Thesis (Ph. D.)--University of Texas at Austin, 2003. / Vita. Includes bibliographical references. Available also from UMI Company.

Thesis (Ph. D.)--University of Virginia, 1993. / Includes bibliographical references (leaves 201-216). Also available online through Digital Dissertations.

Thesis (Ph. D.)--Ohio State University, 2005. / Title from first page of PDF file. Document formatted into pages; contains xvii, 230 p.; also includes graphics. Includes bibliographical references (p. 200-230). Available online via OhioLINK's ETD Center

Thesis supervisor: C. Martin Stoltzfus. Includes bibliographic references (p. 121-143).

Thesis (M.A.) -- Central Connecticut State University, 2006. / Thesis advisor: Damon Mitchell. "... in partial fulfillment of the requirements for the degree of Master of Arts in Criminology." Includes bibliographical references (leaves 28-31). Also available via the World Wide Web.

Thesis (Ph. D.)--University of Missouri-Columbia, 2007. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on October 18, 2007) Vita. Includes bibliographical references.

Thesis (Ph.D.)(Botany)--University of Pretoria, 2006. / Includes summary. Includes bibliographical references. Available on the Internet via the World Wide Web.

Due to the lack of an effective cure for human immunodeficiency virus (HIV-1), with approximately twenty million new infections expected by 2031, research has moved towards optimised prevention strategies. Drug transporters, characterised extensively in the human liver, kidney and gastrointestinal tract, can be manipulated to improve the pharmacokinetic properties of orally delivered anti-retrovirals (ARV's). There is paucity in knowledge of drug transporter expression in the human cervicovaginal (CV) tract and representative pre-clinical models, where characterisation and manipulation may enable optimisation of topically applied ARVs for prevention of sexual transmission of HIV-1. In this thesis, RT-qPCR was used to characterise drug transporter profiles of CV pre-clinical models (in vitro, ex vivo and in vivo) for comparison with human CV tissue profiles, where distinguishable differences were observed, most notably in the efflux transporters P-gp and MRP2-4. This may explain the contrasting efficacy observed between pre-clinical and clinical trials of ARV-microbicides. Additionally, CV physiological factors (hormones, immunoregulatory proteins, microbes, pH) and microbicide candidate ARV's (dapivirine and darunavir) were shown to modulate expression of ARV-relevant drug transporters in CV cell lines. This highlights the potential intra-variability and inter-variability challenges associated with microbicide development and optimisation, in addition to potential drug-drug interactions in combination ARV-microbicides. Modulation of cellular pharmacokinetic properties in response to physiological pH levels and pro-inflammatory cytokines, observed within drug transport experiments, further emphasises these challenges. Molecular cloning experiments demonstrated the potential to develop a robust high throughout in vitro screening tool for the development of optimised microbicides. In conclusion, this thesis provides evidence exposing the limitations of pre-clinical CV models commonly used during ARV-microbicide screening, development and optimisation. The potential clinical implications of physiologically-induced and ARV-induced modulation of ARV accumulation in the CV tract when topically applied is highlighted within this thesis. It is imperative these key factors be incorporated into the pre-clinical screening and development of optimised microbicides.

