The thesis is based on the use of mathematical theories and techniques to gain qualitative and quantitative insight into the transmission dynamics of hepatitis C virus (HCV) in an IDU (injecting drug user) population. A deterministic model, which stratifies the IDU population into eight mutually-exclusive compartments (based on epidemiological status), is considered. Rigorous qualitative analysis of the model establishes, for the first time, the presence of the phenomenon of backward bifurcation in HCV transmission dynamics. Three routes (or causes) to such a dynamic phenomenon have been established. Furthermore, five main parameters that play a dominant role on the transmission dynamics of the disease have been identified. Numerical simulations of the model show that the re-infection of recovered individuals has marginal effect on the HCV burden (as measured in terms of the cumulative incidence and prevalence of the disease) in the IDU community.

This thesis first investigates within-host HIV models for the acute stage. These models incorporate the immune responses and helper T cells produced from the activation of naive CD4 T cells. Because both naive CD4 T cells and helper T cells are susceptible classes, backward bifurcation and bistability may occur. We start with a simple model that ignores the CD8 T cell dynamics, then extend it to include this dynamics. We also extend our model to consider the latent infection of naive CD4 T cells. Backward bifurcation occurs in all these models. We numerically investigate the stability of viral equilibria, and show the bistability caused by backward bifurcation. Increasing the inflow of CTLs prevents the backward bifurcation. With a large homeostatic source of healthy naive CD4 T cells, the disease is easier to establish when the basic reproduction number is less than one. Reducing the reproduction number below one is not sufficient to control the infection of HIV. Secondly, this thesis investigates the development of AIDS caused by viral diversity, as proposed by Wodarz et al. using a model that does not include the details of immune responses. We extend their model to include density dependence, and show that the viral load increases with viral diversity. To study if this result still holds with more realistic HIV dynamics, we incorporate viral diversity into our first model. We conclude theoretically that the total viral load is positively correlated with the number of viral strains, and viral diversity can drive the development of AIDS. We also find that the total CD4 T cell count does not always decrease with viral diversity. Thus further investigation is needed to fully understand the development of AIDS. / Graduate

>Magister Scientiae - MSc / Tuberculosis (TB) is currently one of the major public health challenges in South Africa, and in many countries. Mycobacterium tuberculosis is among the leading causes of morbidity and mortality. It is known that tuberculosis is a curable infectious disease. In the case of incomplete treatment, however, the remains of Mycobacterium tuberculosis in the human system often results in the bacterium developing resistance to antibiotics. This leads to relapse and treatment against the resistant bacterium is extremely expensive and difficult. The aim of this work is to present and analyse mathematical models of the population dynamics of tuberculosis for the purpose of studying the effects of efficient treatment versus incomplete treatment. We analyse the spread, asymptotic behavior and possible eradication of the disease, versus persistence of tuberculosis. In particular, we consider inflow of infectives into the population, and we study the effects of screening. A sub-model will be studied to analyse the transmission dynamics of TB in an isolated population. The full model will take care of the inflow of susceptibles as well as inflow of TB infectives into the population. This dissertation enriches the existing literature with contributions in the form of optimal control and stochastic perturbation. We also show how stochastic perturbation can improve the stability of an equilibrium point. Our methods include Lyapunov functions, optimal control and stochastic differential equations. In the stability analysis of the DFE we show how backward bifurcation appears. Various phenomena are illustrated by way of simulations.

This thesis is based on the use of mathematical theories, modelling, and simulations to study the transmission dynamics of HIV/AIDS in the presence of PrEP (pre-exposure prophylaxis) in the MSM (men who have sex with men) population in the United States. A new deterministic model for HIV/AIDS that incorporates PrEP is designed and used to assess the population-level impact of the use of PrEP on the transmission dynamics within an MSM population. Conditions for the effective control (or elimination) and persistence of HIV/AIDS in the MSM population are determined by rigorously analyzing this model. Uncertainty and sensitivity analysis is carried out to determine the effect of the uncertainties in the parameter values on the response variable (the associated reproduction number) and to identify the top-five parameters that have the most effect on the disease transmission dynamics. Numerical simulations show that HIV burden decreases with increasing PrEP coverage. / October 2015

The thesis is based on the use of mathematical modeling and analysis to gain insightinto the transmission dynamics of malaria in a community. A new deterministic model for assessing the role of age-structure on the disease dynamics is designed. The model undergoes backward bifurcation, a dynamic phenomenon characterized by the co-existence of a stable disease-free and an endemic equilibrium of the model when the associated reproduction number is less than unity. It is shown that adding age-structure to the basic model for malaria transmission does not alter its essential qualitative dynamics. The study is extended to incorporate the use of anti-malaria drugs. Numerical simulations of the extended model suggest that for the case when treatment does not cause drug resistance (and the reproduction number of each of the two strains exceed unity), the model undergoes competitive exclusion. The impact of various effectiveness levels of the treatment strategy is assessed.

