In South Africa 1 000 people die of AIDS everyday and 100 000 more people require ARVs every year. There is therefore an urgent need to provide access to ARVs andother essential medicines. The South African Constitution requires the government totake reasonable measures to ensure access to health care. The government has cited financial constraints as the major ohstacle to fulfilling this constitutional imperative. In an effort to stretch their budgetary resource other medium-income countries have used measures such as compulsory licences, voluntary licences and parallel importation. These measures, provided for in the TRIPS Agreement and the Doha Declaration, are available under South African legislation but have not been properly implemented due to a lack of political will. The proper use of compulsory licences by the South African government is vital because all twelve of the ARVs on the World Health Organisation's Essential Medicines List are protected in South Africa by our patent laws. However, in order to issue compulsory licences more easily and quickly the South African Legislature will need to pass legislation which clarifies the ambiguities contained in TRIPS and the Doha Declaration. Other methods to lower the price of medicines include the segmentation of the South African market in order to facilitate differential pricing. The State must balance its use of such measures with programmes to incentivise research and development into neglected diseases and HIV/AIDS. Such programmes will also assist the State's capacity to conduct its own research and development into new medicines, whilst bolstering its domestic pharmaceutical manufacturing capacity. The ultimate solution to South Africa's access to medicine problem is to create a pharmaceutical manufacturing industry capable of producing the most complex medicines, so as to lessen its dependence on drug manufacturers reducing their prices. The way to create a sophisticated pharmaceutical manufacturing capacity is to use the flexibilities in TRIPS and to uphold South Africa's high patent standards. The Constitutional Court's involvement is essential in order to force the State to implement its own policies so as to provide access to affordable medicines. / Thesis (LL.M.)-University of KwaZulu-Natal, Durban, 2008.

Sepsis is a systemic inflammatory response that causes, increased heart rate, respirations, fever, and inadequate blood flow to organs. One of the most prevalent causes of sepsis is Staphylococcus aureus (S. aureus). With increasing numbers of strains of bacteria becoming antibiotic resistant, new methods for the treatment and clearance of sepsis are needed. Studies have shown that the lipid lowering drug simvastatin is protective for incidence of sepsis, having immunomodulatory effects and anti-inflammatory properties, specifically. Thus, it may be an alternative way to prevent sepsis due to S. aureus infections. Studies in our laboratory have shown that simvastatin pretreatment increases survival of mice infected with S. aureus and alters the adaptive immune response such that levels of IgG2c are reduced to the level of uninfected controls. Our studies have demonstrated that while simvastatin does not enhance bacterial clearance, or affect serum C5a levels, it does decrease serum levels of TNF. / Department of Biology

ENGLISH ABSTRACT: HIV/AIDS is the leading cause of death in Sub-Saharan Africa. According to 2001 estimates, there are 28.5 million people living with HIV in Africa, comprising more than 70% of the world’s HIV-infected population. HIV/AIDS remains one of the most important social and public health threats in Sub-Saharan Africa. UNAIDS 2006 estimates that 5.5 million people are living with HIV, and almost 1,000 AIDS deaths occur every day in South Africa. South Africa is currently one of the most severely affected countries in the world. Antiretroviral therapy (ART) is currently the only treatment available for HIV. It does not cure HIV infection, but reduces HIV related mortality and morbidity. / AFRIKAANS ABSTRACT: No abstract available

HIV/AIDS is a global pandemic that poses a great threat especially in Sub-Saharan Africa where the highest population of those infected with the virus is found. It has far reaching medical, socio-economic and scientific implications. The HIV-1 protease enzyme is a prime therapeutic target that has been exploited in an effort to reduce morbidity and mortality. However problems arise from drug toxicity and drug-resistant mutations of the protease which is a motivation for research for new, safer and effective therapies. Evidence exists to show that there are significant genomic differences in Subtype B and C that have a negative effect on the intrinsic binding of inhibitors. It is imperative to look at all perspectives from epidemiological, molecular to the pharmacological ones so as to achieve rational design of therapeutic agents. This study involved the use of in silico structural analysis of the effects of mutations in the active site. The data was provided by the National Institute of Communicable Diseases consisting of HIV-1 Subtype C protease sequences of 29 infants exhibiting drug-resistance to ritonavir and lopinavir. The major active site mutations causing drug resistance identified in this study were M46I, I54V and V82A using the Stanford HIV database tool. Homology modeling without extra restraints produced models with improved quality in comparison to those with restraints. MetaMQAPII results differed when models were visualized as dimers giving erroneous modeled regions in comparison to monomers. A broader study with a larger dataset of HIV-1 subtype C protease sequences is required to increase statistical confidence and in order to identify the pattern of drug resistant mutations. Homology modeling without extra restraints is preferred for calculating homology models for the HIV-1 subtype C. Further investigations needs to be done to ascertain the accuracy of validation results for dimers from MetaMQAPII as it is designed for evaluation of monomers.

