Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2007. / Härtill 4 uppsatser.

Thematic Paper (M.C.T.M. (Clinical Tropical Medicine))--Mahidol University, 2006. / LICL has E-Thesis 0011 ; please contact computer services. LIRV has E-Thesis 0011 ; please contact circulation services.

Thematic Paper (M.C.T.M. (Clinical Tropical Medicine))--Mahidol University, 2007. / LICL has E-Thesis 0024 ; please contact computer services. LIRV has E-Thesis 0024 ; please contact circulation services.

Thesis (D.P.H.)--University of Alabama at Birmingham, 2008. / Title from first page of PDF file (viewed on June 25, 2009). Includes bibliographical references.

Philosophiae Doctor - PhD / AIDS is considered a pandemic causing millions of deaths worldwide and a cure for this disease is still not available. Failure to implement early treatments due to the poor diagnostic methods and ineffective therapeutic regimens to treat HIV patients to achieve complete viral eradication from the human body has encouraged the escalation of this disease at an exponential rate. Though the current treatment regimens (High Active Antiretroviral Therapy) have aided in increasing the lifespan of HIV patients, it still suffers from some shortcomings such as adverse side effects and non-eradication of the virus. Thus, there is a need for a non-toxic therapeutic regimen to stop further infection of HIV-infected patients. Antimicrobial Peptides (AMPs) are naturally occurring peptides which are components of the first line of defence of many organisms against infections and have been proven to be promising therapeutic agents against HIV. The use of AMPs as anti-microbial agents is due to the fact that most AMPs have a net positive charge and are mostly hydrophobic molecules. These features allow AMPs to be site directed electro-statistically to the mostly negatively charged pathogens. In a previous study, a number of novel anti-HIV AMPs was identified using a predictive algorithm Profile Hidden Markov Models (HMMER). The AMP's threedimensional structures were predicted using an in-silico modelling tool I-TASSER and an insilico protein-peptide interaction study of the AMPs to HIV protein gp120 was performed using PatchDock. Five AMPs were identified to bind gp120, at the site where gp120 interacts with CD4 to prevent HIV invasion and HIV replication. Therefore, the aims of this research were to perform in-silico site-directed mutation on the parental anti-HIV AMPs to increase their binding affinity to the gp120 protein, validate the anti-HIV activity of these peptides and confirm the exclusivity of this activity by testing possible anti-bacterial and anti-cancer activities of the AMPs. Firstly, the five parental anti-HIV AMPs were used to generate mutated AMPs through insilico site-directed mutagenesis. The AMPs 3-D structures were determined using I-TASSER and the modelled AMPs were docked against the HIV protein gp120 using PatchDock. Secondly, an "in house" Lateral Flow Device (LFD) tool developed by our industrial partner, Medical Diagnostech (Pty) Ltd, was utilised to confirm the in-silico docking results. Furthermore, the ability of these AMPs to inhibit HIV-1 replication was demonstrated and additional biological activities of the peptides were shown on bacteria and cancer cell lines. In an effort to identify AMPs with increased binding affinity, the in-silico results showed that two mutated AMPs Molecule 1.1 and Molecule 8.1 bind gp120 with high affinity, at the point where gp120 bind with CD4. The molecular binding however showed that only Molecule 3 and Molecule 7 could prevent the interaction of gp120 protein and CD4 surface protein of human cells, in a competitive binding assay. Additionally, the testing of the anti-HIV activity of the AMPs showed that Molecule 7, Molecule 8 and Molecule 8.1 could inhibit HIV-1 NL4-3 with maximal effective concentration (EC₅₀) values of 37.5 μg/ml and 93.75 μg/ml respectively. The EC₅₀ of Molecule 8.1 was determined to be around 12.5 μg/ml. This result looks promising since 150 μg/ml of the AMPs could not achieve 80% toxicity of the human T cells, thus high Therapeutics Index (TI) might be obtained if 50% cytotoxic concentration (CC₅₀) is established. Further biological activity demonstrates that Molecule 3 and Molecule 7 inhibited P. aeruginosa completely after 24 hours treatment with peptide concentrations ranging from 0.5 mg/ml to 0.03125 mg/ml. Nevertheless, moderate inhibition was observed when CHO, HeLa, MCF-7 and HT-29 were treated with these peptides at peptides concentration of 100 μg/ml. The ability of these AMPs to block the entrance of HIV via the binding to CD4 of the host cells is a good concept since they pave the way for the design of anti-HIV peptide-based drugs Entry Inhibitors (FIs) or can be exploited in the production microbicide gels/films to suppress the propagation of the virus. / DST-NIC/Mintek

