Thesis (Dr. P.H.)--University of Michigan School of Public Health. / Includes bibliographical references (leaves 227-243).

Thesis (MMed.)-University of KwaZulu-Natal, Durban, 2009. / Full text also available online. Scroll down for electronic link.

Thesis (MA (Counselling Psychology))--University of Pretoria, 2006. / Includes bibliographical references. Available on the Internet via the World Wide Web.

Thesis (Ph. D.)--University of Texas at Austin, 2006. / Vita. Includes bibliographical references.

The decision to contribute my words to the discussion regarding HIV and AIDS emerged from my experience of the illness and subsequent death of my brother Jay, a gay man who killed himself eighteen months after a diagnosis of AIDS. The inquiry begins from my own experience of confusion, fear and eventual loss. Employing Jay's journal of his eighteen month “journey” with AIDS, I illustrate what can be learned about the social organization of AIDS “suicide” through the method of inquiry known as institutional ethnography. I assumed, when I began the analysis that I had found Jay's standpoint, his voice, that his words would show me the real Jay and how he finally made, by himself, his decision to die. Yet I found the narratives of medical, professional and immune and self-help discourses interjecting, defining, categorizing and being reflected in his words and actions. The analysis (that begins from Jay's journal as entry points) makes visible how a variety of ruling practices, ways of knowing, and authoritative knowledges organized Jay's account of his experience of living with AIDS, as they must have done his life itself and his decision to die. Thus, my central methodological interest has been to illustrate a way of knowing that is not simply a subjective rendering, nor an ideological account available only as discourse, but rather one which offers insight into how various social relations (might have actually) organized the everyday life of a man living/dying with AIDS. This project is not about who owns truth but rather about how HIV disease works today; that is, how concepts, institutional practices, and professional discourses intersect with and become part of the daily lives of actual individuals. The analysis displays the “work” involved in choosing to live or choosing to die by those with HIV disease and the discursive practices that “rule” those choices. The inquiry makes visible from an account of one person who lived with HIV/AIDS and those caring for him, how the standpoint of the everyday differs from the standpoint of professional action. While it is individual people with AIDS who will decide whether to take their own lives, depending on the circumstances in which they find themselves, I have attempted through this inquiry, to articulate how these decisions are fully social. As my research progressed, I discovered how my brother's death by his own act was turned from a heart-breaking attempt to take charge of his life—an unruly act-into conformity with official rules. I have shown what it means to say that his death, as well as his life with AIDS, was discursively organized and ruled. / Graduate

Ph.D. / Despite nearly three decades of intensive research, the HIV/AIDS pandemic remains a major challenge to modern medicine. The discovery and development of antiretroviral agents acting against various essential viral processes and enzymatic targets have greatly enhanced the quality of life for infected individuals, but no cure or preventative vaccine is available as yet and HIV infection is currently considered irreversible. Furthermore, the emergence of viral resistance to every class and type of antiretroviral treatment agent necessitates the continued discovery of antiretroviral agents with novel mechanisms of action. The first antiretroviral agent targeting the retroviral integrase enzyme (InsentressTM, Raltegravir) received regulatory approval from the United States Food and Drug Administration during 2007, validating HIV-1 integrase as a therapeutic target and providing a much-needed second- or third-line treatment option for treatment experienced patients. This enzyme was selected as a target for the current work. As limited data were available on the primary and secondary structure of the biologically relevant HIV-1 integrase enzyme, a first step in the present work was the construction of monomeric, dimeric and tetrameric models of the enzyme with biologically relevant catalytic centres incorporating both viral and host co-factors and DNA. The models were constructed to identify potential inhibitors of the strandtransfer reaction of HIV-1 integrase and were based on observations and interactions reported in the literature and on crystal structure data of HIV-1 integrase sub-domains and related structures available in the Protein Data Bank. The monomeric model was used as the macromolecular target in docking studies with “drug-like” compound databases, identifying the pyrrolidinone compound class as an in silico hit candidate for further development. Initial activity screening of a number of commercially available pyrrolidinone analogues against recombinant HIV-1 subtype B integrase in direct enzyme assays confirmed the predicted potential for strand transfer inhibition of the compound class, and provided initial support in the further development of this compound class as inhibitors of HIV-1 integrase that target the strand-transfer step. Retrosynthetic analysis of the pyrrolidinone hit candidates provided a facile one-pot, three-component synthetic pathway from readily available starting materials, which generally gave the proposed products cleanly and in acceptable yields. A range of closely related analogues were designed and synthesised. The analogues making up this series generally differed by only one functional group, in order to enable initial structureactivity relationship investigations during later stages of the project. Foreword Page XVI The synthesised pyrrolidinone analogues were screened through a range of direct and cell-based in vitro assays to determine the toxicity and strand-transfer activity of each. In general, the pyrrolidinone compounds proved well-tolerated in PM1 cell culture, with clear potential to further develop the strandtransfer inhibition of the compound family in second- and further-generation optimisation stages. Furthermore, the aqueous solubility and membrane permeability of each compound were determined in vitro, providing initial biological profiles of each test compound. As no in vivo testing was performed with any of the compounds during this first round of drug discovery and optimisation, several computational models were employed to extrapolate the in vitro and structural data to possible in vivo scenarios. Two pyrrolidinone analogues (11.6 and 15.2) were identified as low micro-molar strand-transfer inhibitors of wildtype-equivalent HIV-1 integrase, with low toxicity in cell culture and favourable solubility and permeability profiles. Resistance screening of these two compounds against four mutant HIV-1 integrases (Q148H; Q148H/G140S; N155H and N155H/E92Q) has shown some promise, with compound 15.2 retaining a measure of activity against the Raltegravir-resistant N155-mutants. These hit candidates will form the basis of structure-activity relationship optimisations in second- and further generation design stages.