The retention of persons on an HIV programme has been a global challenge. The success of any strategy to optimize adherence to anti-retroviral therapy (ART) depends on the intensive and effective adherence counselling and strategies. It is important to research whether persons receiving anti-retroviral therapy in public hospitals in Ghana are receiving the needed service that would optimize their adherence to the anti-retroviral therapy. Therefore, this study explored and described the experiences of healthcare professionals providing care, support and guidance to persons on ART at public hospitals in Ghana, as well as the best-practice guideline that could contribute to facilitating the ART adherence of patients. This study also explored and described the experiences of persons living with Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) on ART, regarding their adherence to the therapy. The study was organized into three phases. In Phase One: a qualitative, exploratory, descriptive and contextual design was employed. The research population included healthcare professionals, providing services at the HIV clinic at the public hospitals in Ghana, namely the Korle-Bu Teaching Hospital; the 37 Military Hospital and the Ridge Hospital. The healthcare professionals comprised of doctors, nurses, pharmacists and trained counsellors employed in any of the three public hospitals. Persons receiving ART at any of the three public hospitals were also part of the research population. Semi-structured interviews were conducted with healthcare professionals and persons receiving ART. Data were collected from healthcare professionals in relation to their experiences regarding the provision of ART services, their understanding of evidence-based practice and best-practice guidelines, as well as data on the experiences of persons receiving ART in relation to their adherence to the therapy. The data were analysed using Creswell’s six steps of data analysis; and the coding of the data was done according to Tesch’s eight steps of coding. Trustworthiness was ensured by using Lincoln and Guba’s framework which comprised credibility, transferability, dependability, confirmability and authenticity. Ethical principles such as beneficence and non-maleficence, respect for human dignity, justice, veracity, privacy and confidentiality were considered in the study. In phase two, the literature was searched by using an integrative literature review approach and critically appraising the methodological quality of the guidelines in order to identify the best available evidence related to adherence to ART. In Phase Three, a best-practice guideline for facilitating adherence to ART was developed for public hospitals in Ghana based on the findings of the empirical research of Phase One and the integrative literature review in Phase Two. The guideline was submitted to an expert panel for review; and it was modified, according to the recommendations of the panel.

The world has entered the third decade of the HIV and AIDS epidemic under different times in which the epidemic is treatable. The International Labour Organisation (ILO) (2005) declares HIV and AIDS a developmental crisis destroying developmental gains over generations. Since HIV and AIDS affect the most productive segment of the labour force, it is therefore not only a threat to development but also to the world of work without which development will be sacrificed (ILO, 2001). Collaborative response efforts that seek to mitigate the HIV pandemic by government, business and higher education institutions have been fraught with challenges. The main challenge that beset these efforts is that, in the absence of an HIV vaccine, voluntary counselling and testing remains the gateway to access treatment and care. Regrettably, participation in VCT has been confronted by challenges of low utilisation. This precedes the objectives of this study, which were to explore and describe factors that serve as barriers and facilitators of workplace VCT programmes with the objective to improve participation in these programmes. The current study was a product of a qualitative and exploratory-descriptive research design. A nonprobability convenience sampling method was used to sample participants for this study. The targeted population in this study were the non-academic employees of an academic institution in the Eastern Cape. Data was collected by means of focus group discussions and by using semi-structured interviews. The focus group samples comprised of an equal number of men and women with an overall participation of fifty-six participants. Data obtained was transcribed, thematically analysed and coded using Henning, Van Rensburg, and Smit's (2004) qualitative analysis and interpretation method. Findings of this research revealed that factors that facilitate and inhibit voluntary counselling and testing are psychosocial and cultural by nature. At psychosocial level, participants reported factors that facilitate voluntary counselling and testing to include psychological readiness to go for HIV testing, reassurances of confidentiality of HIV test results and normalising HIV testing (making the process more like that for screening and diagnostic testing). Cultural factors included cultural practices and beliefs such as "intonjane" and traditional circumcision - positive cultural nurturers that could facilitate VCT participation. Results of this study showed a lack of basic knowledge about VCT and fear of knowing one's status, fear of breach of confidentiality, fear of being stigmatised and a lack of trust towards health professional as the major psychosocial factors that serve as barriers to VCT participation. The cultural barriers to VCT pointed to hegemonic masculinity as a socially constructed gender identity that encourages gender inequalities and undermines efforts to improve HIV testing. The study suggested that strategies to increase VCT participation should consider leadership support of VCT programmes, incentivisation of VCT programmes, institutionalisation of HIV and AIDS education and the establishment of integrated wellness services for employees.

