Master of Public Health - MPH / Background: As South Africa’s HIV programme increases in size, increasingly complex HIV/TB cases occur that are often beyond the clinical scope of primary health care clinicians. In the Eastern Cape (EC) province, health facilities are geographically widespread, with a discrepancy of specialist availability outside of academic/tertiary institutions. The use of WhatsApp, a Mobile Instant Messaging (MIM) application, could facilitate learning and mentoring of primary healthcare clinicians in peripheral facilities. The aim of this study is to describe this app and its use as an alternative learning tool to improve clinician access to specialized management of complicated HIV/TB cases, as part of Continuing Medical Education (CME). Method: A an observational, descriptive cross-sectional study was conducted among a group of clinicians from the EC province that formed part of a Wits RHI WhatsApp HIV/TB clinical discussion group from January 2016 to July 2017. Data was collected using a structured anonymous internet questionnaire, distributed to the clinicians that formed part of the WhatsApp group, informed consent being obtained from participants prior to completion. Data was analysed with Epi Info, using descriptive and analytic statistics. Frequency distributions and cross tabulations were generated and bi-variate analysis was done to determine significant associations between relevant variables.

Master of Public Health - MPH / Background: As South Africa’s HIV programme increases in size, increasingly complex HIV/TB cases occur that are often beyond the clinical scope of primary health care clinicians. In the Eastern Cape (EC) province, health facilities are geographically widespread, with a discrepancy of specialist availability outside of academic/tertiary institutions. The use of WhatsApp, a Mobile Instant Messaging (MIM) application, could facilitate learning and mentoring of primary healthcare clinicians in peripheral facilities. The aim of this study is to describe this app and its use as an alternative learning tool to improve clinician access to specialized management of complicated HIV/TB cases, as part of Continuing Medical Education (CME). Method: A an observational, descriptive cross-sectional study was conducted among a group of clinicians from the EC province that formed part of a Wits RHI WhatsApp HIV/TB clinical discussion group from January 2016 to July 2017. Data was collected using a structured anonymous internet questionnaire, distributed to the clinicians that formed part of the WhatsApp group, informed consent being obtained from participants prior to completion. Data was analysed with Epi Info, using descriptive and analytic statistics. Frequency distributions and cross tabulations were generated and bi-variate analysis was done to determine significant associations between relevant variables.

A pesquisa teve como objetivo analisar o Programa de Controle da Tuberculose (PCT) no município de Ribeirão Preto -São Paulo, no período de 1998 a 2006. Utilizou-se para este propósito indicadores epidemiológicos e de desempenho construídos a partir de dados das fichas de notificação de tuberculose (TB) armazenadas no sistema de informação o EPI-Tb, da Secretaria municipal de saúde deste município e os dados populacionais de estimativas do DATASUS, do período de estudo. Selecionaram-se para o estudo casos novos de TB notificados e residentes no município, por ano de diagnóstico, excluindo-se casos atendidos em outros municípios e presidiários. No período compreendido entre 1998 a 2006 foram notificados no EPI-Tb da SMS/Ribeirão Preto 1623 casos novos de tuberculose, sendo que houve queda no número absoluto de casos e no coeficiente de incidência de 47,8% (50,01- 26,08) dos casos no período ou 5,3% ao ano. O risco de ser um caso novo de TB foi 2,4 vezes maior para homens que para as mulheres. Apesar do número de casos notificados serem maiores na faixa etária de 15 a 49 anos, o risco de adoecer por TB foi maior na faixa etária acima de 50 anos, a partir de 2001. O percentual de co-infecção HIV/TB ficou em 27,1% (prevalência mínima), mas a prevalência máxima foi de 32,7%. A forma clínica mais freqüente para os casos novos foi a pulmonar com 85%, enquanto para os casos co-infectados esta forma esteve presente em 58,3% deles e a extra pulmonar em 27,8%. O local de descoberta dos casos de TB foi 51% em ambulatórios (públicos e privados), 39% em hospitais (universitários, público e privados) e 10% outras formas. Uma das fragilidades observadas foi a baixa detecção de casos de