Background: Long term survival of children living with HIV due to improved early access to antiretroviral therapy (ART) is contributing to a growing population of adolescents living with perinatally acquired HIV (PHIV+) at risk of developing chronic multisystem comorbidity. There is limited knowledge on the overall burden, progression and causes of morbidity in PHIV+ adolescents, especially in resource limited settings. Much of what is known about morbidity in PHIV+ adolescents relates to single organ system pathology and there is a lack of a holistic approach to PHIV+ adolescents and their overall health. The aim of this PhD project was therefore to investigate the spectrum and determinants of chronic morbidity, the progression of disease and intercurrent illness in PHIV+ adolescents on ART over a 4- year period. Methods: This was a prospective study of participants enrolled in the Cape Town Adolescent Antiretroviral Cohort (CTAAC), a longitudinal cohort study, that recruited 515 PHIV+ adolescents and 110 HIV negative (HIV-) adolescents matched by age from 7 health care sites in Cape Town, South Africa. Eligibility criteria included PHIV+ adolescents who were aged 9-14 years, who had been on ART for at least 6 months and were aware of their HIV status. All adolescents and caregivers gave informed consent/assent. Participants were followed 6-monthly with questionnaires, clinical examination with detailed pulmonary (lung function), neurocognitive (magnetic resonance imaging and a battery of neurocognitive tests), cardiovascular (echocardiogram and ECG) and laboratory investigations. Analyses for each specific objective of the PhD were developed. Three analyses used data from the enrolment visit and were primarily descriptive and two were longitudinal and examined the incidence of hospitalizations, QuantiFERON conversion (an interferon gamma release assay used to measure Mycobacterium tuberculosis infection) and Tuberculosis (TB) disease. Results: Five hundred fifteen PHIV+ and 109 HIV- participants had a median follow-up of 4.1 years (IQR: 3.7–4.6). At enrollment, PHIV+ adolescents had a median duration of ART of 7.6 years (IQR: 4.6–9.2), median CD4 count of 713 cells/mm3 (IQR: 561.0–957.5) and 387 (75%) had a viral load of <50 copies/mL. Neurocognitive impairment was present in more than half of the PHIV+ cohort (56.3% vs. 45.3% in HIV-, p=0.05) but renal impairment was rare (2.3% in PHIV+ vs. 2.1% in HIV-, p=0.89). Microalbuminuria was also rare (8.0 in PHIV+ vs. 9.0% in HIV-, p=0.80). Respiratory or cardiac impairment were more common in PHIV+ adolescents than in HIV- participants (27.1% vs. 14.7%, p=0.01 and 46.1% vs. 33.7%, p=0.03, respectively). Multisystem impairment (defined as impairment of ≥ 3 systems) was uncommon, with only 10% of PHIV+ adolescents having 4-system impairment. Metabolic abnormalities, such as insulin resistance (IR), were relatively common but IR rates did not differ compared to HIV- adolescents (18 vs. 20%, p= 0.17). Incidence rates for hospitalization were 6.6 per 100-person-years (PY) in PHIV+ adolescents, three times that of HIV- adolescents. Sixty percent of hospitalization episodes were due to non-infectious causes and 24% due to infectious causes, of which pneumonia and TB were the predominant causes. PHIV+ adolescents had a substantially higher incidence of TB disease than HIV- adolescents (2.2/100 PY, 95% CI 1.6-3.1 vs. 0.3/100 PY, 95% CI 0.04-2.2), despite a similar rate of TB infection, as measured by QuantiFERON positivity. TB disease was associated with low CD4 counts and high viral loads in PHIV+ adolescents. Conclusion: Chronic single system morbidity experienced by PHIV+ adolescents on ART was common and merits further study, as this population begins to engage in adult lifestyle factors, such as smoking and alcohol use, that may compound these abnormalities. However, multisystem morbidity was relatively rare. In addition, in a relatively small percentage of adolescents there were subclinical metabolic abnormalities (IR and microalbuminuria) that may result in increased morbidity especially with regards to diabetes and cardiovascular disease in later life. The high burden of hospitalization and intercurrent disease, mainly due to TB, could be prevented by proven strategies, such as TB preventive therapy and ensuring adherence to optimal ART regimens.

