A thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg in fulfilment of the requirements for the degree of Doctor of Philosophy. Johannesburg, 28 May 2018. / Since their discovery, protease inhibitors continue to be an essential component of antiretroviral treatment for human immunodeficiency virus type 1 (HIV-1). However, the development of resistance to protease inhibitors remains one of the most significant challenges in the fight for sustained viral suppression in those infected with HIV-1. Studies show that specific mutations arising within the HIV-1 gag and protease genes can lead to the development of resistance. In this research, a South African HIV-1 subtype C Gag-protease variant (W1201i) was investigated. This variant was considered due to the presence of a mutation and insertion (N37T↑V), located within the hinge region of the protease enzyme. Moreover, the variant displayed the following polymorphisms: Q7K, I13V, G16E, M36T, D60E, Q61E, I62V and M89L. Genotyping of W1201i Gag revealed a previously unreported MSQAG insertion between the CA/p2 and p2/NC cleavage sites. Additionally, a mutation and insertion (I372L↑M), and multiple polymorphisms (S369N, S371N, I373M and G377S) were discovered within the p2/NC cleavage site. Single-cycle phenotypic assays were performed to determine the drug susceptibility and replication capacity of the variant. The results show that the mutations present in the N37T↑V protease conferred a replicative advantage and reduced susceptibility to lopinavir, atazanavir and darunavir. Interestingly, the mutations in W1201i Gag were found to modulate both replication capacity and protease inhibitor susceptibility. In silico studies were performed to understand the physical basis for the observed variations. Molecular dynamics simulations showed that the N37T↑V protease displayed altered dynamics around the hinge and flap region and highlighted the amino acids responsible for the observed fluctuations. Furthermore, induced fit docking experiments showed that the variant bound the iv protease inhibitors with fewer favourable chemical interactions than the wild-type protease. Collectively, these data elucidate the biophysical basis for the selection of hinge region mutations and insertions by the HI virus and show that protease, as well as Gag, needs to be evaluated during resistance testing. / EM2018

Indiana University-Purdue University Indianapolis (IUPUI) / More than 20 million people have died of AIDS since the early eighties, while nearly 34 millions are currently infected with the HIV. Anti-retroviral therapy (ART) directed at key viral enzymes has changed AIDS from uniformly fatal to a manageable chronic disease. However, ART-associated drug resistance and toxicity have posed a great challenge for long-term management of the disease and have called for development of new therapeutics. In this study, we focused on the viral factor Nef and the host factor Sam68. Nef is a major pathogenic viral determinant for HIV-1, and no therapeutics have been targeted to this factor. Sam68 is indispensible for HIV-1 propagation. We revealed that Sam68 variants were very potent in preventing Nef expression. We found that these effects were associated with their ability to form a macromolecular structure called stress granules (SG). In addition, we demonstrated that these variants bound to nef mRNA in a sequence-specific manner. Furthermore, we showed that these variants co-localized with nef mRNA in SG. Importantly, we validated these findings in the context of HIV-1 infection of its natural target cells and found significant loss of Nef function in these cells. Taken together, these results demonstrate that SG induction and nef mRNA sequestration account for translational suppression of Nef expression and offer a new strategy for development of anti-HIV therapeutics. Sam68 is implicated in a variety of other important cellular processes. Our findings that Sam68 variants were able to induce SG formation prompted us to investigate whether wild-type Sam68 was also recruited to SG. We found that Sam68 was increasingly recruited into SG under oxidative stress, and that its specific domains were involved. However, Sam68 knockdown had no effects on SG assembly, suggesting that Sam68 is not a constitutive component of SG assembly. Lastly, we demonstrated that Sam68 complexed with TIA-1, an essential SG component. Taken together, these results provide direct evidence for the first time that Sam68 is recruited into SG through complexing with TIA-1, and suggest that SG recruitment of Sam68 and ensuing changes in Sam68 physiological functions are part of the host response to external stressful conditions.