TB no município que nos últimos anos ficou próxima de 45% e que as unidades básicas de saúde e PCTs realizam apenas um quinto das baciloscopias de escarro para diagnóstico que deveriam realizar (segundo estimativas do MS). No entanto uma das fortalezas foi a implantação do tratamento supervisionado no município, que iniciou efetivamente em 1998, e foi aumentando gradativamente, chegando em 2006 a supervisionar 76% dos casos. Houve melhora nas taxas de cura, ficando próximo à 72% e 50,5%, para os casos novos sem co-infecção e com co-infecção HIV/TB, respectivamente. A taxa de mortalidade por TB no município apresentou ligeira tendência de queda no período. Apesar da baixa letalidade no período, 50,8% dos óbitos por TB só foram diagnosticados e notificados após o óbito; indicando dificuldade de acesso ao diagnóstico e tratamento da TB nestes casos. Conclui-se que para melhorar a detecção de casos de TB no município serão necessárias mudanças na forma de acolher os indivíduos suspeitos de TB na atenção básica de saúde, facilitando seu acesso a essas unidades, além de investigar mais sintomáticos respiratórios na comunidade. Algumas ações de controle da doença poderiam ser descentralizas, como o tratamento supervisionado e controle de comunicantes. Para os pacientes co-infectados HIV/TB apenas o tratamento supervisionado não está sendo suficiente para alcançarem sucesso no tratamento. / The objective of the present investigation was to analyze the Program of Tuberculosis Control (PTC) in the municipality of Ribeirão Preto- São Paulo, during the period from 1998 to 2006. Epidemiological and performance indicators were used for this purpose, constructed from data of the charts of tuberculosis (TB) notification stored in the information system of EPI-Tb, of the municipal health Secretariat of this municipality and from estimate population data of DATASUS regarding the study period. New TB cases notified regarding patients residing in the municipality were selected according to year of diagnosis, with cases attended in other municipalities and prisoners being excluded. A total of 1623 new cases of TB were notified to EPI-Tb of the SMS/Ribeirão Preto during the period from 1998 to 2006, with a fall in the absolute number of cases and a 47.8% (50,01-26,08) reduction of the coefficient of incidence being observed during this period, corresponding to 5.3% per year. The risk of being a new TB case was 2.4 times higher for men than for women. Although the number of notified cases was higher for the 15 to 49 year age range, starting in 2001 the risk of becoming ill with TB was higher in the age range above 50 years. The percentage of HIV/TB co-infection was 27.1% (minimum prevalence), but the maximum prevalence was 32,7%. The most frequent clinical form for the new cases was the pulmonary one (85%), while this form was present in 58.3% of co-infected cases and the extrapulmonary form in 27.8%. The site of detection of TB cases was public and private outpatient clinics in 51% of cases, university, public and private hospitals in 38%, and other sites in 10%. One of the fragilities observed was the low detection of TB cases in the municipality, which remained close to 45% over the last few years and the fact that the basic health units and PTCs perform only one fifth of the sputum bacilloscopies they should perform for diagnosis (according to Health Ministry estimates). However, one of the strong points was the implantation of supervised treatment in the municipality, which was effectively started in 1998 and increased gradually, with 76% of cases being supervised in 2006. There was an improvement in cure rates, that reached 72% and 50.5% for non-co-infected new cases and HIV/TB co-infected cases, respectively. The TB mortality rate in the municipality showed a slight tendency to a fall during the period. Despite the low lethality observed, 50.8% of the TB deaths were only diagnosed and notified after death, indicating a difficulty in access to diagnosis and treatment of TB in these cases. We conclude that, in order to improve the detection of TB cases in the municipality, changes are needed in the reception of individuals suspected to have TB at basic health units, facilitating their access to these units, in addition to the investigation of more persons with respiratory symptoms in the community. Some actions for the control of the disease such as supervised treatment and the control of communicants could be decentralized. Supervised treatment alone is not sufficient for HIV/TB-co-infected patients to achieve successful treatment.