The thesis is based on the use of mathematical modeling and analysis to gain insightinto the transmission dynamics of malaria in a community. A new deterministic model for assessing the role of age-structure on the disease dynamics is designed. The model undergoes backward bifurcation, a dynamic phenomenon characterized by the co-existence of a stable disease-free and an endemic equilibrium of the model when the associated reproduction number is less than unity. It is shown that adding age-structure to the basic model for malaria transmission does not alter its essential qualitative dynamics. The study is extended to incorporate the use of anti-malaria drugs. Numerical simulations of the extended model suggest that for the case when treatment does not cause drug resistance (and the reproduction number of each of the two strains exceed unity), the model undergoes competitive exclusion. The impact of various effectiveness levels of the treatment strategy is assessed.

abstract: Cancer is a worldwide burden in every aspect: physically, emotionally, and financially. A need for innovation in cancer research has led to a vast interdisciplinary effort to search for the next breakthrough. Mathematical modeling allows for a unique look into the underlying cellular dynamics and allows for testing treatment strategies without the need for clinical trials. This dissertation explores several iterations of a dendritic cell (DC) therapy model and correspondingly investigates what each iteration teaches about response to treatment. In Chapter 2, motivated by the work of de Pillis et al. (2013), a mathematical model employing six ordinary differential (ODEs) and delay differential equations (DDEs) is formulated to understand the effectiveness of DC vaccines, accounting for cell trafficking with a blood and tumor compartment. A preliminary analysis is performed, with numerical simulations used to show the existence of oscillatory behavior. The model is then reduced to a system of four ODEs. Both models are validated using experimental data from melanoma-induced mice. Conditions under which the model admits rich dynamics observed in a clinical setting, such as periodic solutions and bistability, are established. Mathematical analysis proves the existence of a backward bifurcation and establishes thresholds for R0 that ensure tumor elimination or existence. A sensitivity analysis determines which parameters most significantly impact the reproduction number R0. Identifiability analysis reveals parameters of interest for estimation. Results are framed in terms of treatment implications, including effective combination and monotherapy strategies. In Chapter 3, a study of whether the observed complexity can be represented with a simplified model is conducted. The DC model of Chapter 2 is reduced to a non-dimensional system of two DDEs. Mathematical and numerical analysis explore the impact of immune response time on the stability and eradication of the tumor, including an analytical proof of conditions necessary for the existence of a Hopf bifurcation. In a limiting case, conditions for global stability of the tumor-free equilibrium are outlined. Lastly, Chapter 4 discusses future directions to explore. There still remain open questions to investigate and much work to be done, particularly involving uncertainty analysis. An outline of these steps is provided for future undertakings. / Dissertation/Thesis / Doctoral Dissertation Applied Mathematics 2020

Deterministic models for the transmission dynamics of HIV/AIDS and trichomonas vaginalis (TV) in a human population are formulated and analysed. The models which assumed standard incidence formulations are shown to have globally asymptotically stable (GAS) disease-free equilibria whenever their associated reproduction number is less than unity. Furthermore, both models possess a unique endemic equilibrium that is GAS whenever the associated reproduction number is greater than unity. An extended model for the co-infection of TV and HIV in a human population is also designed and rigorously analysed. The model is shown to exhibit the phenomenon of backward bifurcation, where a stable disease-free equilibrium (DFE) co-exists with a stable endemic equilibrium whenever the associated reproduction number is less than unity. This phenomenon can be removed by assuming that the co-infection of individuals with HIV and TV is negligible. Furthermore, in the absence of co-infection, the DFE of the model is shown to be GAS whenever the associated reproduction number is less than unity. This study identifies a sufficient condition for the emergence of backward bifurcation in the model, namely TV-HIV co-infection. The endemic equilibrium point is shown to be GAS (for a special case) when the associated reproduction number is greater than unity. Numerical simulations of the model, using initial and demographic data, show that increased incidence of TV in a population increases HIV incidence in the population. It is further shown that control strategies, such as treatment, condom-use and counselling of individuals with TV symptoms, can lead to the effective control or elimination of HIV in the population if their effectiveness level is high enough. / Dissertation (MSc)--University of Pretoria, 2017. / DST-NRF SARChI Chair in Mathematical Models and Methods in Biosciences and Bioengineering (M3B2) / Mathematics and Applied Mathematics / MSc / Unrestricted