Includes bibliographical references / Objective: To establish whether there is an association between HIV exposure and infectious disease mortality in children admitted to hospital in the Western Cape. Also to identify additional risk factors associated with mortality and the prevalence of HIV exposure. Methods: A case-control design was used to compare the HIV exposure status of 93 cases admitted with an infectious disease who died with 93 controls admitted with an infectious disease who did not die. Clinical and demographic data were collected via record review at three hospitals in the Western Cape . Factors associated with mortality were identified through regression analysis. Findings: 38.71% (36/93) of cases were HIV exposed versus 22.58% (21/93) of controls (p=0.017). 32.36% (30/93) of cases were HIV exposed uninfected (HEU) versus 18.28% (17/93) of controls (p=0.06). Being HEU was a risk factor for mortality after adjusting for age, sex, feeding practice, and main infection. The odds of death in HEU children was 2.29 times greater than in HUU (aOR: 2.29, 95% CI: 1.06-5.0). Age, sex, and feeding practice confounded the association between HIV exposure-infection and mortality. LRTI, septicaemia, and meningitis were all significantly associated with mortality at the 5% level. Children admitted with septicaemia demonstrated a 13.44 times increased odds of death (aOR: 13.44, 95% CI: 3.35-53.99). Conclusion: Children born to HIV positive mothers should be considered a vulnerable group even if vertical transmission has been prevented. Determination of exposure status could be a valuable tool for identifying children at increased risk of death. Septicaemia and meningitis also present a challenge in critical care in our sample.

Includes bibliographical references / Aims: To assess the clinical and cerebrospinal fluid characteristics, and the role of tuberculous meningitis (TBM) as a confounder, in a cohort of HIV positive individuals with positive varicella zoster virus (VZV) positive cerebrospinal fluid PCR. Methods: Patients in the NHLS database at Groote Schuur Hospital with positive CSF VZV PCR who were also HIV co-infected and whose folders were available for clinical review were reviewed. Clinical and biochemical data were collected. Patients were divided into two groups based an accepted case definition for TBM. Differences between groups were assessed using Mann-Whitney U or Chi squared tests as appropriate. Results: There were 437 for VZV PCR over three years. Of these 98 were positive and, after exclusions, 31 HIV positive patients were included for further analysis. Median age was 31 and median CD4 count was 146 cells/mm³. 11 (35%) had meningitis and 8 (25%) had encephalitis. 13 (42%) met the case definition for TBM. Patients with CNS varicella were frequently confused whereas those with TBM presented sub-acutely. There were no differences in CSF characteristics. Additional organisms were detected 6 (19%) patients. 4 (13%) patients died in hospital. CSF TB culture was requested in 24 (77%) patients and extra CNS samples were sent in only 4 patients. Conclusion: The clinical and CSF presentation of CNS Varicella and TBM overlap and in this cohort patients were under investigated for TB. In settings of high TB prevalence the possibility of false positive PCR or incidental varicella reactivation should be considered.

No description available.