Submitted in fulfillment of the requirements for the Degree in Master of Health Sciences (Nursing), Durban University of Technology, Durban, South Africa, 2016. / Background South Africa, especially KwaZulu-Natal remains heavily burdened with HIV and AIDS. Timely HIV testing is the cornerstone to HIV prevention in terms of early diagnosis and access to treatment, care and support services. Factors that influence delayed HIV testing must be investigated and reported to inform plans that are directed at improving implementation of HIV testing services and access to care, treatment and support services for people living with HIV. Purpose of the study This study was aimed at identifying factors that lead to delayed HIV testing in a sample of people attending a Primary Health Care clinic in KwaZulu-Natal, South Africa. Methodology A descriptive qualitative design was used in this study. The population in this study was HIV positive patients who had recently tested for HIV and received their first CD4 count result of 350 mm3 or less. Purposive sampling, which is a type of non-probability sampling, was used to select the study participants from the population. Semi structured interviews using an interview schedule were used to collect data. Data was collected until data saturation was reached. Results The data was analysed by means of content analysis and raw data was coded and sorted into sub categories and categories. The underlying meaning of categories was formulated into one overarching theme: Testing for HIV is daunting and embedded with issues of stigma, denial and a fear of knowing one’s positive status. Conclusion To encourage early HIV testing before HIV positive people become noticeably ill requires efforts directed at change of attitude and improvement of support for HIV positive people in families, communities and health service institutions. Community forums to be actively involved in eliminating the stigma and discrimination associated with HIV positive people by creating awareness of these matters and encouraging community and family support for people with HIV. / M

A series of the Baylis-Hillman adducts have been obtained by reacting protected O-benzylated and unprotected substituted salicylaldehydes with methyl acrylate or tertbutyl acrylate, respectively, using DABCO as catalyst. Treatment of the Baylis-Hillman adducts with HCl in a mixture of acetic acid and acetic anhydride afforded the corresponding 3-(chloromethyl)coumarin derivatives with yields of up to 94%. Similar use of HI afforded the corresponding 3-(iodomethyl)coumarins but, depending on the reaction time, the reduced 3-methyl analogues could also be obtained. Arbuzov reactions of the 3-(halomethyl)coumarin derivatives have been undertaken to afford 4-phosphorylated and 1’-phosphorylated derivatives, regioselectivity being dependent on the halide-leaving group. The 3-(chloromethyl)coumarin derivatives have been subjected to nucleophilic (SN) attack by benzylamine to give the corresponding 3- [(benzylamino)methyl]coumarin derivatives in yields of up to 74%. Further treatment of the 3-[(benzylamino)methyl]coumarin derivatives with chloroacetyl chloride afforded the chloroacetamide derivatives, which exhibit hindered rotation about the amine C(O)-N bond. The acetamide derivatives have also been subjected to Arbuzov reaction conditions to afford the phosphorylated derivatives in yields of up to 86%. In a preliminary modelling study, hydrolysed analogues of the synthesized phosphorylated derivatives have been docked into the active site of the HIV-1 protease enzyme using the Cerius-2 Ligandfit software module to provide an insight into potential receptor-ligand hydrogen bonding interactions.