A pesquisa teve como objetivo analisar o Programa de Controle da Tuberculose (PCT) no município de Ribeirão Preto -São Paulo, no período de 1998 a 2006. Utilizou-se para este propósito indicadores epidemiológicos e de desempenho construídos a partir de dados das fichas de notificação de tuberculose (TB) armazenadas no sistema de informação o EPI-Tb, da Secretaria municipal de saúde deste município e os dados populacionais de estimativas do DATASUS, do período de estudo. Selecionaram-se para o estudo casos novos de TB notificados e residentes no município, por ano de diagnóstico, excluindo-se casos atendidos em outros municípios e presidiários. No período compreendido entre 1998 a 2006 foram notificados no EPI-Tb da SMS/Ribeirão Preto 1623 casos novos de tuberculose, sendo que houve queda no número absoluto de casos e no coeficiente de incidência de 47,8% (50,01- 26,08) dos casos no período ou 5,3% ao ano. O risco de ser um caso novo de TB foi 2,4 vezes maior para homens que para as mulheres. Apesar do número de casos notificados serem maiores na faixa etária de 15 a 49 anos, o risco de adoecer por TB foi maior na faixa etária acima de 50 anos, a partir de 2001. O percentual de co-infecção HIV/TB ficou em 27,1% (prevalência mínima), mas a prevalência máxima foi de 32,7%. A forma clínica mais freqüente para os casos novos foi a pulmonar com 85%, enquanto para os casos co-infectados esta forma esteve presente em 58,3% deles e a extra pulmonar em 27,8%. O local de descoberta dos casos de TB foi 51% em ambulatórios (públicos e privados), 39% em hospitais (universitários, público e privados) e 10% outras formas. Uma das fragilidades observadas foi a baixa detecção de casos de TB no município que nos últimos anos ficou próxima de 45% e que as unidades básicas de saúde e PCTs realizam apenas um quinto das baciloscopias de escarro para diagnóstico que deveriam realizar (segundo estimativas do MS). No entanto uma das fortalezas foi a implantação do tratamento supervisionado no município, que iniciou efetivamente em 1998, e foi aumentando gradativamente, chegando em 2006 a supervisionar 76% dos casos. Houve melhora nas taxas de cura, ficando próximo à 72% e 50,5%, para os casos novos sem co-infecção e com co-infecção HIV/TB, respectivamente. A taxa de mortalidade por TB no município apresentou ligeira tendência de queda no período. Apesar da baixa letalidade no período, 50,8% dos óbitos por TB só foram diagnosticados e notificados após o óbito; indicando dificuldade de acesso ao diagnóstico e tratamento da TB nestes casos. Conclui-se que para melhorar a detecção de casos de TB no município serão necessárias mudanças na forma de acolher os indivíduos suspeitos de TB na atenção básica de saúde, facilitando seu acesso a essas unidades, além de investigar mais sintomáticos respiratórios na comunidade. Algumas ações de controle da doença poderiam ser descentralizas, como o tratamento supervisionado e controle de comunicantes. Para os pacientes co-infectados HIV/TB apenas o tratamento supervisionado não está sendo suficiente para alcançarem sucesso no tratamento. / The objective of the present investigation was to analyze the Program of Tuberculosis Control (PTC) in the municipality of Ribeirão Preto- São Paulo, during the period from 1998 to 2006. Epidemiological and performance indicators were used for this purpose, constructed from data of the charts of tuberculosis (TB) notification stored in the information system of EPI-Tb, of the municipal health Secretariat of this municipality and from estimate population data of DATASUS regarding the study period. New TB cases notified regarding patients residing in the municipality were selected according to year of diagnosis, with cases attended in other municipalities and prisoners being excluded. A total of 1623 new cases of TB were notified to EPI-Tb of the SMS/Ribeirão Preto during the period from 1998 to 2006, with a fall in the absolute number of cases and a 47.8% (50,01-26,08) reduction of the coefficient of incidence being observed during this period, corresponding to 5.3% per year. The risk of being a new TB case was 2.4 times higher for men than for women. Although the number of notified cases was higher for the 15 to 49 year age range, starting in 2001 the risk of becoming ill with TB was higher in the age range above 50 years. The percentage of HIV/TB co-infection was 27.1% (minimum prevalence), but the maximum prevalence was 32,7%. The most frequent clinical form for the new cases was the pulmonary one (85%), while this form was present in 58.3% of co-infected cases and the extrapulmonary form in 27.8%. The site of detection of TB cases was public and private outpatient clinics in 51% of cases, university, public and private hospitals in 38%, and other sites in 10%. One of the fragilities observed was the low detection of TB cases in the municipality, which remained close to 45% over the last few years and the fact that the basic health units and PTCs perform only one fifth of the sputum bacilloscopies they should perform for diagnosis (according to Health Ministry estimates). However, one of the strong points was the implantation of supervised treatment in the municipality, which was effectively started in 1998 and increased gradually, with 76% of cases being supervised in 2006. There was an improvement in cure rates, that reached 72% and 50.5% for non-co-infected new cases and HIV/TB co-infected cases, respectively. The TB mortality rate in the municipality showed a slight tendency to a fall during the period. Despite the low lethality observed, 50.8% of the TB deaths were only diagnosed and notified after death, indicating a difficulty in access to diagnosis and treatment of TB in these cases. We conclude that, in order to improve the detection of TB cases in the municipality, changes are needed in the reception of individuals suspected to have TB at basic health units, facilitating their access to these units, in addition to the investigation of more persons with respiratory symptoms in the community. Some actions for the control of the disease such as supervised treatment and the control of communicants could be decentralized. Supervised treatment alone is not sufficient for HIV/TB-co-infected patients to achieve successful treatment.