Adolescents and young adults represent a growing proportion of people living with HIV around the world and have worse outcomes than all other age groups. Retention along each step of the HIV care cascade is essential for optimal care, but importantly, achieving sustained adherence to antiretroviral therapy (ART) and subsequent viral suppression is necessary for decreasing morbidity and mortality and reducing further transmission. The overarching goal of this dissertation was to assess health-services interventions aimed at improving ART adherence among adolescents and young adults living with HIV, and prospectively evaluate one such intervention – point-of-care viral load testing – in a randomized control trial. First, a systematic review was conducted to assess and synthesize recent research on interventions aimed at improving ART adherence among adolescents and young adults living with HIV in a resource-limited setting. Evidence from the review indicated that comprehensive models of HIV care, re-structuring how HIV services were delivered to patients, which included increased monitoring of adolescents and young adults through home visits or case management in addition to standard clinical care improved ART adherence. Second, a randomized control trial was conducted to evaluate the implementation and effect of point-of-care viral load testing compared to standard laboratory-based testing. The trial had two primary objectives: 1) to assess the efficiency of point-of-care viral load testing, and 2) evaluate the effect of point-of-care viral load testing on health outcomes including ART adherence and viral suppression. The research protocol is described including study design, the point-of-care viral load testing intervention, analysis plan, and outcome definitions. Lastly, the results of this trial are reported which indicate that point-of-care viral load testing can be feasibly integrated into a low-resource, clinical setting. A majority of point-of-care viral load test results (81.8%; 148/181) were processed and returned the same day, with a mean time between blood collection and participant receipt of results of 2.7 hours (IQR: 2.5-3.2; range 1.7-6.0). Point-of-care viral load testing also appeared to improve the accuracy of reported ART adherence, an unanticipated finding. In the point-of-care arm, participants who reported sub-optimal ART adherence on any of 3 adherence questions were more likely to have a VL >1,000 copies/mL (OR: 6.57; 95% CI: 2.12-25.21), compared to participants in the standard arm among whom the association was weaker (OR: 2.62; 95% CI: 0.97-7.44). There was no difference in viral load outcomes between arms. Overall, this dissertation addresses gaps in our knowledge about interventions aimed at improving ART adherence among adolescents and young adults living with HIV. The key finding is that point-of-care viral load testing can simplify the viral load monitoring process and help clinicians accurately identify adolescents and young adults with a high viral load in order to provide enhanced adherence counseling or make clinical decisions regarding appropriate treatment options faster. Point-of-care viral load testing could be used in concert with other interventions which address additional barriers to ART adherence among adolescents and young adults such as forgetfulness, stigma, or lack of social support. As the public health field continues to focus on improving HIV outcomes among this vulnerable age group, these findings can guide the optimization of HIV services and the development of combination interventions which could increase the number of adolescents and young adults who achieve sustained ART adherence and viral suppression.