Master of Public Health - MPH / It is well documented that mortality rates have decreased and the survival of HIV and AIDS patients has been prolonged since the introduction of highly active antiretroviral therapy (HAART) in 1996. Although HAART has dramatically improved the prognosis of HIV disease, some HIV patients on HAART still die of HIV related illnesses. It is important to understand what these factors are in order to mitigate the impact on these factors on patient survival and achieve better outcome for these patients. The aim of this study was to determine risk factors for long term survival of patients on HAART in Uganda. Data for 2,244 out of 30,000 clients receiving care and treatment at TASO Entebbe was retrospectively analyzed. TASO Entebbe is a non-governmental HIV clinic that provides care and treatment to HIV positive clients. Long term survival in this case was defined as survival for more than 5 years after initiation on HAART. Logistic regression and survival analysis were conducted. Female clients had a 12% lower risk of death compared to the male clients (AHR=0.88 [CI: 0.443- 0.936]). Clients that had pulmonary TB had 1.3 times higher risk of death compared to clients that did not have pulmonary TB (AHR=1.33 [CI: 1.162-2.733]). Clients initiated at CD4 cell counts less than 250 cells/μl had almost 7 times higher adjusted odds of death compared to those initiated at CD4 cell counts greater than 500 cells/μl (AOR= 6.95 [CI: 2.882-16.744]) and clients initiated at CD4 cell counts between 250 cells/μl and 500 cells/μl almost 3 times higher adjusted odds of death compared to clients initiated at CD4 cell counts greater than 500 cells/μl (AOR 2.56 [CI: 1.004-6.520]). It is recommended that an aggressive HIV testing strategy be put in place to facilitate early identification of HIV positive patients. Early identification would enable early initiation into HAART well before the CD4 cell counts fall below 500 cells/μl. The observed higher risk of mortality amongst men suggests interventions to promote early HIV testing and treatment initiation amongst men. The observed high risk of mortality for patients with pulmonary TB, calls for aggressive TB case finding and treatment of positive in order to reduce the HIV/TB related mortality.