There are an estimated 2 billion individuals infected with Mtb, and 37.7 million people living with HIV (PLWH) worldwide. HIV/Mtb co-infection increases the risk of developing active tuberculosis by over 20-fold, and 210,000 of 1.5 million deaths from TB were among co-infected PLWH in 2020. Therefore, development of effective TB vaccination, particularly within the vulnerable PLWH population, is an urgent global issue. With limited in vivo models to study co-infection, humanized NRG (huNRG) mice and humanized DRAG-A2 mice (a next-generation of huNRG mice expressing HLA class I and II transgenes with improved human immune reconstitution, huDRAG-A2) are promising tools for HIV and TB reserach as they develop robust human immune cell populations and recapitulate many aspects of HIV or TB clinical disease. HIV/Mtb co-infection was investigated using huNRG and hu-DRAG-A2 mice in separate experiments where intravaginal (with DMPA pre-treatment) or intraperitoneal HIV-1 infection was administered, respectively, and intranasal infection of Mtb was administered 3.5 weeks later. Both huNRG and huDRAG-A2 mice recapitulated hallmark features of HIV/Mtb co-infection such as severe granuloma pathology, hCD4+ T cell depletion in lung and spleen tissue, and human like lung pathology such as Mtb-infected foamy macrophages in the granuloma. Co-infected huDRAG-A2 mice also displayed significantly higher bacterial burden in the lungs, increased extrapulmonary dissemination into spleen and liver, and significantly lower hCD4+ T cells in the peripheral blood post-Mtb infection when compared to the Mtb-only infected group. To investigate TB vaccine immunogenicity, huNRG and huDRAG-A2 mice were immunized with a novel trivalent vaccine, AdCh68MV. Upon intranasal immunization, both models showed trends of developing higher Mtb antigen-specific hCD4+ T cell responses in the lung and spleen. Overall, this project sets the initial stages of a pre-clinical HIV/Mtb co-infection model in huNRG and huDRAG-A2 mice appropriate for immune investigations, therapeutic and vaccination development. / Thesis / Master of Science in Medical Sciences (MSMS) / There are over 2 billion individuals infected with TB and 37.7 million people living with HIV (PLWH) worldwide. When someone is co-infected with both diseases, the risk of death is greatly increased. Research in co-infection and developing effective TB vaccination for PLWH are urgent global issues. Animal studies are currently limited because studying HIV requires human immune cells. Our lab has established humanized mice (hu-mice) that develop many different human immune cells and are useful for HIV/Mtb co-infection research. When hu-mice were co-infected, they showed more dying lung tissue, immune cell loss, and bacteria in the lungs. Hu-mice were also used to study human immune responses to a novel TB vaccine delivered to the lungs. Trends of higher immune responses towards TB were observed in the lung and spleen of immunized hu-mice. Overall, this project shows the utility of hu-mice as pre-clinical models of HIV/Mtb co-infection and Mtb vaccine studies.

