Thesis (PhD)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: Introduction In the era of antiretroviral therapy (ART), people living with Human Immunodeficiency Virus (HIV) now have prolonged life spans. An emerging trend of non- acquired immune deficiency syndrome (AIDS) related complications now prevails in the aging HIV infected population. Increased levels of inflammation and chronic immune activation are associated with HIV infection. In the era of ART people living with HIV are at an increased risk of cardiovascular disease (CVD). Platelets play a pivotal role in both inflammation and immune activation and upon activation platelets degranulate and secrete various inflammatory, coagulatory and adhesion molecules. Activated platelets express surface P-selectin (CD62P) and are a key component of the coagulation pathway and serve as a link between inflammation and thrombosis. Activated platelets have been implicated in inflammatory and cardiovascular disease and have been identified as immune cells that play a crucial role in pathogen recognition and modulation of immune cells during infections. Several antiviral and antibacterial properties of platelet alpha granule contents have been established. Platelet aggregometry remains the most widely used technique to evaluate platelet function even though this technique is limited by many pre-analytical variables. Platelet flow cytometry on the other hand offers a rapid measurement of platelet function in their physiological environment with minimal artefactual activation. Few studies have however reported on standardized methods to evaluate platelet function in the context of HIV. Platelet function remains unclear and data on HIV infected treatment naïve individuals remains scarce. The aim of this project was to examine the relationship between platelet function and immune activation in patients with HIV Materials and methods This study consisted of five sub-studies, firstly platelet indices and levels of platelet activation were determined in a cohort of 330 participants (185 HIV infected ARV naïve and 145 uninfected healthy controls) using; flow cytometry and haemotology analyzers. The relationship between these indices and markers of platelet activation, disease progression and immune activation were assessed. Furthermore, levels of platelet activation and aggregation were evaluated in a cohort of 82 participants (41 HIV infected (ARV naïve) individuals and 41 uninfected healthy controls), using a novel whole blood flow cytometry based functional assay. These baseline levels were then correlated with markers of immune activation and disease progression in HIV. In a subsequent study, platelet function in a cohort consisting of 58 HIV infected (ARV naïve) and 38 uninfected controls was evaluated using flow cytometry. Platelet response was measured post stimulation with adenosine diphosphate (ADP) at concentrations known to induce reversible (0.04mM) and irreversible (0.2mM) platelet aggregation. In order to assess platelet function in HIV, platelet response was evaluated in a cohort consisting of 58 HIV infected (ARV naïve) and 38 uninfected controls. Platelets were activated using varying concentrations of ADP, arachidonic acid (AA) and collagen and platelet function was measured using flow cytometry. Levels of circulating platelet leukocyte aggregates (PLAs) were also measured using flow cytometry in a cohort consisting of 35 HIV-infected (ARV naïve) individuals and 32 uninfected healthy controls. Associations between PLAs, immune activation and disease progression in HIV infected individuals were determined. The final study evaluated platelet aggregates, platelet derived microparticles (PMPs) and microparticles (MPs) in a cohort consisting of 46 HIV infected (ARV-naïve) and 40 uninfected healthy controls. Associations between MPs, PMPs, platelet aggregates and markers of immune activation and disease progression were evaluated. Results HIV infected individuals showed decreased mean platelet volume levels (HIV mean 7.91 ± 0.85 vs. 8.52 ± 1.12, p<0.0001) that directly correlated with CD4 counts (r=-0.2898, p=0.0075) and viral load (r=0.2680, p=0.0177). Platelet distribution width (PDW) levels directly correlated (r=0.3455, p=0.0362) with active coagulation and inversely correlated (r=-0.3666, p=0.0463) with platelet aggregation. HIV infected individuals showed increased levels of platelet activation (%CD62P median 11.33[5.96-29.36] vs. control group 2.48[1.56-6.04], p=0.0001). In HIV, platelet function is retained and platelets showed increased