpartum among WLHIV, including associated risk factors. Methodology: The study population is from phase 2 of the Maternal and Child HealthAntiretroviral Therapy (MCH-ART) study. It is a single-arm observational cohort study of 628 WLHIV who attended antenatal care (ANC). Enrolment into phase 1 began in March 2013, the final deliveries from phase 2 were in December 2014, and the final follow-up visits were completed in 2016. MCH-ART is an ongoing study with global approval examining strategies for providing HIV care and treatment to HIV-infected women who initiate ART during pregnancy and their HIV-exposed infants. This study took place at the Midwife-Obstetric Unit (MOU) at Gugulethu Community Health Centre, Western Cape South Africa. It consists of three connected study designs and three phases through the antenatal and postnatal periods. Phase 1 is a cross-sectional study, phase 2 is a cohort study and phase 3 is a randomized trial. Kaplan-Meier survival analysis was used to assess the incidence of TB and hospitalization over time among ix WLHIV up to four years postpartum and Cox regression was used to measure the effect of risk factors on the incidence of TB and hospitalization. Results: Thirty-five (35) WLHIV developed TB postpartum at a total person-time of 2365.1 woman-years. The incidence rate (IR) of developing TB among WLHIV postpartum was 1.48 (95% CI=1.03-2.06) cases per 100 woman-years from 2013 to 2018. Twenty-three (23) WLHIV was hospitalized postpartum and a total person-time of 552.8 woman-years was spent. The IR of hospitalization among WLHIV postpartum was 4.16 (95% CI=2.64-6.24) cases per 100 womanyears from 2013 to 2018. The IR of TB and hospitalization among WLHIV postpartum is statistically significant. Adjusting, for other risk factors, the history of diabetes at ANC, the history of TB at ANC and CD4 count (200 - <500) cells/mm3 at ANC also significantly increases the incidence of TB postpartum, whereas, obstetric reasons is associated with the hospitalization of WLHIV.

Magister Scientiae - MSc (Chemistry) / Tuberculosis (TB) is one of the major infectious diseases that affect the health of people all over the world. South Africa is one of the countries that account for most of the TB cases; it is the leading cause of death in South Africa and is known to be lethal when combined with HIV in patients. Various tests have been used to diagnose tuberculosis infected patients, but some of these tests give false positive results. Studies have shown that tuberculosis-related cytokines can serve as biological markers for the diagnosis of TB. Cytokines are signalling proteins secreted by immune cells and one such cytokine is interferon-gamma (IFN-?). Interferon-gamma is secreted by immune cells in response to various pathogens and has many physiological roles in the immune system and inflammatory stimuli. IFN-? was first detected using antibody-based immunosensing techniques but this approach is expensive, time consuming and has low stability, it is therefore vital that an alternative detection method for IFN-? be developed.

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Yes / Objectives: Resistance-associated variants (RAVs) in Rv0678, a regulator of the MmpS5-MmpL5 efflux pump, have been shown to lead to increased MICs of bedaquiline (2- to 8- fold) and clofazimine (2- to 4-fold). The prevalence of these Rv0678 RAVs in clinical isolates and their impact on treatment outcomes are important factors to take into account in bedaquiline treatment guidelines. Methods: Baseline isolates from two bedaquiline MDR-TB clinical trials were sequenced for Rv0678 RAVs and corresponding bedaquiline MICs were determined on 7H11 agar. Rv0678 RAVs were also investigated in non-MDRTB sequences of a population-based cohort. Results: Rv0678 RAVs were identified in 23/347 (6.3%) of MDR-TB baseline isolates. Surprisingly, bedaquiline MICs for these isolates were high (>0.24 mg/L, n¼8), normal (0.03 0.24 mg/L, n¼11) or low(<0.03 mg/L, n¼4). A variant at position 11 in the intergenic region mmpS5–Rv0678 was identified in 39 isolates (11.3%) and appeared to increase the susceptibility to bedaquiline. In non-MDR-TB isolates, the frequency of Rv0678 RAVs was lower (6/ 852 or 0.7%). Competition experiments suggested that rifampicin was not the drug selecting for Rv0678 RAVs. Conclusions: RAVs in Rv0678 occur more frequently in MDR-TB patients than previously anticipated, are not associated with prior use of bedaquiline or clofazimine, and in the majority of cases do not lead to bedaquiline MICs above the provisional breakpoint (0.24mg/L). Their origin remains unknown. Given the variety of RAVs in Rv0678 and their variable effects on the MIC, only phenotypic drug-susceptibility methods can currently be used to assess bedaquiline susceptibility. / This work was supported by Janssen Pharmaceutica. N. C. was supported by a Baekeland PhD scholarship from the Flemish Institute for Scientific Technology (IWT 130308, Belgium). C. J. M., L. R. and B. d. J. were supported by a European Research Council Starting Grant INTERRUPTB (311725).