Includes bibliographical references. / The study objectives were to: determine the prevalence of perinatal mortality (PNM) and causes of early neonatal deaths (ENNDs), describe socio-demographic factors of mothers with PNM and assess some of the associations with PNM at Kamuzu Central Hospital.

Includes bibliographical references / Background: In recent years there has been increasing debate about the impact of scaled-up ART and PMTCT programmes on the uptake and outcomes of reproductive health services, in particular the potential detrimental effects of HIV-care on the overall capacity of fragile health systems. The objective of this study was to evaluate changes in the uptake of reproductive health services as well as the main pregnancy outcomes during the scaling up of ART and PMTCT in Thyolo District, Malawi. Methods : Study design: retrospective descriptive district-wide cohort analysis for the period 2005 to 2009. Setting: Thyolo District, an area with around 600,000 inhabitants, an adult HIV-prevalence of 21% and a Total Fertility Rate of 5.7 in 2004. HIV-care including ART and PMTCT was scaled up since 2004 in Thyolo District to reach district-wide coverage in 2007. HIV-care is provided at district hospital, health centre and community health post levels. Outcomes: uptake of antenatal, intrapartum and postpartum care, family planning and treatment of sexually transmitted infections; infrastructural changes, and changes in maternal and perinatal pregnancy outcome. Data collection and analysis: data were collected from facility antenatal, intrapartum and postpartum records, as well as from MoH and MSF databases maintained for routine programme monitoring. Chisquare tests were performed comparing the baseline year (2005) with the year of study end (2009). Results: Uptake of peripartum care had improved markedly by the end of the five-year study period: the percentages of pregnant women who took up antenatal, intrapartum and postpartum care increased by 30%, 25% and 20% respectively. The number of family planning consultations increased by almost 50% and the number of women treated for sexually transmitted infections more than doubled. Interactions between HIV-care and general reproductive health care had positive effects on key health system components, including governance, health financing, human resources and drug supply. Reliable pregnancy outcome indicators for the entire observation period were difficult to obtain due to likely under-reporting of facility-based maternal and perinatal mortality. However, previously documented results from Thyolo show a reduction of facility-based severe maternal complications, including uterine rupture, between 2007 and 2009. Conclusions: Uptake of reproductive health services and facility-based maternal outcomes increased markedly during the period of HIV scale–up. This implies that the scale up of HIV-care did not inhibit, and likely increased, uptake of reproductive health services, while quality improvements in perinatal care could still be successfully implemented. The finding that ART and PMTCT care may be successfully integrated into broader reproductive health services with satisfying outcomes is a strong argument for continued scale up of ART and PMTCT in similar settings.

Includes abstract. Includes bibliographical references.

Includes bibliographical references. / Syphilis is a common sexually transmitted disease in South Africa and infection acquired during pregnancy is associated with an increased rate of miscarriage, stillbirth, preterm labour, intra uterine growth restriction (IUGR), neonatal death and congenital syphilis in the newborn. This study was undertaken in the Potchefstroom and Wolmaranstad Districts of the North West Province and was aimed at contributing to reducing perinatal mortality and morbidity within these districts. The objectives of this study were: + To determine the prevalence of syphilis amongst women attending antenatal and/or delivery care in the two selected districts. + To evaluate the effectiveness of antenatal screening and management of syphilis + To determine the perception of consumers (antenatal attendees) concerning screening for syphilis at antenatal clinics. + To determine the perception and understanding of health workers concerning the provision of antenatal syphilis screening and treatment. + To analyse any inadequacies revealed in the antenatal screening and management of syphilis in the two districts + To make recommendations for guidelines arising from the results of the research in order to improve syphilis screening in service delivery.

