3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item Moral justification of continued exceptionalism of HIV care in South Africa(2024) Maserumule, Letjie CharmainSouth Africa has the largest population of people living with HIV (PLWHIV) in the world, and specialized HIV clinics to treat them are unsustainable. Decentralisation of care to primary health care (PHC) facilities reduces the burden on HIV clinics, but the PHC facilities are already overburdened with limited human and infrastructure resources. My aim is to defend that it is morally and legally justified to temporarily continue exceptionalism of HIV care in South Africa while strengthening health systems. My arguments are based on patients’ right to healthcare, the bioethical principles of beneficence and non-maleficence, and deontological moral theory. I contend that the complete abandonment of HIV clinics would burden PHC facilities even more, thus affect rendered care negatively, and violate patients’ intrinsic dignity. The complete decentralization of HIV care will be morally and legally justified when PHC facilities are improved for the progressive realisation of access to quality healthcare for all.Item The prevalence and predictors of HIV-hypertension comorbidity among youth living with HIV in South Africa, 2010-2016(2018) Makuapane, Lerato PatriciaOver the last two decades, AIDS mortality rates has decreased substantially due to extensive HIV treatment in South Africa, which left HIV as a chronic illness. Therefore, since the disease nature of HIV predisposes patients to other clinical conditions; many HIV patients also suffers from other AIDS-related and non-AIDS diseases resulting in comorbidities. It is most prevalent among population aged 14-35 years. At the same time, NCDs are rapidly increasing among youth with hypertension being amongst the leading cause of HIV comorbidities. High prevalence of both HIV/ AIDS and hypertension in this cohort rise a concern of their simultaneous occurrence to develop HIV-hypertension comorbidity. Abbreviation abstract)Item Characterisation of inhibitor binding to the LEDGF/p75-binding domain of HIV-1 integrase(2018) Harrison, Angela TheresaHuman immunodeficiency virus type 1 (HIV-1) integrase (IN) catalyses the irreversible integration of the viral genome into the host genome with the aid of the host co-factor lens epithelium derived growth factor (LEDGF/p75). LEDGF/p75 protects HIV-1 IN from proteasomal degradation, facilitates transport and directs DNA binding. Allosteric IN inhibitors (ALLINIs) were discovered in 2010 by Christ et al and then several research groups followed suite. ALLINIs were found to cause aberrant multimerisation of HIV-1 IN and have a profound effect on virion maturation. In previous studies lovastatin and cefdinir were identified to be inhibitors of the HIV-1 IN-LEDGF/p75 interaction. In this study, the aim was to characterise the interaction of both compounds in comparison with a known ALLINI, CX05168 with HIV-1 IN, and determine their modes of action. After the expression and purification of the recombinant proteins, the compounds were screened through an AlphaScreen assay to assess their ability to inhibit the HIV-1 IN-LEDGF/p75 interaction. All three of the compounds: lovastatin, cefdinir and CX05168 inhibited the interaction with IC50 values of 1.97 ± 0.28 µM, 4.05 ± 0.18 µM and 1.33 ± 0.5 5µM for subtype B HIV-1 IN and 1.98 ± 0.28 µM, 5.22 ± 0.92 µM and 1.79 ± 0.63 µM for subtype C HIV-1 IN, respectively. The AlphaScreen was then adjusted for the addition of donor DNA. This caused a reduction in the potency of CX05168 and cefdinir but had no effect on lovastatin. The IC50 values for cefdinir and CX05168 increased to 52.02 ± 1.82 µM and 20.46 ± 0.76 µM for subtype B HIV-1 IN and 41.87 ± 0.95 µM and 21.28 ± 0.52 µM for subtype C HIV-1 IN, respectively. This was the first indication that lovastatin had a different mode of action. With the findings that ALLINIs cause HIV-1 IN to aberrantly multimerise follow up tests included the compounds in two separate assays to determine if they caused multimerisation. The first assay was a cross-linking study and the second was differential light scattering assay. The only compound shown to have the ability to cause aberrant multimerisation was CX05168. Follow up tests were conducted to determine if the compounds had any stabilising effect on the HIV-1 IN enzyme. In agreement with the multimerisation assay only CX05168 showed any effect on the stability of HIV-1 IN. In this assay