response to submaximal concentrations of endogenous agonists. HIV infected individuals showed increased levels of circulating platelet monocyte aggregates (25.26[16.16-32.28] vs. control group 14.12[8.36- 18.83], p=0.0001) that directly correlated with markers of immune activation; %CD38/8 (r=0.54624, p=0.0155), viral load (r=0.633, p<0.009). Furthermore we report on increased levels of circulating MPs (median %MPs 1.7[0.95-2.83] vs. Control group 1.12[0.63-1.57], p=0.0160); PMPs (median %PMPs 26.64[11.33-36.62] vs. Control group 20.02[18.08-26.08], p=0.0133); activated PMPs (median CD62P MFI 3.81[3.46-4.54] vs. Control group 3.41[3.16-3.6], p=0.0037) and platelet aggregates (Median %CD62P 14.10[5.49-39.94] vs. Control group 0.17[0.10-10.99], p= 0.0097) in HIV infected asymptomatic individuals. Conclusion This study supports the potential use of the MPV and PDW as readily available markers of platelet activation and immune activation in HIV. We also showed elevated levels of activated platelets in HIV infected individuals that were hyper responsive to endogenous agonists in a concentration dependent manner. Platelet flow cytometry is a rapid and valuable technique in the evaluation of platelet function in HIV. The measurement of platelet function using flow cytometry allows the evaluation of platelet signalling pathways that may be modified in HIV infected individuals. Lastly we describe an optimized whole blood flow cytometry based assay for the evaluation of circulating microparticles (MPs), platelet derived microparticles (PMPs) and levels of activated platelets and aggregates which mimics the in vivo physiological environment of MPs. To the best of our knowledge, this study is the first to report on a novel approach in evaluating platelet function in HIV using a series of optimised whole blood flow cytometry based platelet assays. In addition, minimal work has been performed previously on platelet function in the context of HIV-infection; and particularly in a cohort of asymptomatic, untreated patients as defined for this study. / AFRIKAANSE OPSOMMING: Inleiding In die era van antiretrovirale terapie (ART), het mense wat met die menslike immuniteitsgebreksvirus (MIV) leef, het nou 'n verlengde lewensduur. 'N opkomende neiging van nie-verworwe immuniteitsgebreksindroom (vigs) heers nou in die verouderende MIV-besmette bevolking. Verhoogde vlakke van inflammasie en chroniese immuun aktivering word geassosieer met MIV-infeksie en in die era van ART loop mense wat met MIV leef, 'n verhoogde risiko van kardiovaskulêre siekte (KVS). Plaatjies speel 'n belangrike rol in beide inflammasie en immuun aktivering en met aktivering degranulate en skei plaatjies verskeie inflammatoriese, coagulatory en adhesie molecule af. Geaktiveerde plaatjies druk oppervlak P-selectin (CD62P) is 'n belangrike komponent van die stollings weg en dien as 'n skakel tussen inflammasie en trombose. Geaktiveerde plaatjies is in beide inflammasie en kardiovaskulêre siekte betrokke en is geïdentifiseer as immuun selle wat 'n deurslaggewende rol speel in die patogeen erkenning en modulasie van immuun selle tydens infeksies. Verskeie antivirale en antibakteriese eienskappe van plaatjie alpha korrel inhoud is vasgestel. Plaatjie aggregometry bly die mees gebruikte tegniek om plaatjie funksie te evalueer, alhoewel hierdie tegniek is beperk deur baie pre-analitiese veranderlikes. Plaatjie vloeisitometrie aan die ander kant bied 'n vinnige meting van plaatjie funksie in hul fisiologiese omgewing met 'n minimale artefactual aktivering. Min studies het egter berig op gestandaardiseerde metodes om plaatjie funksie in die konteks van MIV te evalueer. Plaatjie funksie is steeds onduidelik en data oor MIV besmet behandeling naïef individue bly skaars. Die doel van hierdie projek was om die verhouding tussen die plaatjie funksie en immuun aktivering in pasiënte met MIV te ondersoek. Materiaal en metodes Hierdie studie het bestaan uit vyf sub-studies. In die eerste plekis plaatjie indekse en vlakke van plaatjie aktivering bepaal in 'n groep van 330 deelnemers (185 MIV-besmette ARV naïef en 145 onbesmette gesonde kontrole) met behulp van vloeisitometrie en hematologie ontleders. Die verhouding tussen hierdie indekse en merkers van plaatjie aktivering, die siekte se progressive en immuun aktivering is beoordeel. Verder is die vlakke van plaatjie aktivering en samevoeging in 'n groep van 82 deelnemers (41 MIV-besmette (ARV naïef) individue en 41 onbesmette gesonde kontrole) geëvalueer, met behulp van 'n nuwe vol bloed vloeisitometrie gebaseerde funksionele