Magister Public Health - MPH / Background: The hallmark of HIV infection is immunosuppression which predisposes to unusual infections and malignancies generally known as opportunistic diseases (ODs). Globally, ODs are the major cause of morbidity and mortality in people living with HIV (PLHIV). Since the advent of Highly Active Antiretroviral Therapy (HAART), a significant decline in AIDS progression and ODs has been observed globally. However, most of the evidence suggesting sustained decline in AIDS progression and ODs has come from high-income settings with relatively less burden of ODs in the pre-HAART era. The findings of studies in high-income settings may not be generalizable to resource-limited settings. Lack of information regarding the burden of ODs in HAART-experienced populations in Nigeria and the risk factors for their occurrence has made it difficult to fully assess the sustained efficacy of HAART in the country. The aim of this study was to investigate the prevalence of and risk factors for HIV-related opportunistic diseases amongst HAART patients at the Federal Medical Centre (FMC) in Owerri, Nigeria. Study design and setting: A quantitative, cross-sectional descriptive and analytical study was conducted with 354 adult HIV-infected patients 15 years and above, who were on HAART for a minimum of 12 weeks at the HIV clinic of the FMC, Owerri, South-east Nigeria. Patients currently manifesting an OD whose onset ante-dated the commencement of HAART were excluded. The participants were recruited by simple random sampling. Data collection: Using a structured questionnaire, data was collected by clinicians through interviews, physical and laboratory examinations for patients that provided informed consent and met the study criteria. The questionnaire captured patient’s socio-demographic information and other relevant clinical/laboratory data. Data Analysis: The data was analysed using Epi info version 3.5.1 and Open Epi Version 2.2.1. Descriptive statistics for HIV-related ODs were carried out using percentages and frequencies tables for categorical variables and means (SD) or medians (IQR) for numerical variables. In univariate analysis, the Chi-square test was used to determine significance of association between OD and socio-demographic and clinical variables while the Student "t"-test was used to compare group means. Logistic regression model (multivariate analysis) was used to determine the independent risk factors for the occurrence of ODs using parameters that had a p-value of <0.25 on univariate analysis. All reported p-values <0.05 were considered statistically significant. Results: The mean age of the participants was 41.1 ± 10.0 years; and females were in the majority (65.8%). Over 40% of them were rural dwellers, 50.4% belonged to the lower socioeconomic class, and 55% had a monthly household income less than 20,000 Naira. Fifty percent (50%) of them had advanced immunosuppression at first presentation. The median duration of HAART (3 years) paralleled the median duration of HIV diagnosis (3.4 years) and HAART adherence rate was 78%. The overall prevalence of ODs was found to be 22.4%. Among the 76 patients diagnosed with ODs, the leading conditions were candidiasis (38.2%), TB (34.2%), dermatitis (25%), chronic diarrhoea (6.6%) and sepsis (6.6%). The independent risk factors for the occurrence of ODs were household income less than 20,000 Naira (Adjusted odds ratio [AOR] = 2.4, 95% CI 1.1-5.1), HIV duration of less than 3 years (AOR= 2.1, 95% CI 1.1- 4.2), advanced WHO clinical stage at baseline (AOR= 8.1, 95% CI 4.0-16.4), baseline haemoglobin less than 10 g/dl (AOR= 2.9, 95% CI 1.3-56.1), current CD4 cell count less than 200 cells/μl (AOR= 3.0, 95% CI 1.14-6.2), and HAART non-adherence (AOR= 5.4, 95% CI 2.6-11.2). Past history of TB was found to be a strong predictor of TB (AOR= 5.3, 95% CI 1.4-20.2). Conclusions: Opportunistic diseases are common in patients receiving HAART in Nigeria and candidiasis and TB remain the leading conditions. Late presentation and HAART non-adherence are among the strongest risk factors for ODs in patients receiving HAART. Others include duration of HIV diagnosis less than 3 years, presence of anaemia at the time of first presentation and having a low CD4 cell count while on HAART. Beyond these clinical risk factors, poverty increases the risk of developing an OD during HAART and may emerge a strong determinant of HIV-related ODs in developing countries. Recommendations: A high index of suspicion for ODs remains necessary in HAART patients. Health education on HIV screening and early presentation should be intensified. PLHIV who are anaemic before commencement of HAART, those with low CD4 cell count despite HAART use, and low-income earners should become target groups for a more aggressive evaluation for ODs. Prophylaxis for TB and fungal infections in the absence of active disease should be widely implemented in developing countries. HAART adherence should be intensified.