The socio-economic impact of HIV/AIDS on South Africa has resulted in lower gross domestic product, loss of skills in key sectors such as education, and increased health-care costs in providing access to treatment. Currently active pharmaceutical ingredients (API’s) such as stavudine (d4T) and azidothymidine (AZT) are imported from India and China, while formulation is conducted locally. A strategy was initiated between CSIR Biosciences and LIFElab under the auspices of Arvir Technologies to investigate the feasibility of local antiretroviral manufacture (d4T and AZT) or the manufacture of a key intermediate such as β- thymidine (dT). Several advantages associated with successful implementation of this strategy include ensuring a local supply of API’s, thus reducing reliance on procurement from foreign sources and reducing the effect of foreign exchange rate fluctuations on providing cost effective access to treatment. A local supply source would also reduce the imports and thus aid the balance of payments deficit, and in addition to this, provide stimulus in the local pharmaceutical manufacturing industry (which has been in decline for several decades), resulting in increased skills and employment opportunities. This thesis describes the development of a superior chemo-enzymatic process for the production of β-thymidine (72 percent yield, prior to isolation), a key intermediate in the preparation of anti-retrovirals. Alternative processes based purely on chemical or bioprocess transformations to prepare either 5-methyluridine (5-MU) or dT suffer from several disadvantages: lengthy transformations due to protection/deprotection strategies, low selectivties and product yields (30 percent in the chemical process) and isolation of the product from dilute process streams requiring the use of large uneconomical reactors (bioprocesss). This contributes significantly to the cost of d4T and AZT manufacture. Our novel chemoenzymatic process comprises of a biocatalytic reaction for the production of 5-MU, with subsequent chemical transformation into dT (3 steps) negating and circumventing the limitations of the chemical or bioprocess routes. During the course of this project development, the β-thymidine selling price declined from 175 $/kg (2005) to 100 $/kg (2008). However, the process described in this work is still competitive based on the current β- thymidine selling price of 100 $/kg. The process economics show that with further optimization and increasing the isolated dT yield from 70 percent to 90 percent, the variable cost decreases from 136 $/kg to 110 $/kg. The increase in isolated yield is highly probable, based on solubility data of β-thymidine. The decrease in β-thymidine selling price and technological improvement in dT manufacture should translate into lower API manufacture costs and more cost effective access to treatment. Our novel biocatalytic process producing 5-MU uses a coupled enzyme system employing PNP, Purine Nucleoside Phosphorylase and PyNP, Pyrimidine Nucleoside Phosphorylase. The overall transglycosylation reaction may be decoupled into the phosphorolysis reaction (PNP) and synthesis reaction (PyNP). During the phosphorolysis reaction, guanosine is converted into guanine and ribose-1-phosphate (R-1-P) in the presence of PNP enzyme. The reaction intermediate R-1-P is then coupled to thymine in the presence of PyNP enzyme during the synthesis reaction, producing 5-MU. The process was scaled up from lab-scale to bench-scale (10 - 20 L) and demonstrated to be robust and reproducible. This is evident from the average guanosine conversion (94.7 percent ± 2.03) and 5-MU yield (88.2 percent ± 6.21) and mole balance (104 percent ± 7.61) which were obtained at bench-scale (3 replicates, 10 L). The reaction was carried out at reactor productivities of between 7 – 11 g.L-1.h-1. The integration of the biocatalytic process and chemical processes was successfully carried out, showing that 5-MU produced using our novel biocatalytic process behaved similarly to commercially available 5- MU (ex. Dayang Chemicals, China). A PCT patent application (Ref. No. P44422PC01) on this chemo-enzymatic process has been filed and currently public private partnerships are being explored through Arvir Technologies to evaluate and validate this technology at one ton scale.

This study aimed to explore and describe the quality of life of adolescents living with early childhood HIV infection on Highly Active Antiretroviral Therapy (HAART) in Port Elizabeth. The advent of HAART has resulted in HIV being managed as a chronic illness, instead of the fatal disease that it once was. Children born with HIV can now live longer lives, progressing to adolescence and beyond. Chronic illness is known to impact one’s quality of life, so does adolescent development. A convenient sample of 31 adolescents was used in this study, with an exploratorydescriptive research design. The data was gathered using a cross cultural structured questionnaire developed by the World Health Organization, as well as through individual interviews. The data was then analysed by means of descriptive statistics and thematic content analysis. The results identified and presented the quality of life issues that are specific to this population. The results indicate that HIV as a chronic illness does impact the quality of life of adolescents. The adolescents living with early childhood HIV-infection on HAART in this study were very satisfied with their perceptions of their overall quality of life and general health perceptions. They were least satisfied in the Spirituality/Religion/Personal Beliefs and Social Relationships domains; and were most satisfied in the Level of Independence and the Psychological domains. There is a need for the development of (medical and psychosocial) services that can focus on adolescents as a special population with specific developmental needs in order to improve their treatment outcomes and quality of life.