toets. Hierdie basislyn vlakke is dan gekorreleer met merkers van immuun aktivering en die progreessie van die siekte in MIV. In 'n daaropvolgende studie, is plaatjie funksie in 'n groep wat bestaan uit 58 MIV besmet te (ARV naïef) en 38 onbesmette beheer geëvalueer met behulp van vloeisitometrie. Plaatjie reaksie is na stimulasie gemeet met adenosine diphophate (ADP) by konsentrasies bekend omkeer (0.04mM) te oorreed en onomkeerbaar (0.2mm) plaatjie aggregasie. Ten einde plaatjie funksie in MIV te evalueer, is plaatjie reaksie in 'n groep wat bestaan uit 58 MIV-besmette (ARV naïef) en 38 onbesmette kontrole geëvalueer. Die plaatjies is geaktiveer deur gebruik te maak van wisselende konsentrasies van ADP, is aragidoonsuur (AA) en kollageen en plaatjie funksie gemeet met behulp van vloeisitometrie. Vlakke van sirkulerende plaatjie leukosiet gemiddeldes is ook gemeet met behulp van vloeisitometrie in 'n groep wat bestaan uit 35 MIV-positiewe (ARV naïef) individue en 32 onbesmette gesonde kontrole. Assosiasies tussen leukosiet gemiddeldes, immuun aktivering en die progressive van ie siekte in MIV-besmette individue is ook bepaal. Die finale studie het plaatjie-gemiddeldes, plaatjie afgelei mikrodeeltjies en mikrodeeltjies geëvalueer in 'n groep wat bestaan uit 46 MIV besmet (ARV-naïewe) en 40 onbesmette gesonde kontrole. Assosiasies tussen mikrodeeltjies, plaatjie afgelei, plaatjie gemiddeldes en merkers van immuun aktivering en die siekte se progressie is geëvalueer. Resultate MIV-besmette individue het gedaalde gemiddelde plaatjie volume vlakke getoon (HIV gemiddelde 7,91 ± 0,85 8,52 ± 1,12 teen, p <0,0001) wat direk gekorreleer het met CD4-tellings (r = -0,2898, p = 0,0075) en virale (r = 0,2680, p = 0,0177). Plaatjie verspreiding breedte vlakke het direk gekorreleer met (r = 0,3455, p = 0,0362) met 'n aktiewe koagulasie en omgekeerd gekorreleer (r = -0,3666, p = 0,0463) met plaatjie aggregasie. MIV-besmette individue het verhoogde vlakke van plaatjie aktivering getoon (% CD62P mediaan 11,33 [5,96-29,36] teen kontrole groep 2,48 [1,56-6,04], p = 0,0001). In MIV, was plaatjie funksie behou en plaatjies het 'n verhoogde reaksie op submaksimale konsentrasies van endogene agoniste getoon. MIVbesmette individue het verhoogde vlakke van sirkuleer plaatjie monosiet-gemiddeldes gedemonstreer (25.26 [16,16-32,28] teen kontrole groep 14,12 [8,36-18,83], p = 0,0001) wat direk gekorreleer het met merkers van immuun aktivering; % CD38 / 8 (r = 0,54624, p = 0,0155), virale lading (r = 0,633, p <0,009). Verder rapporteer ons op verhoogde vlakke van sirkulerende mikrodeeltjies (mediaan% LP 1.7 [0,95-2,83] teen kontrole groep 1,12 [0,63-1,57], p = 0,0160); PMPs (mediaan% PMPs 26,64 [11,33-36,62] teen kontrole groep 20,02 [18,08-26,08], p = 0,0133); geaktiveer PMPs (mediaan CD62P MFI 3,81 [3,46-4,54] teen kontrole groep 3,41 [3,16- 3,6], p = 0,0037) en plaatjie gemiddeldes (Mediaan% CD62P 14,10 [5,49-39,94] teen 0.17 [0,10- 10,99], p= 0.0097) in MIV besmet asimptomatiese individue. Gevolgtrekking Hierdie studie ondersteun die potensiële gebruik van die MPV en PDW as waardevolle geredelik waardevolle merkers van plaatjie aktivering en immuun aktivering in MIV. Ons het ook getoon verhoogde vlakke van geaktiveer de plaatjies in MIV-besmette individue getoon wat hyper reageer op endogene agoniste was in 'n konsentrasie-afhanklike wyse. Plaatjie vloeisitometrie is 'n vinnige en waardevolle tegniek in die evaluering van plaatjie funksie in MIV. Die meting van plaatjie funksie gebruik vloei cytometry maak die evaluering van plaatjie sein paaie wat in MIVgeïnfekteerde individue verander moontlik. Laastens het ons beskryf 'n hele bloed vloeisitometrie gebaseer de toets vir die evaluering van sirkulerende mikrodeeltjies, plaatjie afgelei mikrodeeltjies en vlakke van geaktiveer plaatjies en gemiddeldes wat lyk soos die in vivo fisiologiese omgewing van MP's. Na die beste van ons kennis, is hierdie studie die eerste om te rapporteer oor 'n nuwe benadering in die evaluering van plaatjie funksie in MIV met behulp van 'n reeks van new hele bloed vloeisitometrie gebaseer de plaatjie toetse. Daarbenewens is minimale werk voorheen uitgevoer op die plaatjie funksie in die konteks van MIV-infeksie; en veral in 'n groep van asimptomatiese, onbehandelde pasiënte soos vir hierdie studie. Hierdie projek het bewyse bygevoeg tot die teorie dat plaatjies, in MIV, kan 'n skakel wees tussen die aktiewe inflammatoriese reaksie en die toename in die aantal trombotische en kardiovaskulêre siekte waargeneem in pasiënte wat met hierdie siekte saamleef.