Background: South Africa accounts for more than a seventh of the global population living with HIV/AIDS and TB, and ranks highest in HIV/TB co-infection worldwide. Consequent high child mortality is exacerbated by child malnutrition, which is an important indicator of health status and is associated with morbidity as well as mortality. Rural areas usually present with the greatest burden of morbidity and mortality, yet the extent of geographical disparities in child mortality, malnutrition and HIV/TB has hardly been explored. This is a reservoir of information useful for effective public health interventions. In this thesis we investigated the factors associated with childhood HIV/TB mortality and malnutrition, how they interrelate and their spatial distribution in the rural Agincourt sub-district located in north-east South Africa close to the border with Mozambique. Rationale: Africa at large lacks data that are routinely and reliably collected then validated, to guide policy and intervention programmes. Causes of deaths and even death counts are often misclassified and underestimated respectively, especially for children. To bridge this gap, a health and socio-demographic surveillance systems located in the rural Agincourt sub-district hosts which annually collects and collates data on vital events including fertility, mortality and migration. These data have been collected since 1992 to-date and now cover 80,000 people living in more than 16,000 households situated in 27 villages; all households are fully geo-coded. These hierarchical data allow us to address several epidemiological questions on how person, place (spatial) and time (temporality) have impacted on mortality and malnutrition patterns in children living in the rural Agincourt sub-district. Objectives: The aims of this thesis were both methodological and applied: Methodological (1) To investigate the presence of spatial autocorrelation in the Agincourt sub-district and model this using geographical and geo-statistical procedures (2) To model large spatial random effects accurately and efficiently (3) To model hierarchical data with zero inflated outcomes Applied (1) To investigate childhood HIV/TB mortality determinants and their geographical distribution using retrospective and cross-sectional data (2) To determine factors associated with malnutrition outcomes adjusting for their multivariate spatial random effects and selection bias for children under five years (3) To model how the associated factors were interrelated as either underlying or proximate factors of child mortality or malnutrition using pathway analysis. Methods: We conducted a secondary data analysis based on retrospective and cross-sectional data collected from 1992 to 2010 from the Agincourt sub-district in rural northeast South Africa. During the period of our study 71,057 children aged 0 to 9 years from 15,703 households were observed. All the data in the thesis were for children aged 1 to under 5 except for the chapter 6 (last paper) who were aged from 0 to 9 years of age. Child HIV/TB death and malnutrition were the outcome measures; mortality was derived from physicianbased verbal autopsy. We investigated presence of spatial autocorrelation using Moran’s and Geary’s coefficients, semi-variograms and estimated the spatial parameters using Bayesianbased univariate and multivariate procedures. Regression modelling that adjusted for spatial random effects was done using linear regression and zero inflated variants for logistic, Poisson and Negative Binomial regression models. Structural equation models were used in modelling the complex relationships between multiple exposures and child HIV/TB mortality and malnutrition portrayed by conceptual frameworks. Risk maps were drawn based on spatial residuals (posteriors) with prediction (kriging) procedures used to estimate for households where no data were observed. Statistical inference on parameter estimation was done using both the frequentist; maximum likelihood estimation and Bayesian; Markov Chain Monte Carlo (MCMC) directly and sometimes aided with Metropolis Hastings or Integrated Nested Laplace Approximations (INLA). Results: The levels of child under-nutrition in this area were: 6.6% wasted, 17.3% stunted and 9.9% underweight. Moran’s (I) and Geary’s (c) coefficients indicated that there was global and local clustering respectively. Estimated severity of spatial variation using the partial-sill-to-sill ratio yielded 12.1%, 4.7% and 16.5%, for weight-for-age, height-for-age and weight-for-height Z-scores measures respectively. Maternal death had the greatest negative impact on child HIV/TB mortality. Other determinants included being a male child and belonging to a household that had experienced multiple deaths. A protective effect was found in households with better socio-economic status and where older children were present. Pathway analyses of these factors showed that HIV had a significant mediator effect and the greatest worsening effect on malnutrition after controlling for low birth-weight selection bias Several spatial hot spots of mortality and malnutrition were observed, with these regions consistently emerging as areas of greater risk, which reinforces geographical differentials in these public health indicators. Conclusion: Modelling that adjusts for spatial random effects, is a potentially useful technique to disclose hidden patterns. These geographical differences are often ignored in epidemiological regression modelling resulting in reporting of biased estimates. Proximate and underlying determinants, notably socioeconomic status and maternal deaths, impacteddirectly and indirectly on child mortality and malnutrition. These factors are highly relevant locally and should be used to formulate interventions to reduce child mortality. Spatial prediction maps can guide policy on where to best target interventions. Child interventions can be more effective if there is a dual focus: treatment and care for those already HIV/TB infected, coupled with prevention in those geographical areas of greatest risk. Public health population-level interventions aimed at reducing child malnutrition are pivotal in lowering morbidity and mortality in remote areas. Keywords: HIV/TB, Child mortality, Child malnutrition, Conceptual framework, Spatial analysis, MCMC, Path analysis, South Africa

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.