Background Many critically ill children in South Africa are cared for in regional hospitals by general Paediatricians. Critically ill adults and children are usually cared for in the same units. There is limited data on the numbers of children admitted and the outcomes of these children. Objective To describe the patient profile and outcomes of children admitted to a general high care unit (HCU) in a regional hospital in the Western Cape, South Africa. Methods This was a retrospective descriptive study of all children admitted to the HCU of George Regional Hospital during a one year period (2016). Demographic data, HIV, anthropometric data, immunisation status, diagnoses, medical interventions, length of stay, death or survival, and referral data to the tertiary paediatric intensive care unit (PICU) were collected. The PIM3 score and Standardized Mortality Ratio (SMR) was calculated. Results Thirty percent (144/468) of the HCU admissions were children. Most (70%) were admitted after hours. Half were under 9 months (range 3 days to 149 months). Sixty-five percent of the children required respiratory support and 45% needed inotropic support. Twenty percent of the children were transferred to the PICU. Twelve children (8,5%) died with most deaths (75%) occurring at regional level. Half of the deaths were due to sepsis with pneumonia (25%) and diarrhoea with shock (25%) accounting for the rest. The cumulative PIM3 score was 9.049 (95%CI 6.430-11.668) with an SMR of 1.326 (95%CI 1.028-1.866) observed. Conclusion Critically ill children accounted for a third of HCU admissions. Most children needed medical interventions. These require specific training and equipment that are often lacking. After hours admissions also put strain on limited staff. Most children were successfully discharged demonstrating a good outcome. This was achievable with good channels of communication and transport to a tertiary PICU.

Background: Breast milk provides optimal nutrition for infants. Human milk banks allow breast milk feeding for infants who do not have access to their own mother's milk. However, there are variable perceptions and attitudes towards human milk banking. Aim: This study aimed to evaluate community members' and healthcare workers' knowledge, perceptions and attitudes towards breast milk donation and use in Empangeni, KZN. Methodology: The research was conducted at a large regional hospital and an affiliated primary health care centre in the area. There were five focus group discussions held with healthcare workers employed at the two sites which explored the attitudes regarding donating and receiving breast milk. In addition, there were sixteen individual semi-structured interviews held with community members. Content analysis was used to analyse the data. Results and Discussion: Five main themes were found which includes: “Breastfeeding is an optimal feeding choice”, “Infant feeding choice”, “Misperceptions of HIV”, “Knowledge of DHM” and “Acceptance of DHM”. Though most participants were aware of breastfeeding benefits, there are poor breastfeeding rates within the area. Many mothers choose to formula feed their infants due to the fear of HIV transmission. There is also a fear of HIV transmission when using DHM. Acceptance of DHM was largely related to knowledge of DHM and exposure to its use. Conclusion: Healthcare workers need to be given updated, evidence-based information (in accordance with national guidelines and policies) to ensure appropriate counselling of caregivers. Furthermore, community awareness and engagement is required to improve breastfeeding rates and acceptability of DHM.

Bibliography: leaves 129-163. / There is little information on the aetiology and outcome of HIV-associated pneumonia in African children and no comprehensive data from South Africa. Studies of HIV-infected adult in Africa reported that the spectrum of pulmonary disease differs from that of developed countries with tuberculosis and pyogenic pneumonia predominating and Pneumocystis carinii pneumonia (PCP) occurring uncommonly. Knowledge of the aetiology and outcome of pneumonia is important for the development of paediatric management guidelines and of policies for allocation of resources especially in South Africa, where the HIV pandemic has resulted in increasing numbers of HIV-positive children requiring admission to hospital or intensive care units for pneumonia. Furthermore in countries with limited resources, development of cost effective diagnostic procedures to investigate the aetiology of pneumonia is necessary.