Thesis (MSc)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: Since its discovery in the 1980’s, HIV has affected the lives of millions of individuals around the globe. Despite obvious need and an enormous amount of research a cure has remained elusive due to the rapid onset of mutated forms of the virus. However, there has been considerable success in reducing viral levels of infected individuals through the use of highly active antiretroviral therapy (HAART). The first-line regimen HAART mainly targets reverse transcriptase (RT) through the employment of two nucleoside RT inhibitors (NRTIs) and a nonnucleoside RT inhibitor (NNRTI). NNRTIs target an allosteric pocket situated about 10 Å from the catalytic site and cause a conformational change in the enzyme upon binding, leading to the inhibition of viral replication. There are currently 5 FDA approved NNRTIs on the market which successfully inhibit viral replication, but the use of these drugs is becoming limited due to the onset of drug resistant strains of the virus. In light of this need for the development of novel NNRTIs, we set out to explore new territory in NNRTI drug design with a goal of maintaining efficacy in the presence of both wild-type and mutated forms of HIV-1. To this end we designed three different NNRTI scaffolds along three different research thrusts. The first of these focused on the synthesis of 15 novel flexible triazole containing compounds. With these compounds we sought to achieve π-π stacking interactions with conserved amino acid residue Trp229 in the hope that we would be able to maintain efficacy in the presence of mutated forms of the virus. An additional feature included hydrogen bonding interactions to the backbone of Lys103. However, despite having thoroughly explored the triazole ring with multiple substitution arrangements, these compounds had very poor to no activity against whole cell HIV-1. Secondly we focused on the synthesis of a 4-hydroxyindole scaffold as a potential NNRTI. The focus here was to achieve interactions to Trp229 and simultaneously achieve hydrogen bonding interactions to the backbone of Lys101 at the entrance of the pocket. This was a novel concept in this class of compounds. We were able to successfully synthesize the indole core as a proofof-concept using the Knoevenagel-Hemetsberger method however; this compound had no activity against HIV-1. Lastly, in our quest to synthesize a novel NNRTI that could maintain efficacy against HIV-1 we decided to attempt to improve upon the stability of a lead indole-based compound synthesized previously within our research group. The lead compound was found to be potent with an IC50 of 1 nM but was unstable in acidic media due to the presence of a methoxy functionality situated at the 3-position on the indole. We sought to overcome this issue by introducing a substituted aryl amine functionality at this position. We were successful in synthesizing our desired compound but unfortunately it was significantly less active against whole cell HIV-1 than the lead compound. However, we were not completely deterred as there are a number of unexplored bioiososteres as possibilities to improve upon the stability of the lead compound while maintaining its excellent activity profile. / AFRIKAANSE OPSOMMING: Sedert die ontdekking van die menslike immuniteitsvirus (MIV) in die 1980’s, het die virus al die lewens van miljoene mense wêreldwyd geaffekteer. Ten spyte van die ooglopende behoefte aan ‘n geneesmiddel sowel as meer navorsing, bly ‘n keermiddel sover onbekombaar as gevolg van die verskillende mutasies wat binne die virus gebeur. Ten spyte hiervan, was daar al heelwat sukses in terme van ‘n verlaging van die virale vlakke in besmette individue deur die gebruik van hoogsaktiewe antiretrovirale terapie (HAART). As ‘n eerste behandeling, teiken HAART meestal trutranskriptase (RT) deur die inspanning van twee nukleosied trutranskriptase inhibeerders (NRTIs) en ‘n nie-nukleosied trutranskriptase inhibeerder (NNRTI). NNRTIs teiken ‘n allosteriese leemte wat ongeveer 10 Å weg van die katalitiese posisie is en veroorsaak dan ‘n konformasie verandering in die ensiem tydens die bindingsproses, wat dan lei tot die inhibisie van die virus se replikasie. Daar is tans 5 FDA goedgekeurde NNRTIs op die mark wat virale replikasie inhibeer, maar die gebruik van hierdie middels word alhoemeer belemmer as gevolg van die onwikkeling van weerstandige stamme van die virus. Met die oog op hierdie nood aan die ontwikkeling van nuwe NNRTIs, het ons gepoog om new gebiede te ondersoek in terme van die ontwerp van NNRTIs, met die doel om die effektiwiteit teen beide die wilde-tipe sowel as die gemuteerde vorme van HIV-1 te behou. Vir hierdie doeleindes het ons drie verskillende NNRTI steiers ontwerp, wat drie navorsingsdoeleindes na streef. Die eerste van hierdie doeleindes was die sintese van 15 nuwe buigsame triasool-bevattende middels. Met hierdie middels het on gepoog om π-π pakkingsinteraksies te behaal met aminosuur residu, Trp229, en sodoende die effektiwiteit van die NNRTIs in die gemuteerde vorm van die virus te behou. ‘n Additionele eienskap wat bygevoeg is, is ‘n waterstofbindingsinteraksie met die ruggraat van Lys103. Ten spyte van pogings om verskeie substitusie patrone om die triasool-ring te ondersoek, het hierdie middels baie swak tot geen aktiwiteit teen heel sel HIV-1 getoon nie. Tweedens, was die fokus op die sintese van ‘n 4-hidroksieindool steier as ‘n potensiele NNRTI. Die fokus hier was om ‘n interaksie met Trp229 te kry terselfdetyd as ‘n waterstofbindingsinteraksie met die ruggraat van Lys101, wat by die opening van die bindingssak is. Hierdie was ‘n nuwe konsep vir hierdie klas van middele. Ons het die indool-kern van hierdie molekules suksesvol gesintetiseer deur middel van ‘n Knoevenagel-Hemetsberger metode, maar ongelukkig het hulle geen aktiwiteit teen HIV-1 getoon nie. Laastens het ons gepoog om ‘n nuwe NNRTI te sintetiseer wat effiktiwiteit teen HIV-1 behou, deur te probeer om vorderings te maak op die stabiliteit van ‘n indool-gebaseerde hoof-middel wat al voorheen deur ons navorsingsgroep geraporteer is. Hierdie hoof-middel het ‘n IC50 waarde van 1 nM gelewer, maar was onstabiel in suur medium as gevolg van die teenwoordigheid van ‘n metoksie-groep in die 3-posisie van die indool. Ons het gepoog om hierdie probleem te oorkom deur ‘n gesubtitueerde arielamien in hierdie posisie te plaas. Ons was suksesvol hierin, maar ongelukkig was die middel heelwat minder aktief teen die heel sel HIV-1 as die metoksie-weergawe. Ten spyte hiervan, is ons optimisties dat ons hierdie probleem kan oorkom, aangesien daar verskeie bioisostere is wat die stabilitiet van middel kan verbeter terwyl dit moontlik die effektiwiteit kan behou.