HIV and Tuberculosis (TB) co-infection place an immense burden on health care systems as they act in synergy to worsen disease prognoses. TB is the most common cause of death in people living with HIV (PLWH) and in turn, HIV is the most significant risk factor for progressing from latent to active TB disease. While HIV and TB are endemic in sub-Saharan Africa, they also disproportionately affect marginalized populations in Canada. Unfortunately, the only licensed TB vaccine, BCG, does not protect from adult pulmonary TB and is not recommended for PLWH. Thus, the development of novel TB vaccines, which are safe and effective in PLWH, remains an urgent global necessity. We have found that humanized mice (hu-mice) are ideal models to research this as they can be successfully infected with HIV, TB and HIV/TB and recapitulate human disease pathology. A next-generation respiratory mucosal (RM) trivalent chimpanzee adenoviral-vectored vaccine (Tri:ChAd68) was developed and tested in our naïve and HIV-infected hu-mice. When immunizing naïve hu-mice, a trend of increased M.tb-specific CD4+ T cells producing IFNγ and TNFα in the lungs and spleen was observed. After subsequent M.tb infection, the vaccinated naïve hu-mice also exhibited significantly reduced lung mycobacterial burden, tissue dissemination and lung pathology. We then investigated the vaccine immunogenicity and ability to protect from TB in the context of HIV. Our immunized HIV-infected hu-mice were also able to produce M.tb-specific T cells and when challenged with M.tb, we observed a decreased trend in mycobacterial load in the lungs, indicating that the vaccine may be able to offer protection against TB when a prior HIV infection is present. These findings demonstrate the protective potential of the RM Tri:ChAd68 vaccine against TB disease for PLWH. In the future, we will test this vaccine in antiretroviral treated HIV-infected hu-mice to increase clinical significance. / Thesis / Master of Science in Medical Sciences (MSMS) / HIV and TB are major diseases that can occur together, severely worsening patients’ health and challenging global healthcare systems. The current TB vaccine, BCG, isn’t ideal for people living with HIV (PLWH), causing this vulnerable population to be at greater risk of getting TB infection. Therefore, developing a new TB vaccine that is safe and effective in PLWH is an urgent global issue. We used humanized mice that develop human immune cells to test a novel TB vaccine delivered to the lungs (Tri:ChAd68) to see if it could protect against TB and overcome immune challenges from HIV. We saw increased immune responses and lower TB infection in our vaccinated humanized mice and the vaccine appeared to also be beneficial in the mice that had prior HIV infection. This suggests the Tri:ChAd68 vaccine may be able to offer protection against TB in PLWH; however, more studies are needed to conclude this.

Philosophiae Doctor - PhD / The global impact of the converging dual epidemics of tuberculosis (TB) and human immunodeficiency virus (HIV) is one of the major public health challenges of our time, because in many countries, human immunodeficiency virus (HIV) and mycobacterium tuberculosis (TB) are among the leading causes of morbidity and mortality. It is found that infection with HIV increases the risk of reactivating latent TB infection, and HIV-infected individuals who acquire new TB infections have high rates of disease progression. Research has shown that these two diseases are enormous public health burden, and unfortunately, not much has been done in terms of modeling the dynamics of HIV-TB co-infection at a population level. In this thesis, we study these models and design and analyze robust numerical methods to solve them. To proceed in this direction, first we study the sub-models and then the full model. The first sub-model describes the transmission dynamics of HIV that accounts for behavior change. The impact of HIV educational campaigns is also studied. Further, we explore the effects of behavior change and different responses of individuals to educational campaigns in a situation where individuals may not react immediately to these campaigns. This is done by considering a distributed time delay in the HIV sub-model. This leads to Hopf bifurcations around the endemic equilibria of the model. These bifurcations correspond to the existence of periodic solutions that oscillate around the equilibria at given thresholds. Further, we show how the delay can result in more HIV infections causing more increase in the HIV prevalence. Part of this study is then extended to study a co-infection model of HIV-TB. A thorough bifurcation analysis is carried out for this model. Robust numerical methods are then designed and analyzed for these models. Comparative numerical results are also provided for each model. / South Africa

In this thesis, we study these models and design and analyze robust numerical methods to solve them. To proceed in this direction, first we study the sub-models and then the full model. The first sub-model describes the transmission dynamics of HIV that accounts for behavior change. The impact of HIV educational campaigns is also studied. Further, we explore the effects of behavior change and different responses of individuals to educational campaigns in a situation where individuals may not react immediately to these campaigns. This is done by considering a distributed time delay in the HIV sub-model. This leads to Hopf bifurcations around the endemic equilibria of the model. These bifurcations correspond to the existence of periodic solutions that oscillate around the equilibria at given thresholds. Further, we show how the delay can result in more HIV infections causing more increase in the HIV prevalence. Part of this study is then extended to study a co-infection model of HIV-TB. A thorough bifurcation analysis is carried out for this model. Robust numerical methods are then designed and analyzed for these models. Comparative numerical results are also provided for each model.