Yes / Background In the context of advanced immunosuppression, M. tuberculosis is known to cause detectable mycobacteremia. However, little is known about the intra-patient mycobacterial microevolution and the direction of seeding between the sputum and blood compartments. Methods From a diagnostic study of HIV-infected TB patients, 51 pairs of concurrent blood and sputum M. tuberculosis isolates from the same patient were available. In a previous analysis, we identified a subset with genotypic concordance, based on spoligotyping and 24 locus MIRU-VNTR. These paired isolates with identical genotypes were analyzed by whole genome sequencing and phylogenetic analysis. Results Of the 25 concordant pairs (49 % of the 51 paired isolates), 15 (60 %) remained viable for extraction of high quality DNA for whole genome sequencing. Two patient pairs were excluded due to poor quality sequence reads. The median CD4 cell count was 32 (IQR; 16–101)/mm3 and ten (77 %) patients were on ART. No drug resistance mutations were identified in any of the sequences analyzed. Three (23.1 %) of 13 patients had SNPs separating paired isolates from blood and sputum compartments, indicating evidence of microevolution. Using a phylogenetic approach to identify the ancestral compartment, in two (15 %) patients the blood isolate was ancestral to the sputum isolate, in one (8 %) it was the opposite, and ten (77 %) of the pairs were identical. Conclusions Among HIV-infected patients with poor cellular immunity, infection with multiple strains of M. tuberculosis was found in half of the patients. In those patients with identical strains, whole genome sequencing indicated that M. tuberculosis intra-patient microevolution does occur in a few patients, yet did not reveal a consistent direction of spread between sputum and blood. This suggests that these compartments are highly connected and potentially seed each other repeatedly.

Thesis (MSc)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: The annual risk of infection (ARI), a measure of recent transmission, has been described as the most important parameter in tuberculosis (TB) epidemics. Nevertheless, mounting evidence suggests all factors contributing to TB transmission are not yet completely understood. This research was performed to investigate the role various parameters, e.g. overcrowding, period of infectivity, ventilation, and infectivity of source cases, play in TB transmission. An established airborne transmission risk model, the Wells-Riley equation (WRE), was modified to account for scenarios where unknown numbers of infectious individuals may be present. Subsequently, the ARI for three indoor locations conducive to TB transmission were calculated. Two locations (households and minibus taxis) were identified in a social mixing survey conducted within a South African community where TB is endemic as a part of this research. The third location (prison) was identified in an earlier independent study in the same community. The impact various interventions could have in reducing the ARI associated with each location was explored. Poor ventilation, severe overcrowding, extended exposure periods, and high incidence rates contributed to high TB transmission risks in each location. The household-associated ARI was related to the number of resident adults. Current TB control programs will only reduce the ARI if household ventilation levels are improved simultaneously. Similar reductions in the ARI could be achieved by trebling current ventilation levels or by separating child and adult sleeping areas. Neighbouring households can also contribute substantially to the ARI. The minibus taxi-associated ARI for drivers and commuters was considerable but readily reduced by opening windows or keeping the fresh-air fan on. Reducing TB case prevalence through active or passive case-finding would reduce the ARI substantially. The prison-associated ARI was proportional to levels of overcrowding. No single intervention, such as improved ventilation, decreased lock-up time, or improved case-finding, would decrease the ARI substantially, but concurrent implementation of all of them to meet national or international standards would. This research shows TB is not only transmitted in epidemics by highly infectious TB cases, but that any TB case, no matter how infectious, has the potential to infect susceptible people under the right conditions. / AFRIKAANSE OPSOMMING:Die jaarlikse infeksierisiko (ARI) – maatstaf van onlangse siekteoordrag – word as die belangrikste parameter in tuberkulose- (TB-)epidemies bestempel. Nietemin dui toenemende bewyse daarop dat nie álle faktore wat tot TB-oordrag bydra, volledig verstaan word nie. Hierdie navorsing is onderneem om ondersoek in te stel na die rol van verskillende parameters – byvoorbeeld oorbevolking, tydperk van aansteeklikheid, ventilasie en die aansteeklikheid van brongevalle – in TB-verspreiding. Gevestigde model vir die raming van siekteverspreiding deur die lug, die Wells-Riley-vergelyking (WRE), is aangepas vir scenario’s waar onbekende aantal aansteeklike individue moontlik aanwesig is. Daarna is die ARI bereken vir drie ingeslote ruimtes wat TB-oordrag bevorder. Twee van die ruimtes (huishoudings en minibustaxi’s) is ten tyde van die navorsing uitgewys in sosialevermengingsopname in Suid-Afrikaanse gemeenskap waar TB endemies is. Die derde ruimte (gevangenisse) is uitgewys in vroeëre onafhanklike studie in dieselfde gemeenskap. Die navorser het gevolglik bepaal watter moontlike impak verskillende intervensies op die verlaging van die ARI in elke ruimte het. Swak ventilasie, ernstige oorbevolking, verlengde blootstellingstydperke en hoë voorkomsyfers het in elke ruimte tot hoë TB-oordragrisiko bygedra. Die huishoudingsverwante ARI het verband gehou met die aantal volwassenes wat in die huis woon. Huidige TB-beheerprogramme sal slegs die ARI kan verlaag indien huishoudelike ventilasievlakke terselfdertyd verbeter word. Drie keer beter ventilasievlakke of die skeiding van kinders en volwassenes se slaapareas kan soortgelyke verlagings in die ARI teweegbring. Buurhuishoudings kan ook aansienlik tot die ARI bydra. Die minibustaxi-verwante ARI vir bestuurders en pendelaars was beduidend, maar kan betreklik maklik verlaag word deur vensters oop te maak of die varslugwaaier aan te hou. Die vermindering van die voorkoms van TBgevalle deur aktiewe óf passiewe gevalle-opsporing kan die ARI ook beduidend verlaag. Die gevangenisverwante ARI het met vlakke van oorbevolking verband gehou. Geen enkele intervensie soos beter ventilasie, korter toesluittye of beter gevalle-opsporing sal die ARI aansienlik verlaag nie, maar die gelyktydige inwerkingstelling van ál hierdie intervensies in pas met nasionale of internasionale standaarde kan wél. Hierdie navorsing toon dat TB in epidemies nie net deur hoogs aansteeklike TB-gevalle oorgedra word nie, maar dat enige TB-geval, ongeag hoe aansteeklik, die siekte in die regte omstandighede na vatbare mense kan oordra.