1. Introduction: Obtaining Informed consent is an ethical prerequisite for enrollment in clinical research. There is a perception that Informed consent documents used in biomedical research are lengthy, overly complex and above the reading capability of typical research participants. In South Africa, ethical committees regulating research on human participants (HRECs) are mandated by the Department of Health’s National Health Research Ethics Council’s (NHREC) guidelines to ensure that researchers have made special considerations for vulnerable groups when conducting research. This includes considerations made for populations with low literacy. For example, the Standard Operating Procedure (SOP) of the University of Cape Town’s Human Research Ethics Committee (UCTHREC), requires that the language used in Informed consent documents should be directed at a reading level of grade 6 to 8 and that common, everyday words should be used rather than complex language syntax. The HREC expects researchers to translate the approved English version documents into local languages such as isiXhosa and Afrikaans. Since ethics committee focus approval on the English language consent documents and only acknowledge translated versions, a potential gap in this process is whether the translated versions meet the same required readability levels. This study aims to investigate whether translated versions of English language informed consent documents used at a single busy clinical research site are readable and meet the readability levels specified by UCTHREC. 2. Methodology: A quantitative descriptive statistical design was used to explore readability levels of informed consent documents used at a single clinical research facility based in a semi-rural community. Informed consent documents approved by UCTHREC over the past thirteen years (2004 to 2017) that met the inclusion criteria were analysed for readability. The LIX readability test tool was used to calculate readability scores and the levels of reading difficulty. These scores were then matched to a grade level conversion chart to determine the equivalent number of education years required to be able to easily understand the information. Readability levels were determined for isiXhosa and Afrikaans translations of the documents and compared to the levels of the English document. 3. Results: The results indicate that informed consent documents used at this single clinical research facility, independent of language type, are difficult to read. A total of 259 sub-sections of informed consent documents from 10 different studies were analysed. The analysis showed that informed consent documents were classified as “very difficult to read” according to the LIX readability tool in a large proportion of English, isiXhosa and Afrikaans languages: 41 (16%), 255 (98%), and 85 (33%) of informed consent sections respectively. Of all the subsections of English, isiXhosa and Afrikaans documents respectively, 98 (38%), 0 (0%) and 126 (49%) were classified as “difficult to read”, while 79 (31%), 3 (1%) and 38 (15%) were found to have an “average” readability level. Twenty eight (11%), 1 (0%) and 10 (4%) were found to be “easy to read” and 13 (5%), 0 (0%) and 0 (0%) had a “very easy” readability level. The mean LIX readability scores across English, isiXhosa, and Afrikaans languages were respectively 42.27 (95% CI 41.20 – 43.34) corresponding to a readability level of “average”, 74.64 (95% CI 73.79-75.49), corresponding to “very difficult to read” and 46.73 (95% CI 45.66-47.8) “difficult to read”. These findings suggest a high level of difficulty in reading of the text in the Informed consent documents. 4. Conclusion: Translations of Informed consent documents used at a single busy clinical research site are difficult to read and are written at high school to tertiary reading level. These reading levels are above the recommended level prescribed by the site’s research ethics committee (UCTHREC). Local ethics committees should employ more stringent guidelines and checks to ensure readability of translated informed consent documents. Researchers and Sponsors should include readability outcomes in the design and with submissions of new protocols.

Includes bibliographical references / In this study we sought to more comprehensively analyse antigen-specific CD4 T cell responses induced by vaccination and to examine the effects of latent M. tb infection on these responses. We had two broad objectives: Firstly, to determine the effects of latent M. tb infection on epitope recognition by mycobacteria-specific CD4 T cells and to design HLA class II tetramers for detection of these cells. Secondly, to characterise antigen-specific CD4 T cells following vaccination with the novel vaccine candidate, H1:IC31, by measuring transcriptomic, phenotypic and functional attributes, and to determine the effects of latent infection on these responses. Firstly, we found that acquisition of M.tb infection did not alter the breadth and/or pattern of Ag85A/ B CD4 T cell epitopes recognised. We determined the HLA allele restriction of identified epitopes, and designed HLA class II tetramers for detection of Ag85-specific CD4 T cells. These results suggest that latent infection does not alter CD4 T cell epitope breadth within Ag85A/ B elicited by BCG vaccination and/or exposure to environmental mycobacteria. The second finding of this work is that underlying infection drives a more effector-like H1-specific CD4 T response after vaccination. Following vaccination M. tb-infected adolescents had higher frequencies of H1-specific CD4 T cells compared with uninfected adolescents. Additionally, H1-specific CD4 T cells from infected adolescents predominantly displayed a CCR7 - CD45RA - effector memory phenotype, had higher proportions of IFN-γ + TNF-α + IL-2 + cells, and expressed higher levels mRNA transcripts encoding effector molecules such as granzyme K and perforin, compared with uninfected adolescents. By contrast, H1-specific CD4 T cells in uninfected adolescents displayed a less differentiated memory phenotype, and had increased expression of central memory genes, compared to cells from infected adolescents. Thirdly, we found that Ag85B and ESAT-6-specific CD4 T cells exhibited markedly distinct transcriptomic profiles, memory phenotypes and cytokine expression patterns in M.tb infected adolescents. The data suggested that ESAT-6-specific cells preferentially drove the effector-like H1-specific response in M.tb infected adolescents. We conclude that while underlying M.tb infection does not affect the epitopes recognized by mycobacteria-specific CD4 T cells, but may promote and maintain effector memory antigen-specific CD4 T cells endowed with immediate effector function and tissue homing.