The objective of this study was to assess levels of HAART adherence and factors affecting it. An observational, analytic, cross-sectional and quantitative study using IMB model was conducted on a randomly selected 349 HIV/AIDS patients on a HAART regimen. Data collection was done by interviewing respondents using a structured questionnaire. Both descriptive and inferential statistics used in the study. Only 80.2% of the total sample population reported a HAART adherence rate of more than or equal to 95% in this study. The findings highlight the need for on-going educational, informational and other interventions to address the knowledge, motivation and adherence behavioural skills of patients in order to improve the current levels of HAART adherence behaviour. The study also suggested the need for research into objective measures of adherence as well as longitudinal studies on adherence behaviour because strict adherence to treatment is a long-term process and not a one-time activity. / Health Studies / M.A. (Public health)

Thesis presented in partial fulfilment for the degree of Master of Management (in the field of Public Sector Monitoring and Evaluation) to the Faculty of Commerce, Law, and Management, University of the Witwatersrand 2016 / The purpose of this research was to assess outcomes of the antiretroviral treatment intervention in Mankweng. The antiretroviral treatment intervention was conceived with the aim to reduce HIV transmission through viral load suppression. Literature has shown that viral load is used as a tool to measure the performance of the intervention and studies on viral load outcomes in rural settings of Limpopo are limited. For this reason, the research was focused on viral load suppression with the aim of (1) determining the proportion of adults with viral load suppression among people taking antiretroviral treatment for 12 months, and (2) identifying factors associated with failure to achieve viral load suppression among people on antiretroviral treatment for 12 months. Binomial logistic regression model was used to identify factors associated with failure to suppress viral load. This study used the theory of change to interpret its findings as well as theories of behavioural planning and self-regulation models to understand the logic that underpins the theory of change. The findings revealed that the majority (78%) of adults achieved viral load suppression, and a quarter of the individuals failed to suppress the viral load. There was no significant difference in baseline characteristics between people who achieved viral load suppression and those who did not. In addition, males, with a low CD4 and opportunistic illnesses when in the primary disease stages were more likely to fail to suppress the viral load. Moreover, people who were initiated on a 3-pill containing treatment and do not have social support were also likely to fail to achieve viral load suppression. Although the study showed a trend of likelihood towards failure to achieve viral load suppression, the estimates were not statistically significant. Theoretical arguments from this study suggest that failure to achieve viral load was attributed to poor adherence to treatment. This is supported by the logic that underpins the theory of change, in which the assumption of adherence was possibly violated. However, the results chain framework highlighted that the implementation of the intervention was effective as it led to good outcomes and an effective intervention. Drawing all this together, the study highlights the need for intensified adherence counseling during treatment in order to improve the performance of the intervention. Author: Ramatsobane Johanna Ledwaba, Thesis Title: Outcomes of the antiretroviral treatment intervention in Mankweng, Johannesburg, March 2016 / GR2018

Thesis (MTech (Environmental Health))--Cape Peninsula University of Technology, 2010 / This study aimed to evaluate the "Antiretroviral Programme" in two informal townships, Du Noon and Doombacht, in the Westem Cape, South Africa. It evaluated how AIDS patients access Antiretroviral Therapy (ART'), their knowledge of ART's efficacy, their adherence to ART as well as their experiences of the quality of service at the Du Noon Clinic. Employing a questionnaire survey among 124 (12%) respondents on ART of the registered 1, 050 clients at the Du Noon Clinic, a systematic sampling of every 9th client (of the 1,050) was done. To generate findings of a qualitative nature, the study also used focus group discussions with a total of 36 AIDS patients on ART (18 of this number were also part of the survey), 11 community health/home-based workers and in-depth interviews with 2 nurses in charge of the rollout programme at the Clinic. Based on the survey results, the study determined that 93% (n=115) of AIDS patients access ART at the Du Noon Clinic, 75% (n=93) of respondents reported to ART adherence and 75% (n=93) displayed an understanding of ART's efficacy. It also revealed that 77% (n=95) of AIDS patients made good comments regarding the quality of service at the Du Noon Clinic. However, 25% (n=31) of AIDS patients were not adhering to ART. A Mann Whitney U test confirmed a significant relationship between the respondents' length of time on ART and the increase in CD4 count (p=0.01). However, AIDS patients who adhered to ART with the same length of time on ART have a higher CD4 count difference (p=0.04). The focus group discussions revealed AIDS patients' experiences of lack of confidentiality at the Du Noon Clinic. In addition, in five of the six focus group discussions, respondents expressed concern over disability grants not being awarded to patients with CD4 counts 200 cells lML and below². Notably, more than half of the respondents have been on treatment for more than one year. The study concluded that ART access is humanizing in the Western Cape and controversial AIDS treatment discourse has not significantly influenced the perceptions of AIDS patients regarding ART's efficacy. A high percentage (75%) of AIDS patients were adhering to ART in Du Noon and Doombacht. Addressing concerns over lack of confidentiality when accessing ART at the Du Noon Clinic, as well as the quest for disability grants within the context of AIDS treatment, could have further improved ART adherence in these communities. The study recommends that monitoring and evaluation (M&E) should involve measuring factors that influence adherence alongside accessibility to ART. Secondly, there should be mechanisms in place to maintain confidentiality in accessing ART as it is with Voluntary