This thesis firstly presents a nonlinear extended deterministic Susceptible-Infected (SI) model for assessing the impact of public health education campaign on curtailing the spread of the HIV pandemic in a population. Rigorous qualitative analysis of the model reveals that, in contrast to the model without education, the full model with education exhibits the phenomenon of backward bifurcation (BB), where a stable disease-free equilibrium coexists with a stable endemic equilibrium when a certain threshold quantity, known as the effective reproduction number (Reff ), is less than unity. Furthermore, an explicit threshold value is derived above which such an education campaign could lead to detrimental outcome (increase disease burden), and below which it would have positive population-level impact (reduce disease burden in the community). It is shown that the BB phenomenon is caused by imperfect efficacy of the public health education program. The model is used to assess the potential impact of some targeted public health education campaigns using data from numerous countries. The second problem considered is a Susceptible-Infected-Removed (SIR) model with two types of nonlinear treatment rates: (i) piecewise linear treatment rate with saturation effect, (ii) piecewise constant treatment rate with a jump (Heaviside function). For Case (i), we construct travelling front solutions whose profiles are heteroclinic orbits which connect either the disease-free state to an infected state or two endemic states with each other. For Case (ii), it is shown that the profile has the following properties: the number of susceptible individuals is monotone increasing and the number of infectives approaches zero, while their product converges to a constant. Numerical simulations are shown which confirm these analytical results. Abnormal behavior like travelling waves with non-monotone profile or oscillations are observed.

The thesis is based on using dynamical systems theories and techniques to study the qualitative dynamics of herpes simplex virus type 2 (HSV-2), a sexually-transmitted disease of major public health significance. A deterministic model for the interaction of the virus with the immune system in the body of an infected individual (in vivo) is designed first of all. It is shown, using Lyapunov function and LaSalle's Invariance Principle, that the virus-free equilibrium of the model is globally-asymptotically stable whenever a certain biological threshold, known as the reproduction number, is less than unity. Furthermore, the model has at least one virus-present equilibrium when the threshold quantity exceeds unity. Using persistence theory, it is shown that the virus will always be present in vivo whenever the reproduction threshold exceeds unity. The analyses (theoretical and numerical) of this model show that a future HSV-2 vaccine that enhances cell-mediated immune response will be effective in curtailling HSV-2 burden in vivo. A new single-group model for the spread of HSV-2 in a homogenously-mixed sexually-active population is also designed. The disease-free equilibrium of the model is globally-asymptotically stable when its associated reproduction number is less than unity. The model has a unique endemic equilibrium, which is shown to be globally-stable for a special case, when the reproduction number exceeds unity. The model is extended to incorporate an imperfect vaccine with some therapeutic benefits. Using centre manifold theory, it is shown that the resulting vaccination model undergoes a vaccine-induced backward bifurcation (the epidemiological importance of the phenomenon of backward bifurcation is that the classical requirement of having the reproduction threshold less than unity is, although necessary, no longer sufficient for disease elimination. In such a case, disease elimination depends upon the initial sizes of the sub-populations of the model). Furthermore, it is shown that the use of such an imperfect vaccine could lead to a positive or detrimental population-level impact (depending on the sign of a certain threshold quantity). The model is extended to incorporate the effect of variability in HSV-2 susceptibility due to gender differences. The resulting two-group (sex-structured) model is shown to have essentially the same qualitative dynamics as the single-group model. Furthermore, it is shown that adding periodicity to the corresponding autonomous two-group model does not alter the dynamics of the autonomous two-group model (with respect to the elimination of the disease). The model is used to evaluate the impact of various anti-HSV control strategies. Finally, the two-group model is further extended to address the effect of risk structure (i.e., risk of acquiring or transmitting HSV-2). Unlike the two-group model described above, it is shown that the risk-structured model undergoes backward bifurcation under certain conditions (the backward bifurcation property can be removed if the susceptible population is not stratified according to the risk of acquiring infection). Thus, one of the main findings of this thesis is that risk structure can induce the phenomenon of backward bifurcation in the transmission dynamics of HSV-2 in a population.