MSc (Med), Epidemiology and Biostatistics, Faculty of Health Sciences, University of the Witwatersrand / Objectives: To evaluate differences in virologic outcomes between adolescents and pre-adolescents initiated on HAART and to determine the patient baseline variables associated with virologic suppression. Design: Retrospective cohort study using routinely collected clinic and outcome data. Setting: Public sector HIV paediatric facility at Harriet Shezi Children’s Clinic (Chris Hani Baragwanath Hospital) Soweto, South Africa. Patients: HIV infected pre-adolescents (5 to < 11 years) and adolescents (11 to <18 years) initiating HAART between 1 April 2004 and 31 December 2008. Main outcomes and measures: Primary: virologic suppression (HIV viral load ≤ 400 copies/ml) and viral rebound (single HIV viral load ≥ 400 copies/ml after initial suppression) at 24, 48, 72 and 96 week follow up intervals. Secondary: determination of baseline variables associated with virologic suppression. Survival analysis was performed using the Kaplan Meier method and modelling was based on Cox proportional hazards. Results: Both groups exhibited similar incidence rates of virologic suppression by the 24th week from HAART initiation. Adolescents had a slightly lower incidence rate of early virologic suppression in comparison to pre-adolescents (197/100 person years vs. 203/100 person years). However, the observed difference was not statistically significant at 5% significance level (IRR: 0.97, 95%CI: 0.81 - 1.15). In a sub-group of children who had not virologically suppressed by the 24th week (168 days) of follow up, adolescents were 42% less likely to achieve virologic suppression after this time point than pre-adolescents ([IRR: 0.58, 95%CI: 0.35, 0.93). In the sub-group of all female participants, lower hazards of virologic suppression by the 24th week (aHR 0.76, 95%CI 0.59-0.99) and 96th week (aHR 0.70, 0.55-0.90) of follow up were observed among female adolescents when compared with female pre-adolescents. Additionally, clinically advanced disease was observed as a risk factor for non-virologic suppression by the 96th week of follow up among participants of all ages (aHR 0.75, 95%CI 0.64 -0.87). After 60 weeks from the initial virologic suppression, adolescents were twice more likely to experience rebound after this point than pre-adolescents (IRR: 2.33, 95%CI: 1.00 - 5.13). Conclusion: Given the potential for resistant strains of the HIV virus and the public health threat this presents, health care teams face complicated dilemmas regarding initiation of HAART to adolescents, particularly female adolescent patients who are likely to be non-adherent. Findings from the study advocate for intensified adherence and treatment support for all adolescents initiated on HAART to achieve virologic suppression within the first 6 months of treatment, a time after which they have been shown to exhibit inferior virologic suppression rates. Once virologic suppression has been attained, adolescents require prolonged treatment support to maintain long term virologic suppression at levels observed among pre-adolescents. We recommend further research into the comparison of virologic outcomes between pre-adolescents and adolescents on HAART, through prospective study designs. Qualitative study designs are also important to bridge the knowledge gaps on the barriers to HAART encountered by female adolescents.

Background: During the 1980s, the fear of HIV spread over the world. Health professionals'attitudes to patients with HIV, was negatively impacted because of their fear to be infected.Patients with HIV have therefore,during disease history's first two decades, experienced stigma and discrimination in the response from health professionals. Because of the increasing knowledge of HIV it is of interest to study patients' contemporary experiences of the encounter with health professionals. Aim:To explore how patients with HIV experiencing the meeting with health professionals. Method:Literature study with seven qualitative and three quantitative articles. Results:Two themes were found; to be discriminated and to be powerless and extradited. To be discriminated describes that patients in several cases been treated differently than others, by health professionals.To be powerless and extradited describes that patients are not allowed tobe involved in their care and they have distrust to health care providers.Conclusion:Patients with HIV experience discrimination, excessive precautions and ignorance which cause a care suffering. It is important that the nurse is aware of the deficiencies in the treatment to work towards a good care relationship.There is a great need for further research regarding to explore how patients with HIV experiencing the treatment from health professionals.