a difference in the potency of CX05168 on the subtype C HIV-1 IN was seen, where less stabilisation occurs. Hydrogen deuterium exchange mass spectroscopy was used to determine binding sites or allosteric changes to HIV-1 IN. Overall visual allosterism on HIV-1 IN subtype B and C was seen with CX05168. Lovastatin had clear binding areas that differed from CX05168, whereas cefdinir showed few areas of binding or similarities. This indicated that all three compounds displayed different binding models and in combination with the other assays confirmed their different modes of action. Surface plasmon resonance was used to determine the binding kinetics. The noise to signal ratio for lovastatin and cefdinir proved to be too high to obtain VI usable results indicating a possible poor binding ability. CX05168 showed good binding in agreement with our previous results but once again a difference in binding the subtype B HIV-1 IN and subtype C HIV-1 IN could be seen. We finalised our tests with cellular screening. Lovastatin proved to be too toxic to the mammalian cells to test antiviral efficiency. Cefdinir and CX05168 showed viral inhibition with CX05168 being less potent against the HIV-1 subtype C as opposed to the HIV-1 subtype B viruses. In conclusion, this study found that the three compounds (lovastatin, cefdinir and CX05168) inhibit the HIV-1 IN-LEDGF/p75 interaction in different ways. Results highlight that CX05168 functions as a LEDGF/p75 IN inhibitor by causing aberrant IN multimerisation, however, it is less potent towards HIV-1 subtype C, which is the predominant subtype circulating in South Africa. Lovastatin and cefdinir inhibit the direct interaction of HIV-1 IN-LEDGF/p75 without multimerisation which decreases the antiviral potency. The compounds of most value are those causing aberrant multimerisation of HIV-1 IN as they have potent downstream effects, lovastatin and cefdinir in their current chemical structure are not promising ALLINI’s, and require structural modifications to fulfil their promise.Item Inter-rater variability between anaesthetists when classifying patients the american society of anesthesiologists physical status (ASA-PS) classification system(2018) Soni, Zaheera JalaluddinBackground Anaesthetists convey the physical state of patients by use of the American Society of Anaesthesiologists Physical Status classification system (ASA-PS). It is a simple, popular tool with many uses, but not without fault, where variation between anaesthetists when classifying patients exists. To date there is no South African study comparing inter-rater variability between anaesthetists particularly between junior and senior anaesthetists. Our study includes scenarios with patients with Human Immunodeficiency Virus (HIV). A „modifier‟ and it‟s level of acceptance is also proposed. Method A questionnaire comprising of two parts was distributed. The first part assessed demographics and attitude towards a proposed “modifier” and the second consisted of ten hypothetical case scenarios which were created to incorporate a wide variety of conditions including Human Immunodeficiency Virus (HIV). Results After receiving 134 of the 200 questionnaires distributed, 132 were analysed. There were 93 juniors and 39 seniors. A Cohen‟s kappa statistic over all the scenarios of 0.23 (fair agreement) was determined. In none of the scenarios was there complete agreement. In each case there was a majority viewpoint shared by both juniors and seniors except Scenario 2. Large ranges were found in scenarios which included pregnant, geriatric and emergency patients. Conclusion Results are in keeping with other studies. Inter-rater variability is prevalent despite guidelines being available. A simple modifier such as letter “G” denoting a gravid patient may be acceptableItem Expression of envelope proteins by pre-s1/pre-s2 deletion mutants of HBV isolated from Southern African HIV-positive patients(2018) Simelane, DanielHepatitis B Virus (HBV) pre-S deletion mutants of genotypes B and C have been shown to predispose to hepatocellular carcinoma (HCC). Studies have reported that envelope protein expression can be affected by the deletion mutants, leading to endoplasmic reticulum (ER) stress, apoptosis and hepatic injury. In South Africa, genotype A/subgenotype A1 prevails and it also has a relatively high hepatocarcinogenic potential compared to non-A genotypes. The aim of the study was to determine whether strains of HBV subgenotype A1, isolated from HIV-infected patients, affect