La thèse s’inscrit dans le contexte de sûreté nucléaire relatif à l'hydruration des gainages combustibles en Zircaloy, en modélisant, à l’échelle atomique, les phénomènes d’ordre chimique hydrogène - lacune atomique, sur le sous-réseau interstitiel tétraédrique des hydrures de zirconium CFC. Une telle démarche s’est déclinée en deux étapes : en premier lieu, le développement d’un modèle énergétique atomistique à la fois précis et peu coûteux numériquement, puis l’implémentation d’approches thermostatistiques de type Monte-Carlo à l’aide de ce modèle. En prenant pour point de départ un Hamiltonien de Liaisons Fortes (TB), la construction du modèle énergétique a reposé sur la dérivation d’interactions multiatomiques entre atomes d’hydrogène, à l’aide de la méthode des perturbations généralisée (GPM) basée sur une représentation de l’état de désordre interstitiel dans l’Approximation du Potentiel Cohérent (CPA). La démarche a permis de réduire l'énergie d'ordre à un modèle d'Ising effectif dérivé des liaisons fortes (TBIM), basé sur les interactions de paires effectives entre atomes d’hydrogène. Le TBIM a ensuite été validé, en comparant les énergies de structures ordonnées d’une part reconstruites en TBIM, et d’autre part obtenues par des calculs directs d’énergie totale effectués soit en Liaisons Fortes, soit par des méthodes ab initio (DFT). L'implémentation d'une approche Monte-Carlo canonique par le TBIM a permis de caractériser les différentes transitions ordre-désordre, et d'établir un diagramme de phase de l’ordre chimique hydrogène - lacune atomique, sur le sous-réseau interstitiel tétraédrique des hydrures de zirconium CFC. / The thesis addresses the nuclear safety issue of Zircaloy fuel cladding hydruration, by modelling, at atomistic scale, chemical ordering processes between hydrogen and atomic vacancies on tetrahedral interstitial sublattice of CFC zirconium hydrides. This has been achieved into two steps : first the development of an atomistic energetic model sufficiently precise and not too much CPU time consuming, and secondly its implementation in Monte-Carlo thermostatistical simulations. Starting from a Tight-Binding (TB) Hamiltonian, the energetic model has been derived from the calculation of multiatomic interactions between hydrogen atoms, using the Generalized Perturbation Method (GPM) applied to an interstitial disorder described within the Coherent Potential Approximation (CPA). The path allows us to reduce the ordering energy to a Tight-Binding Ising Model (TBIM), based on effective pairwise interactions between hydrogen atoms. The TBIM has been validated by comparing ordering energies of ordered structures either reconstructed using TBIM, or directly obtained from total energy calculations perfor- med both within TB and ab initio (DFT) methods.By implementing a canonical Monte-Carlo with TBIM, we obtain different order-disorder phase transitions, and a phase diagram of H-vacancy chemical ordering, on the tetrahedral interstitial sublattice of CFC zirconium hydrides.