Orientador: Antonio Zuliani / Resumo: A progressão da doença na criança infectada pelo HIV associou-se à elevação do nível sérico de IgE total em alguns estudos. O mecanismo responsável por esta elevação ainda não foi claramente elucidado. O desbalanço na produção e liberação de citocinas de perfil Th1 e Th2, que ocorre após a infecção pelo HIV, tem sido proposto como um possível mecanismo para a elevação da IgE. Foram avaliadas neste estudo, 29 crianças de ambos os sexos, infectadas pelo HIV, acompanhadas no Ambulatório de Imunologia Pediátrica da Faculdade de Medicina de Botucatu-UNESP, com idade variando de 3 a 182 meses, com o objetivo de analisar os níveis séricos de IgE nessas crianças e sua correlação com presença de categorias clínicas e imunológicas mais graves, carga viral elevada e aumento da prevalência de alergia. A classificação clínica destes pacientes mostrou duas crianças (6,9%) na categoria N, sete (24,14%) na A, 12 (41,38%) na B e oito (27,58%) na C. Já a classificação imunológica mostrou três crianças (10,3%) na categoria 1, 16(55,2%) na 2 e 10 (34,5%) na 3. Após a aplicação do questionário alergológico, 11 crianças (37,93%) apresentaram história positiva de sintomas alérgicos, e quatro destes pacientes (13,79%) apresentaram teste cutâneo de hipersensibilidade imediata positivo a um ou mais dos aeroalérgenos testados. Os resultados mostraram níveis elevados de IgE em 17 crianças (58,62%), e estes foram numericamente maiores nos pacientes pertencentes à categoria clínica mais grave (C) em relação àqueles das outras categorias clínicas, mas sem diferença estatisticamente significante. Não foi encontrada diferença entre a freqüência de crianças com IgE elevada pertencentes às categorias clínicas e imunológicas mais graves e aquelas mais leves... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The progression of the disease in the infected child by HIV toke part in the elevation of the serum level of total IgE in some studies. The mechanism responsible for this elevation was still not clearly elucidated. The oscillation in the production and liquidation of Th1 and Th2 cytokines, that occur after the infection by HIV, have been proposed as a possible mechanism to the IgE elevation. In this study was evaluated 29 children of both sex, infected by HIV, accompanied in the Clinic of Pediatric Immunology of Botucatu Medical School - UNESP, with ages from 3 to 182 months, with the objective of analyze the serum levels of IgE in these children and the co-relation with the presence of the categories clinic and immunological more severe, high load viral and increase of the allergic diseases prevalence. The clinic classification of these patients showed two children (6,9%) in N category, seven (24,14%) in B and eight (27,58%) in C. While the immunologic classification showed three children (10,3%) in the category 1, sixteen (55,2%) in the 2 and ten (34,5%) in the 3. After the application of the allergologic questionnaire, eleven children (37,93%) presented positive history of allergic symptoms, and four of these patients (13,79%) presented positive immediate cutaneous hypersensitive test to one or more of the inhalant allergens tested. The outcomes showed high levels of IgE in 17 children (58,62%), and these were numerically greater in the patients in the more severe clinic category (C) in relation to those of the others clinic categories, but without significant statically difference. The difference between the frequency of children with high IgE in the clinic and immunologic categories more severe and that more soft was not founded. The load viral values were significantly lower in the group... (Complete abstract, click electronic access below) / Mestre

Made available in DSpace on 2014-06-11T19:33:27Z (GMT). No. of bitstreams: 0 Previous issue date: 2001Bitstream added on 2014-06-13T21:06:10Z : No. of bitstreams: 1 ripari_vr_me_botfm.pdf: 630015 bytes, checksum: a0b3099a4a3f8f782d7e68393790552a (MD5) / A progressão da doença na criança infectada pelo HIV associou-se à elevação do nível sérico de IgE total em alguns estudos. O mecanismo responsável por esta elevação ainda não foi claramente elucidado. O desbalanço na produção e liberação de citocinas de perfil Th1 e Th2, que ocorre após a infecção pelo HIV, tem sido proposto como um possível mecanismo para a elevação da IgE. Foram avaliadas neste estudo, 29 crianças de ambos os sexos, infectadas pelo HIV, acompanhadas no Ambulatório de Imunologia Pediátrica da Faculdade de Medicina de Botucatu-UNESP, com idade variando de 3 a 182 meses, com o objetivo de analisar os níveis séricos de IgE nessas crianças e sua correlação com presença de categorias clínicas e imunológicas mais graves, carga viral elevada e aumento da