envelope protein expression in vitro. The strains included pre-S deletion mutants (also frequently found in HCC patients) and the strain isolated from HBsAg negative HIV positive individual. Different 1.28 mer replication-competent constructs, generated previously, including two wild type subgenotype A1 strains from an HBsAg-positive infection (A12C15; A12C15 ALT9.3), a strain from an occult infection (SHH193A) and 3 different deletion mutants: SHH011A (with deletions in the pre-S1/pre-S2 regions), SHH045A and SHH167A (with deletions in the pre-S2 region) were used. The plasmids were transfected into Huh7.5 cells and envelope protein expression followed by immunofluorescence using anti-HBs antibody and confocal microscopy on days 1, 3 and 5 post-transfection as well as quantification co-localization of the HBsAg using Zen software (Zeiss). Mean of fluorescence was quantified by Image J software. All the constructs expressed HBsAg and the HBsAg was located mainly in the cytoplasm for 100% of the transfected cells with a diffuse staining for wild-type (A12C15_OL and A12C15 ALT 9.3) and the 3 deletion mutants (SHH011A, SHH045A & SHH167A). The strain from an occult infection (SHH193A) showed aggregates of HBsAg in the cytoplasm with more extensive accumulation at the perinuclear region of the cells, a finding that is suggestive of envelope protein retention in the cellular compartments, which prevented secretion leading to the HBsAg-negative phenotype of the patient. In general, the deletion mutants (SHH011A, SHH045A & SHH167A), expressed envelope proteins at comparable amounts to that shown by the wild-type constructs (A12C15_OL and A12C15 ALT 9.3). Although other groups have shown the expression of the envelope proteins by pre-S deletion mutants of different HBV genotypes, this study is the first to show the expression of the envelope proteins for subgenotype A1 constructs. Immunocytochemistry and high resolution confocal microscopy was successfully used to follow the expression of HBsAg in the secretory pathway. The accumulation of HBsAg in the perinuclear region following transfection with the strain from the occult infection could account for the HBsAg-negative phenotype seen in the patient.Item A working memory intervention for HIV positive children and adolescents(2018) Fraser, ShonaIt is well known tha HIV causes a progressive encephalopathy in the immature brain and preferentially disrupted myelination in the fronto-cortical circuits. This significantly impacts executive functioning, of which working memory Is a component. Antiretroviral treatment is unable to reverse these effects, providing a compelling rationale alternative interventions for neurocognitive disability in adolescent HIV infection. Emerging research has investigated the role of cognitive training interventions in remediating working memory difficulties in children and adolescents with neurodevelopmental disorders, such as Attention Disorders, Dyslexia, and Specific Language Impairement. Such interventions depend largely on the concept of neural plasticity and the subsequent extent to which a child or adolescent's brain is plastic and can change through cognitive stimulation.Item Genotypic characterisation of South African human immunodefiency virus type l isolates(2003) Hunt, Gillian. M.This study was conducted to investigate the genetic diversity of human immunodeficiency virus type 1 in South African individuals. Blood was collected from 58 HIV-1 seropositive adult individuals during the period between 1996 and 1999 attending clinics across Johannesburg, South Africa. These samples were subtypedby heteroduplex mobility assay in the env and gag regions, and the sutype designations confirmed by sequencing and phylogenetic analysis.Item Investigation of the role of human parvovirus B19 in chronic anaemia of hiv infected TB patients(1994-09-30) van Niekerk, Albetus. Bernhardus. Willer.This study was undertaken to determine the role of human parvovirus B19 (B19) in chronic anaemia of HIV infected TB patients. Patients were selected from an existing databank of 307 patients included in a MRC HIV/TB study. Twenty-nine patients, 15 coinfected with HIV/TB and 14 infected with TB only, were identified for further evaluation. These patients’ sera were subjected to serological and DNA detection studies using IgG and IgM ELISA methods and a nested polymerase chain reaction (PCR) assay.Item An exploration of clinic based influences that support or hinder the retention of HIV positive clients in