Since 1988 when the first HIV positive drug user was identified in Poland, for close to two decades, the predominant route of HIV transmission has been through injecting drug use. In mid 2000s, Polish officials reported that injecting drug use no longer contributed to incrasing HIV incidence. The consequences of such a statement are that many of the structural and personal risks associated with HIV infection go unaddressed, that drug users are neglected by HIV prevention efforts, that HIV treatment is not made available to drug users and that the policy environment does not adequately support effective public health initiatives. This case study is based on documentation, archival records, interviews, participant observation, and physical artifacts shows that these assertions were made, and continue to be repeated, in a highly political context. Poland is a post-socialist state with strong neoliberal leanings, and it is highly invested in successful integration with the European Union. Powerful Catholic Church serves as an important backdrop. While people considered "at risk" now have more freedom to conduct their lives, they also have a set of neoliberal expectations and religious pressures placed on them. Country's geographic location adds to this complexity - situated between "Old Europe" where HIV problem has been successfully contained and the former Soviet Union, where the HIV incidence among drug users is the highest in the world, Poland attempts to align itself with the success of the West. Furthermore, examination of the available data suggests that the assertions made by Polish officials omit numerous variables. My research shows that even though Polish leadership in the area of HIV and drug policy wishes to resemble Western Europe, Poland does not meet international standards for the prevention of HIV transmission. The interviews I conducted, as well as the review of the literature on drug and HIV policies and programs suggest that these services are scattered, often unavailable, and that their number is stagnating, at best, and in some cases, even decreasing. This maybe a direct result of lack of engagement of drug users in their design. Excluded from the discussion of risk, drug users are thus not the focus of prevention efforts. Based on gathered data, there are seven crucial issues that require immediate action if Poland is to manage HIV prevention and care for people who use drugs in a manner consistent with the international standards. The areas requiring action are: a change in the drug policy from the current very punitive approach, expansion of needle and syringe programs and other harm reduction services, improved data collection and an increase in the availability of HIV testing, scaled-up substitution treatment, improved quality of other forms of drug treatment, greater investment in civil society organizations, improved access to HIV treatment, and educational and training efforts that encourage greater attention to HIV related matters across disciplines.

Thesis (M. A. (Social Work)) -- University of Limpopo, 2004. / The aim of this study was to explore the impact of culture on the prevention and reatment of HIV/AIDS amongst people in low-resourced areas like Malamulele. he study focused on the lifestyles, beliefs, attitudes and perceptions around ultural elements and practices, which might impact negatively on the prevention nd treatment of the HIV/AIDS epidemic. There were three groups of research espondents namely: learners from three high schools in Malamulele, some arents of the learners and the traditional/cultural leaders. The researcher ollected both qualitative and quantitative data. The data was gathered through he use of an interview schedule (questionnaire), focus group discussions and ound-table discussion sessions. The data was presented, analysed and nterpreted by means of tables and charts. t was found that people in low-resourced (rural) areas have little knowledge about HIV/AIDS, causes, symptoms and how the disease is transmitted. Despite the fact that awareness and educational campaigns and programmes are being rendered, people in low-resourced (rural) areas have little knowledge and needed skills about prevention and treatment of the pandemic. Polygamy and extra-marital relations by men is still highly valued and viewed at high esteem. Religious structures seem to be detached to the issue of HIV/AIDS as they mentioned that talking about HIV/AIDS is immoral and against their principles. The study also tried to explore the extent to which people in low-resourced areas view and use condoms as a protective means.