prevalência de alergia. A classificação clínica destes pacientes mostrou duas crianças (6,9%) na categoria N, sete (24,14%) na A, 12 (41,38%) na B e oito (27,58%) na C. Já a classificação imunológica mostrou três crianças (10,3%) na categoria 1, 16(55,2%) na 2 e 10 (34,5%) na 3. Após a aplicação do questionário alergológico, 11 crianças (37,93%) apresentaram história positiva de sintomas alérgicos, e quatro destes pacientes (13,79%) apresentaram teste cutâneo de hipersensibilidade imediata positivo a um ou mais dos aeroalérgenos testados. Os resultados mostraram níveis elevados de IgE em 17 crianças (58,62%), e estes foram numericamente maiores nos pacientes pertencentes à categoria clínica mais grave (C) em relação àqueles das outras categorias clínicas, mas sem diferença estatisticamente significante. Não foi encontrada diferença entre a freqüência de crianças com IgE elevada pertencentes às categorias clínicas e imunológicas mais graves e aquelas mais leves... / The progression of the disease in the infected child by HIV toke part in the elevation of the serum level of total IgE in some studies. The mechanism responsible for this elevation was still not clearly elucidated. The oscillation in the production and liquidation of Th1 and Th2 cytokines, that occur after the infection by HIV, have been proposed as a possible mechanism to the IgE elevation. In this study was evaluated 29 children of both sex, infected by HIV, accompanied in the Clinic of Pediatric Immunology of Botucatu Medical School - UNESP, with ages from 3 to 182 months, with the objective of analyze the serum levels of IgE in these children and the co-relation with the presence of the categories clinic and immunological more severe, high load viral and increase of the allergic diseases prevalence. The clinic classification of these patients showed two children (6,9%) in N category, seven (24,14%) in B and eight (27,58%) in C. While the immunologic classification showed three children (10,3%) in the category 1, sixteen (55,2%) in the 2 and ten (34,5%) in the 3. After the application of the allergologic questionnaire, eleven children (37,93%) presented positive history of allergic symptoms, and four of these patients (13,79%) presented positive immediate cutaneous hypersensitive test to one or more of the inhalant allergens tested. The outcomes showed high levels of IgE in 17 children (58,62%), and these were numerically greater in the patients in the more severe clinic category (C) in relation to those of the others clinic categories, but without significant statically difference. The difference between the frequency of children with high IgE in the clinic and immunologic categories more severe and that more soft was not founded. The load viral values were significantly lower in the group... (Complete abstract, click electronic access below)

In this thesis, some issues about the human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) have been addressed by concentrating on the stochastic modelling of the dynamics of the viruses. The aim of this thesis is to determine parameters such as the mean number of free HIV, infectious free HIV and non-infectious free HIV which are essential in determining incubation period of the virus, the disease progression of an infected individual and the efficacy of the treatment used. This thesis comprises of six chapters. The first two chapters are introductory to the viruses and reasons why HIV-1 is given priority over HIV-2 are given. The pathogenesis of the virus is addressed. This is because knowledge of the pathogenesis and strains of the virus has become essential in the study of HIV in vivo dynamics which is still paving ways into extensive research of the ways to contain the disease better. In chapter three the distribution functions of the HIV incubation period and seroconversion time are determined via stochastic models by building on previous work of Lui et al. (1988) and Medley et al. (1988). Also AIDS incidence projection was done using the Backcalculation method. Chapter four deals with the formulation of stochastic model of the dynamics of HIV in an infected individual. Two stochastic models are proposed and analysed for the dynamics of the viral load in a HIV infected person and the multiplication process of the virions inside an infected T4 cell. Also a numerical illustration of the stochastic models derived is given. In chapter five, the T4 cell count which is considered one of the markers of disease progression in HIV infected individual is examined. WHO has recently advocated that countries encourage HIV infected individuals to commence antiretroviral treatments once their T4 cell count is 350 cells per ml of blood. This is because when the T4 cell count is