一個大型的多中心臨床試驗 (HPTN052) 於2011年發表研究結論，假如治療中的愛滋病患者能保持病毒載量低水平，他們傳播愛滋病予性伴侶的機會是十分輕微的。這些結論促使利用病毒載量數據去形容愛滋病流行概况及評估高效抗逆轉錄病毒療法 (HAART) 干預策略對流行概况的影響。本研究旨在應用社區病毒載量去模擬香港愛滋病流行概况。 / 本研究收集了香港兩間主要愛滋病專科裡愛滋病患者縱向臨床數據，這些匿名的數據根據美國疾病預防控制中心所提議的人群病毒載量框架整合成流行病數據。其中社區、護理群及監測群病毒載量的計算是為了描述愛滋病流行概況，而新創的全社區病毒載量是用於估計社區裡確診與尚未確診的愛滋病感染者的集體病毒載量。香港未來愛滋病流行概況則利用決定性倉室模型模擬。異性模型透過性別分成兩個 (男女) 有聯繫的小模型，同性模型則用系統進化分析的近鄰結合法去劃分成16個獨立的小模型。除了基於現有情況模擬概況，治療、測試和混合干預策略以及外來感染的影響也被模擬。 / 從4362個病患中，一共收集了76,350CD4、64,412病毒載量和1042基因序列的回顧數據 (1985-2012)。當中有83%病患是男性、72%是中國人、89%是透過性接觸感染、74%曾經接受治療。能達到低病毒載量的病患百分比由1997年11%升至2012年76%，與HAART的推行情況方向一致。全社區病毒載量所顯示的上升趨勢於異性群和同性群中較其他病毒載量指標早五年出現。於2010-2020，異性群的愛滋病流行概況將維持不變，而同性群的流行概況將穩步上升但不是指數上升。干預策略中，以混合干預加上高治療保留率的策略對同性和異性群最有效，但增加重點測試對異性群比較可行，因為它舒緩了診斷延誤。另外，外來感染會影響干預策略的成效。 / 假如沒有包含病毒載量因素、外來感染和劃分模型，推測結果會高估流行概況，而治療覆蓋率的影響也不能被反映。基於人群病毒載量的重要性，定期收集所有專科的病毒載量數據並加以整合應該成為監測的一部份。這對於有廣泛治療覆蓋率的香港去研究流行概況是十分重要。 / Introduction: In 2011, a large multicentre trial (HPTN052) concluded that HIV+ persons on treatment with suppressed viral load (SVL) have minimal risk of virus transmission to their seronegative partners through sexual intercourse. These results provided evidence for the epidemiological use of viral load data to describe the HIV epidemics and assess impacts of treatment interventions. This study aims at modelling the HIV epidemic in Hong Kong by incorporating population-level viral load measures. / Methods: Longitudinal clinical data of patients attending two major HIV specialist services in Hong Kong were collected. The anonymized data were combined, adjusted and incorporated in an epidemiologic dataset in accordance with the CDC framework of viral load measures at population level. Specifically, community, in-care and monitored viral load were calculated to describe the HIV epidemic. Full community viral load, a new measure, was developed to infer the viral load burden of both diagnosed and undiagnosed individuals in the community. The HIV epidemic was then projected in a deterministic compartmental model. Gender was used to divide heterosexual model into two interrelated sub-models, while phylogenetic analysis (neighbour-joining tree) was applied to divide men-who-have-sex-with-men (MSM) model into 16 independent sub-models. Intervention scenarios of treatment coverage, testing coverage and retention expansion, and influence of non-local infection were projected and compared by modelling. / Results: A total of 76,350 CD4 and 64,412 viral load measurements of 4362 patients, and 1042 sequences were collected retrospectively (1985-2012). Among the patients included, 89% had acquired infection through sexual intercourse, and 74% had been started on highly active antiretroviral therapy (HAART). From viral load perspective, the proportion of patients in care with SVL (≤500copies/mL) increased sharply from 11% in 1997 to 76% in 2012, coinciding with the implementation of HAART. The growth curve of full community viral load was 5 years ahead of other viral load measures of heterosexuals and MSM. In 2010-2020, the HIV epidemic in heterosexuals would neither grow nor die down while the epidemic in MSM would continue to grow steadily but not exponentially. Among scenarios examined, test-and-treat intervention with high retention rate would be the most effective strategy for controlling the MSM and heterosexual epidemic. However, increasing the HIV testing rate for high risk people would be more feasible and impactful for the heterosexual, as a result of the early detection of HIV which would otherwise become late diagnoses. Non-local infection would affect the impact of interventions on epidemic control. / Conclusion: Without the inclusion of viral load measures, non-local infection and model delineation by subpopulations, epidemiologic projection results could be overestimated. Also, the impacts of treatment coverage on epidemic cannot be reflected if viral load measure is not included for describing epidemic growth. Acknowledging the importance of viral load measure, regular collection and aggregation of viral load measurements from all HIV clinics is recommended to form part of the HIV surveillance system. Such provision is important for studying HIV epidemiology descriptively and analytically in Hong Kong where coverage of HIV care is relatively extensive. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Wong, Ngai Sze. / Thesis (Ph.D.) Chinese University of Hong Kong, 2015. / Includes bibliographical references (leaves 204-219). / Abstracts also in Chinese.