No description available.

Submitted in complete fulfilment for the Degree of Doctorate of Technology (Biotechnology)--Durban University of Technology, 2013. / South Africa has the largest number of people infected with HIV/AIDS. It also has more than 30 000 species of plants and many of these have a long tradition of medicinal use. It is highly likely that the treatment for HIV will come from this traditional knowledge. The need for effective preventative and therapeutic agents for HIV remains an urgent global priority. The aim of this study was to screen selected South African medicinal plants for anti-HIV activity and to identify and characterise an active compound from a plant that can be used for HIV treatment. The aqueous and methanolic extracts of the roots, leaves, flowers and stems of thirty eight plant species (108 extracts) were screened for anti-HIV activity. The plants which had anti-HIV activity were further screened for anti-reverse transcriptase activity. Thirty-two extracts exhibited varying degrees of anti-HIV activity. Cleome monophylla, Dichrostachys cinerea and Leonotis leonurus aqueous leaf extracts had anti-HIV-1 reverse transcriptase activity. The aqueous extracts of D. cinerea showed the best anti-HIV activity with a Selectivity Index of 43.5 and significant anti-HIV-1 reverse transcriptase activity. Crude phytochemical screening of D. cinerea showed that it had tannins, saponins, flavonoids and alkaloids but did not contain any phlobatannins, terpenoids, steroids or phenols. D. cinerea displayed a high degree of free radical scavenging activity with an IC50 of 25 μg/ml, therefore the anti-HIV activity could be attributed to the flavonoids present in the plant. Bio-guided fractionation was used to isolate and purify the active compound from the D. cinerea extract. Compounds were isolated by thin layer chromatography and were tested for anti-HIV-1 and anti-reverse transcriptase activity. From these results the active compound was identified, and purified using preparative TLC. The active compound was characterised by High Performance Liquid Chromatography, Ultraviolet-visible spectrophotometry, and Ultra Performance liquid chromatography coupled to MS/MS. Structural elucidation was performed using Nuclear Magnetic Resonance. From these results, it was deduced that the compound isolated from D. cinerea was a catechin. In this study we show that the catechins present in D. cinerea are responsible for the anti- HIV-I activity and inhibits the reverse transcriptase activity which is a key factor in the progression of HIV. Potentially, these results can be used to develop a new drug for the treatment of HIV or as a cost effective therapeutic agent in treating HIV-infected individuals with oxidative stress. / National Research Foundation

Thesis (MFamMed)--Stellenbosch University, 2015. / ENGLISH SUMMARY: Background: Sub Saharan Africa is home to approximately two thirds of the world’s population of HIV positive individuals. In view of the socioeconomic challenges of the region governments have provided antiretroviral therapy free to improve chances of survival among patients. However, adherence to antiretroviral therapy is recognised as more important in predicting patient survival. Aim: The study aimed to describe the prevailing factors that influence adherence to antiretroviral therapy. Methods: The study design was carried out using three methods of data collection. Focus group discussions, semi structured interviews and a questionnaire format. Setting: This study has been conducted among adult patients attending the Dora Nginza Hospital Adult wellness clinic. Results: The methods highlighted factors that influence antiretroviral therapy revealing psychosocial factors – lack of family support, not wanting to take medicines in front of people outside the home; patient factors – co morbidities that disturb patient adherence to therapy, a lack of trust in the patient-care giver relationship, fear of the drug side effects; socioeconomic factors – patients’ inability to afford food or transport costs to clinic appointments. In the semi structured interviews, 25% of patients self reported on poor adherence while in the questionnaire 5% of patients reported poor adherence. In assessing the effect of adherence to therapy on CD4 count and viral load there was a general increase in CD 4 count and a drop in viral load indicating clinical improvement in patients on therapy. Recommendation: There is a need for clinicians developing a health relationship with patients to facilitate adherence. The interventions designed to help patients in adherence to therapy should involve the patients in question in the designing of these interventions. Conclusion: Adherence monitoring is an important aspect of managing patients on antiretroviral therapy. The factors highlighted are similar to findings of other studies in similar contexts i.e. resource poor settings. / AFRIKAANSE OPSOMMING: Opsomming nie beskikbaar.