low, the T4 cells are unable to mount an effective immune response against antigens (and any such foreign matters in the body) and consequently, the individual becomes susceptible to opportunistic infections and lymphomas. We developed a stochastic catastrophe model to obtain the mean, variance and covariance of the uninfected, infected and lysed T4 cells; also the amount of toxin produced in a HIV infected person from the time of infection to the present time is derived. A numerical illustration of the correlation structure between uninfected and infected T4 cells, and infected and lysed T4 cells is portrayed. Antiretrioviral treatments were introduced while we await a cure. Treatment with single drug failed due to the fact that HIV evolved rapidly because of its high replication rate. Thus drug resistance to single therapeutic treatment in HIV infected individuals has promoted research into combined treatments. In chapter six a stochastic model under combined therapeutic treatment is derived. Mean numbers of free HIV, infectious free HIV and non-infectious free HIV are obtained. Variance and co-variance structures of our parameters were obtained unlike in previous work of Perelson et al. (1996), Tan and Xiang (1999). / Thesis (PhD)--University of Pretoria, 2009. / Statistics / unrestricted

Introduction: Diffuse large B-cell lymphoma, not otherwise specified (DLBCL NOS) is subdivided according to the cell-of-origin (COO) classification into germinal centre B-cell (GCB) and activated B-cell (ABC) subtypes, each with different molecular profiles and clinical behaviour. This study aims to describe the pattern of the COO subtypes, the proportion of Epstein-Barr virus (EBV) co-infection, and their influence on survival outcomes in a setting of high HIV prevalence. Materials and Methods: This retrospective cohort study included patients diagnosed with de novo DLBCL NOS at our tertiary academic centre in Cape Town, South Africa over a 14-year period. Immunohistochemical stains were performed for COO classification, according to the Hans algorithm. Tumour EBV co-infection was established by EBV-encoded ribonucleic acid in situ hybridisation (EBER-ISH) staining. The effect of the COO subtypes and EBV co-infection on overall survival were described by means of univariate, bivariate and multivariate analyses. Results: A total of 181 patients with DLBCL NOS were included, which comprised 131 HIV-uninfected and 50 HIV-infected patients. There was an equal distribution of GCB and ABC subtypes in the HIV-infected and HIV-uninfected groups. EBV co-infection was detected in 16% of the HIV-infected cases and in 7% of the HIV-uninfected cases (p=0.09). There was no significant difference in the incidence of EBV co-infection between the GCB and ABC subtypes (p=0.67). HIV-infected patients with CD4≥150 cells/mm3 had similar survival to HIV-uninfected patients (p=0.005). Multivariate regression analysis showed that in the HIVinfected group with marked immunosuppression (CD4 <150 cells/mm3), there was significantly poorer overall survival compared to the HIV-uninfected group (HR 2.4, 95% CI 1.3–4.1). There were no statistically significant differences in overall survival by DLBCL COO subtype. Conclusions: There was no difference in the proportion of DLBCL COO subtypes, regardless of HIV status. EBV co-infection was more common in the HIV-infected group, but less than described in the literature. Unexpectedly, there were no significant differences in survival outcomes between the GCB and ABC subtypes. Higher CD4 counts in the HIV-infected group had good survival outcomes, while lower CD4 counts predicted adverse survival outcomes. Further research is needed to explore the genetic mutational landscape of HIVassociated DLBCL.

ABSTRACT Regulatory T cells (Tregs) are CD4+ T lymphocytes that express the gene FOXP3 and suppress other cellular immune responses. Their role in HIV pathogenesis is uncertain. Regulatory T cell (Treg) levels were analysed in peripheral blood of HIV infected patients and controls in South Africa. Immunophenotypic analysis revealed significantly elevated levels of FOXP3 positive Tregs in HIV infected patients (median 6.8%) compared with controls (median 3.7%). Treg levels were inversely correlated with CD4+ T cell count. FOXP3 mRNA expression was dependent on choice of reference gene (GAPDH or 18sRNA) and did not correlate with FOXP3 protein expression analysed flow cytometrically. These findings illustrate that Tregs are elevated in the peripheral blood of patients with late stage HIV disease and suggest a role for Tregs in the clinical immune suppression seen in these patients. Tregs may prove to be useful therapeutic targets for intervention or as a prognostic monitoring tool.