pre-art care at a clinic in Johannesburg, South Africa from January 2010 to July 2014(2017) Mushipe, ShelterBackground: Retaining people living with HIV in the continuum of care (CoC) is a major challenge internationally and in South Africa. However, health care providers can play a role in strengthening retention at different points in the continuum. Understanding the perceptions of health care providers regarding barriers to retention of HIV positive pre-antiretroviral therapy (pre-ART) clients can productively inform pre-ART patient retention programmes. Objective To explore health care worker perceptions on factors associated with retention of pre-ART clients at a clinic in the city of Johannesburg, South Africa. Methods: A cross sectional qualitative study was conducted using semi structured interview guides with a total of 11 health care providers who were comprised of the facility manager, six professional nurses and four lay counsellors in the ART programme. The respondents were purposively sampled. One-on-one interviews were conducted and audio recorded. Field notes were collected during the interviews and the recordings were transcribed after the interviews. Thematic content analysis was conducted using MaxQDA software. Results: The major finding of the research was that there is a lack of understanding of the scope and extent of pre-ART care and not all health care providers seem to get adequate preparation for tracing potential LTFU clients or retaining them in care. Informants in the study indicated as particularly problematic the late return for care by pre-ART clients, which usually occurs when clients are already very sick. Other factors that were identified as challenges include fear of disclosure, shortage of designated health care professional for pre-ART clients, lack of work space in the clinic, inadequate record keeping of patient information, concerns of disclosure and negative attitudes from staff. Clients not returning for their CD4 results, in part due to nonavailability of the results or infrequent health care visits, also led to a loss of care even before eligibility for pre-ART or ART could be determined. Conclusions: This study highlights some of the causes of non-engagement or loss to follow up (LTFU) in the HIV CoC among pre-ART individuals based on the health providers’ perceptions. The research thus provides an impetus for future research involving both health care providers and the pre-ART individuals to explore best practices that will enhance retention of pre-ART individuals in the continuum of care to attain optimal public health services.Item The development of a visual-motor treatment programme for pre-school HIV-infected children with visual motor integration difficulties(2017) Odejayi, RamonaThe purpose of this study is to add to current research on the impact of HIV on neurodevelopment in children and the nature of neurodevelopmental intervention needed to address the delay. The first phase of the study addressed the extent of visual motor integration delay in preschool children living with HIV. In the second phase of this study a visual motor treatment programme to address the delay specific to preschool children with HIV was proposed. Seventy-one children attending an HIV clinic were assessed to determine the extent of their visual motor integration delay on the Beery Developmental Test of Visual Motor Integration and the supplemental tests. The children’s socioeconomic status was determined based on the Household Economic and Social Status Index II. The results revealed that visual perception was the most affected component with a moderate positive correlation to the CD4 count and CD4% of the sample. The middle to low socioeconomic status of the sample had a mediating effect on the results particularly with visual motor integration in relation to the mothers’ level of education and attendance at creche. Therefore the proposed visual motor treatment programme had a large emphasis on visual perception using visual information analysis as a means of acquiring skill. The treatment programme emphasised naming and drawing five basic shapes. Due to the scholastic nature of this intervention, the programme was developed to be used in a preschool setting, with the preschool teacher acting as a mediator to ensure skill development and generalisation of concepts learnt to everyday living. Expert review determined content validity which assisted in developing the first draft of the programme known as the ‘My Shapes Programme’.