PhD Faculty of Health Sciences, University of the Witwatersrand, 2009. / HIV/AIDS was discovered almost a quarter of a century ago and has so far claimed the lives of more than 25 million people worldwide. Developing countries remain disproportionately affected, with sub-Saharan Africa contributing more than two-thirds of infections globally. Sexual transmission is the primary route of HIV/AIDS acquisition, and women bear the greatest burden of this pandemic. We are now at a stage where biotechnological advances are needed that can either cure HIV/AIDS, stimulate the immune system to produce anti-HIV-antibodies by vaccination, or prevent HIV infections. One of these advances has been the development of various microbicides. However, a lack of effective drug delivery systems for these agents has remained as a rate-limiting step towards successful HIV prevention. In an attempt to overcome this problem, this study aimed at designing and developing a novel intravaginal bioadhesive polymeric device (IBPD) as a delivery system to effectively deliver a microbicide {polystyrene sulfonate (PSS)} and antiretroviral (ARV) {3'-azido-3'-deoxythymidine (AZT)} combination to the vagina. The development of a successful intravaginal microbicidal drug delivery system requires the design of a formulation to deliver the microbicide-ARV combination in a safe, effective, and consistent manner. The first step therefore was to undertake extensive preliminary screening studies on various polymeric materials using a one variable at a time (OVAT) approach to find suitable polymers for developing an IBPD. Initially 18 biodegradable and biocompatible polymers were employed to produce 62 formulations that were further screened through the OVAT approach to result in 15 lead formulations. Two major concerns of this study were the attainment of satisfactory residence time of the IBPD in the vagina as well as the ability of the IBPD to contain and release the microbicide-ARV in a controlled manner. Therefore, optimization of the IBPD was based on these two requirements for which proper matrix integrity was a pre-requisite. Artificial neural networks (ANNs), a computational technique that is able to simulate the neurological processing ability of the human brain through mathematical modeling, was employed for optimization. The ANN approach confirmed that 5 of the 18 studied polymers could be suitable for the development of an optimized IBPD. To finally attain good vaginal retention for the developed delivery system, extensive bioadhesivity testing was undertaken on the optimized device. Thorough in vitro and ex vivo bioadhesivity analysis was conducted using physicomechanics and computational structural modeling. Allyl penta erythritolcrosslinked poly acrylic acid (APE-PAA) appeared to contribute most to the bioadhesivity. Apart from being employed as a matrix component, PAA was further used as a coating agent to achieve extended bioadhesivity within the posterior fornix of the vagina. Since prolonged release and suitable permeation of the microbicide-ARV across the vaginal tissue was a critical requirement of this study, the device was designed to provide a controlled and prolonged drug release. Prolonged release for up to 72 days was achieved. Furthermore, the design was constructed to ensure that the released drug could permeate into the vaginal tissue and be retained substantially. This was determined by measuring drug flux through ex-vivo permeation studies using freshly excised pig vaginal tissue in a Franz Diffusion Cell (FDC) apparatus. The ultimate aim of the study was to have the IBPD well accommodated in the vagina for successful prevention of STIs and HIV infection. Achievement of this aim was ensured by undertaking extensive in vivo studies in Large White pig model. The IBPDs were inserted under anaesthesia into the posterior fornix of the vagina, using a novel applicator. To detect the retention of the IBPDs and determine their sequential biodegradation pattern in the vagina, X-ray imaging was employed, using radio-opaque Barium Sulphate (BaSO4). To demonstrate that the developed drug delivery system acted locally and was only minimally absorbed systemically, blood samples were taken from the jugular vein of each pig at pre-determined time intervals and subjected to UPLC analysis. The drug content in the vaginal tissue at the end of the study was also determined. Histopathological evaluation was carried out on vaginal epithelium to access the potential for toxicity of the IBPDs. The drug content analysis revealed that greater amounts of AZT and PSS were retained in the vaginal tissue with relatively small quantities (AZT:17%; PSS:13%) crossing into the systemic circulation. The results from the toxicity studies showed that the IBPDs were safe for use. This suggests that the developed drug delivery system (the IBPD) may be suitable for application in the prevention of STIs and HIV infections.

Includes abstract. Includes bibliographical references (leaves 77-84).