Background: Breastfeeding amongst HIV-infected and HIV-exposed mother-infant dyads is a wide-ranging and persistent field in which more investigation is needed. The literature widely recognizes the multifactorial and syndemic nature of HIV and infant feeding, specifically pertaining to maternal and other breastfeeding-associated risks. Findings differed regarding breastfeeding and general developmental outcomes amongst HIV-exposed and HIV-infected infants when compared with HIV-unexposed infants. Evidence, however, suggests slight neurodevelopmental differences in HIV-exposed infants when compared with HIV-unexposed infants, suggesting possible feeding differences. Recent literature also indicated a lack of knowledge among allied health care staff regarding evidence-based counselling content to be provided to mothers concerning single option feeding, breastfeeding outcomes and risks in HIV-affected mother-infant dyads in South Africa. Owing to these varied findings related to HIV-affected mother-infant dyads, synthesising of knowledge regarding HIV, infant breastfeeding outcomes and associated risk factors is warranted. Objective: To critically appraise recent literature regarding breastfeeding outcomes and associated risks in HIV-infected and HIV-exposed infants using the PRISMA-P statement guidelines. Method: Five electronic databases were systematically searched to obtain English publications from the last ten years pertaining to breastfeeding outcomes and associated risks of HIV-infected and HIV-exposed infants and children. Grey literature sources were also included. Data were extracted according to various data items and were synthesised using thematic synthesis. Results: Of the initial 7151 sources identified, 42 articles were deemed eligible for final inclusion. The final selection included 19 cohort studies and two expert committee reports, classified as grey literature. The remaining 21 studies compromised of case-control, cross-sectional, and randomized controlled trial studies. The following themes were identified from the review objectives: breastfeeding outcomes, breastfeeding risk factors, infant growth and developmental outcomes and barriers and facilitators to feeding decisions. Most studies focused on HIV-exposed infants’ growth and developmental outcomes. Exclusive breastfeeding was confirmed to have the best outcomes for all infants, regardless of their HIV status, which in turn supports national and international policies. The most prevalent factors that made it difficult for mothers to breastfeeding were maternal factors affecting decision-making for breastfeeding, followed by biological risk factors. Conclusion: Knowledge regarding breastfeeding outcomes in HIV-exposed and HIV-infected infants remains lacking and further research is necessary. This review emphasised that the majority of HIV-affected mother-infant dyads reside in sub-Saharan Africa, illustrating that health professionals, especially those in sub-Saharan Africa (SSA), have to look beyond their traditional assessment and management focuses to include the factors that can impact successful exclusive breastfeeding. Addressing both infants’ needs and maternal HIV-related needs and risks on macro, meso, and microsystem levels is necessary. / Dissertation (MA (Speech-Language Pathology))--University of Pretoria, 2021. / Speech-Language Pathology and Audiology / MA (Speech-Language Pathology) / Unrestricted

Bakgrund: Hiv är ett folkhälsoproblem som cirka 30-35 miljoner människor runt om i världen lever med. I Sverige rapporteras 400-500 nya fall varje år. Att ha hiv kan leda till att människor utsätts för stigmatisering från omgivningen. Syfte: Syftet med denna litteraturöversikt är att belysa upplevelser av stigmatisering hos människor som har hiv. Metod: En litteraturöversikt genomfördes där tio vetenskapliga artiklar valdes med både kvalitativa och kvantitativa studier. Resultat: Resultatet presenterades i fyra huvudteman: Upplevelsen av social stigmatisering, Självstigmatisering hos människor som lever med hiv, Fysiskt avstånd och Att uppleva psykisk ohälsa. Diskussion: Resultatet har diskuterats utifrån omvårdnadsteoretikern Katie Eriksson om den caritativa vårdteorin samt fyra konsensusbegrepp som hon har beskrivit: den mångdimensionella hälsan, lidande- en del av hälsan, vårdande- att lindra patientens lidande och den unika människan. Resultatet har även diskuterats genom Erikssons tolkning av: försoning och värdighet. / Background: HIV is a public health problem that about 30-35 million people live with around the world. HIV. 400-500 new cases are reported each year in Sweden. Having HIV can lead to stigmatization from people around you. Aim: The experience of stigmatization in people who are living with HIV. Method: The literature review was based on ten scientific articles, both qualitative and quantitative studies. Results:  The results were presented in four main themes: Experiences of social stigmatization, Self-stigmatization with people who are living with HIV, Physical distance and Experiences of mental illness. Discussion: The result has been discussed based on nursing theorist Katie Eriksson´s theory about the caritative theory and the four consensus concepts she mentioned: the multi-dimensional health, suffering- a part of health, care- to relieve the patient´s suffering and the unique human. The result has also been discussed through Eriksson´s important concepts such as: atonement and dignity.