The introduction of highly active antiretroviral therapy (HAART) has resulted in a significant decrease in the mortality and morbidity associated with the acquired immunodeficiency syndrome (AIDS). Several problems are associated with HAART and include high costs of treatments, poor availability of drugs in low-income countries, poor compliance, severe adverse effects and drug resistance. Therefore, the focus of current research is the development of new antiretroviral drugs, improved treatment strategies and the discovery of new drugs derived from plants. Green tea (GT) and its active constituent epigallocatechin gallate (EGCg) have been found to be protective against cancer, cardiovascular and neurodegenerative diseases and were found also to have antimicrobial, antimalarial and more importantly antiviral activity. EGCg, in vitro has been shown to inhibit the human immunodeficiency virus (HIV) viral enzymes reverse transcriptase and protease, destroy viral particles and interfere with the attachment of gp120 to cellular receptor CD4. The aims of this study were firstly to investigate the in vitro antiretroviral activity of GT and EGCg on the LP-BM5 defective murine leukemia virus (MuLV) that induces a disease in C57BL/6 mice similar to AIDS in humans and secondly to investigate the effects of GT and EGCg on the in vitro cytotoxicity and antiretroviral activity of current antiretroviral drugs zidovudine (AZT), indinavir (IDV), hydroxyurea (HU) and chloroquine (CQ). To achieve the above aims an in vitro model that represents cell-to-cell spreading of the LP-BM5 MuLV was developed. Firstly the presence of the LP-BM5-defective virus in the BM5 cell line was confirmed using transmission electron microscopy (TEM) to identify viral particles, PCR and RT-PCR were used to determine the presence of viral DNA and RNA respectively and viral infectivity was confirmed in C57BL/10 mice. The cytotoxicity of each drug and combination was evaluated with the MTT assay in the SC-1 cell line, the predominant cell type in the in vitro cell culture model. GT was the least cytotoxic, followed by AZT, IDV, EGCg, HU and CQ. Co-cultures (BM5:SC-1, 1:10000) that represented cell-to-cell transmission of the virus were established. Real time PCR for proviral DNA revealed that IDV, AZT and HU completely suppressed, CQ dose dependently reduced while GT and EGCg had no effect on viral transmission. Findings using AZT and IDV thus validated the use of this in vitro co-culture model for first line screening of new drugs and plant extracts. The effect of GT or EGCg in combination with AZT, IDV, HU or CQ was also evaluated as GT or EGCg could enhance the antiretroviral effects or decrease cellular toxicity of these drugs. For GT with AZT a mix of synergism and antagonism on cell toxicity was observed with little to no effect on the antiretroviral activity of AZT. Antagonism on cell toxicity was observed for GT with IDV, with no effect on the antiretroviral activity of IDV. In contrast EGCg significantly reduced the antiretroviral activity of IDV. A strong antagonistic effect was observed for GT with HU, with GT reducing the antiretroviral effect of HU. For combinations of AZT with EGCg and HU with EGCg a similar effect was observed as for AZT and HU respectively combined with GT. Synergism in cytotoxicity was observed between GT and CQ associated with a significant decrease in viral loads while EGCg combined with CQ had an opposite effect at higher concentrations. In conclusion, the in vitro co-culture model of BM5 and SC-1 cells was successfully used to evaluate combinations of GT and EGCg with AZT, IDV, HU and CQ. Interesting and often contradicting effects were observed, such as seen for IDV in combination with GT and EGCg as well as CQ in combination with GT and EGCg. These effects may be of clinical relevance and further investigation is warranted. / Dissertation (MSc)--University of Pretoria, 2009. / Anatomy / unrestricted

Due to the increasing availability of ART (antiretroviral therapy),HIV is starting to be seen as a chronic disease. This has several effects on families, one of which is the need to disclose their HIV status to children who were born with the illness. Potential barriers and available support structures with regards to paediatric HIV disclosure need to be considered before specific guidelines can be given to caretakers and health care providers. This study aimed to explore and describe the patterns of paediatric HIV disclosure or non-disclosure using a sample of caretakers or parents of children/adolescents who were born with HIV. The Disclosure Decision Making Model (DDMM) was used as a framework to understand the decision-making process that leads to either disclosure or non-disclosure. Qualitative data was gathered by means of in-depth, semi-structured interviews, conducted in English. Ten participants were recruited from a community health care centre that offers HIV counselling and testing in the Nelson Mandela Bay Health District. Data gathered was transcribed and analysed using thematic analysis. Lincoln and Guba’s model was used to determine the trustworthiness of the data. The two themes that emerged from the study were (1) caretakers wish to disclose HIV status to the child but identified barriers to doing this and, (2) caretakers identified factors that helped them to disclose the child’s status. This study provides a more in-depth understanding of the factors that influence disclosure in a resource-limited setting in the Eastern Cape.