Word processed copy. / Includes bibliographical references (leaves 84-98). / Until recently, the national implementation of a public sector Antiretroviral Therapy (ART) programme in South Africa seemed financially impossible. Drastically reduced prices for Antiretrovirals (ARVs) combined with substantial donor funding and the long-awaited adoption of a national treatment plan, have, however, shifted the debate. Now the question is not so much should universal ART be provided by government but, rather, is it possible to implement in severely resource-constrained environments and, if so, what are the best ways to deliver these services.

Incudes bibliographical references. / The thesis is based on the story of a 36 year old HIV positive middle class black Zimbabwean woman, Maidei Chivi (pseudonym). Maidei is well educated, financially secure and wields enormous power both within her family and at her workplace. She therefore, unlike many women, does not fall into the typical HIV victim category, characterised by poverty, coerced sex and desperation. Maidei's story demonstrates that economic security does not necessarily result in women taking decision making roles during sex.

Includes bibliographical references.

Testing is widely acknowledged to be a useful and necessary secondary tool of Human Immunodeficiency Virus (HIV) prevention. It is the method by which to identify people who are living with the virus, so that their behaviour may be modified and medical condition treated in order to prevent further infection. Unfortunately, many persons in South Africa (SA) remain undiagnosed and therefore unaware of their HIV-positive status. This thesis explores why it is necessary to test for HIV in SA, where the incidence of the virus remains the highest in the world. Voluntary Counselling and Testing (VCT) or the âopt-inâ approach has been adopted as the norm or âsine qua nonâ. The efficacy of this method will be interrogated and shortcomings identified. The most notable is that few people in SA undergo an HIV test in order to learn their status. When they do, it is often late in the progression of opportunistic infections, requiring hospitalisation that increases pressure on an already over-stretched healthcare system. Reasons for the poor uptake of VCT are explained, including pervasive stigma and deficiencies in leadership of SAâs HIV and AIDS response. The expansion of testing is a proposed response to the challenge of persons remaining undiagnosed, and includes the acceleration of âopt-outâ or routine HIV testing (RHT) among SAâs high prevalence population. This model offers an HIV test routinely to persons attending government healthcare settings with an illness or for a routine check-up. Although the provider initiates the test, consent is necessary in order to proceed and there is an option to decline. While the key focus of this thesis is routine HIV testing, other approaches are explored in brief, including mandatory testing, mobile clinics and wellness screening. The thesis argues that if SA is to achieve the HIV and AIDS and STI National Strategic Plan (NSP) target of increasing the number of adults who have ever had a test to 70 percent by 2011, new approaches to testing, and especially opt-out, will need to be explored and more widely adopted. Key words: HIV/AIDS; Voluntary Counselling and Testing (VCT); Routine HIV Testing (RHT); Routinely Recommended Testing (RRT); Opt-out Testing; Provider-Initiated Testing and Counselling (PITC).

Includes abstract. / Includes bibliographical references (leaves 86-91). / South Africa is a highly unequal society, comprised of a small, wealthy elite class and a large population living in deep, chronic poverty plagued with unemployment. Those suffering from the greatest poverty are unemployed women caring for children. In the context of a distinct underclass that has been historically marginalized from the labour market and a welfare system does not provide assistance for the unemployed, these women are left to cope with their own poverty. Additionally, the HIV/AIDS epidemic exacerbates existing vulnerabilities and compromises the capabilities of these women and children. Guided by a livelihood framework and based on a multi-dimensional definition of poverty, the study explored how women navigate within their difficult environment to respond to the poverty of their children.

Word processed copy. Includes bibliographical references (leaves 117-123).

This study explores the links between masculinity and the spread of HIV/AIDS by examining adolescents’ conceptions of manhood and the ways in which hegemonic masculinity manifests itself through peer pressure. The study employed qualitative methods, including in-depth interviews and focus group discussions. Interviews were conducted with fifteen adolescent males between the ages of twelve to sixteen, who live in areas with high levels of HIV prevalence outside Pietermaritzburg in KwaZulu-Natal.

Includes bibliography. / This thesis is based on a series of interviews with key informants and a census of orphan households in Nguludi Mission Community, Southern Malawi, in 2000. The thesis argues that although HIV/AIDS is a relatively recent phenomenon, any contemporary understanding of the epidemic must be informed by an understanding of the past. The impact of the HIV/AIDS epidemic and the "orphan problem" at the local level, is, therefore, situated within the broader socio-economic context of the history of the region.