Purpose: To describe the clinical presentation, ocular complications and clinical implications of acute HZO in HIV positive patients. Method: Prospective descriptive clinical case series of 54 individuals aged 18 – 50 years with confirmed HIV infection and acute presentation of HZO. Results: A female preponderance (1.7:1) and mean age of 36.6 years (range 18 – 49 years) was recorded. The majority of patients were referred from CHC and only 28% of referred patients received appropriate antiviral treatment at the referral site. Mean duration of rash at presentation was 4.7 days (range 1 – 12 days) with 31% of patients presenting within 3 days of rash eruption. Patients attended a mean of 2.7 clinical visits. Equal proportions had known and unknown HIV serostatus at presentation. Mean CD4+ was 276 cells/mm3 (range 44 - 859 cells/mm3). 67% of patients had a CD4+ count < 350 cells/mm3. Periocular discomfort was the most common presenting symptom (70%); decreased VA (2%) was an uncommon presenting symptom. Multidermatomal involvement was uncommon (7%). At presentation normal VA was seen in 69% of patients and 94% had no global visual impairment. Corneal complications (89%) and intraocular inflammation (46%) were the most common ocular complications. Ocular complications at presentation and multiple complications were the rule (70% and 61%). Hutchinson sign was found to be of little clinical value. Visual outcome was fair, 22% of patients having residual visual impairment. Post-herpetic neuralgia was common (74%). Conclusion: HZO is a common HIV marker condition with ocular complications. It may have an application as an indication for the initiation of ARV treatment.

A Research Report Submitted to the School of Public Health, University of the Witwatersrand, Johannesburg, in Partial Fulfilment of the Requirements for the Degree of Master of Science in Medicine in the Field of Epidemiology and Biostatistics: March 25, 2013 / Background: More than 33 million people are estimated to be living with HIV worldwide. Sub-Saharan Africa bears a disproportionate share of the global HIV burden. An estimated 15 million people living with HIV in low and middle income countries were in need of (HAART) in December 2009. HAART services require advanced laboratory technologies to monitor disease progression and therapeutic response, which are scarce in developing countries. Several simple and widely available markers have been proposed for use in low income countries including total lymphocyte count (TLC), haemoglobin and body mass index. Methodology: This study is a secondary data analysis of prospectively collected cohort data from HIV positive adults. The study measured the effect of exposure variables of haemoglobin (Hb) and body mass index (BMI). All cause mortality was the outcome of interest. Crude estimates of mortality were made with Kaplan-Meier mortality curves. Cox proportional hazards models were used to estimate adjusted hazard ratios. Exposure status was considered at initiation period. Outcomes were measured from two weeks post initiation of treatment to a maximum of two years of follow-up period. A composite score was developed to estimate the overall risk of mortality. Results: A total of 11,884 patients who satisfied the inclusion criteria were included in the analysis. A total of 1,305 deaths were observed during the follow-up period, representing 10.2% of the cohort at baseline. Most of the deaths were observed during the first four months of follow-up period. Patients with moderated to severe anaemia experienced 2.6 (HR = 2.6, 95% CI 1.8 - 3.6) times greater hazard of mortality adjusted for possible confounders. Patients with very iv low BMI experienced twice (HR=2.0, 95% CI 1.6, -2.5) greater hazard of mortality adjusted for a list of predictors. Race, age at initiation, employment status, smoking, alcohol consumption, baseline TB and baseline WHO stage did not show significant effect in the multivariate cox regression model. A composite score was developed to estimate the overall risk of mortality in patients based on measurements of baseline BMI and haemoglobin. Cox regression model adjusted for CD4 cell count shows high risk patients experienced 4.7 (HR = 4.7, 95% CI 2.9 – 7.6) times greater hazard of mortality compared to patients in the low risk group. Patients in the medium risk group experienced 3.4 (HR = 2.6, 95% CI 2.6 – 4.4) times greater hazard of mortality as opposed to patients in the low risk group. Conclusion: Haemoglobin and body mass index provide excellent prognostic information independent of CD4 cell count in HIV positive patients newly initiated on HAART. They can be used to reliably predict mortality. Combining measurements of haemoglobin and BMI through composite scoring improves their predictive ability. They can have good clinical application in rural and remote facilities to screen patients for clinical and diagnostic services.

Both HIV and tuberculosis (TB) have been documented to have detrimental effects on the nutritional status of those infected and nutritional status is a strong predictor of disease progression and survival. Body composition measures can be used as a proxy for nutritional status and takes into account body fat, muscle and water. It constitutes Fat Mass(FM), Fat Free Mass (FFM), Total Body Water (TBW), Extracellular Water (ECW), Intracellular water (ICW), Daily Energy Expenditure (DEE), Basal Metabolic Rate (BMR), phase angle and BMI which can be analysed as separate outcomes. Its use in evaluation of nutritional status has been reported to give more accurate results than the use of weight alone. We compared body composition measures and changes over a 12 month period in patients with HIV alone to patients with HIV and TB.

HIV-associated sensory neuropathy (HIV-SN) is a common complication associated with human immunodeficiency virus (HIV)-infection. A common symptom of HIV-SN is pain. Variation at specific loci within certain candidate genes has been suggested to alter susceptibility to developing HIV-SN as well as the susceptibility to developing pain and the intensity of the pain experienced. Few studies, however, have been conducted in individuals of black African ancestry. The aim of the current research was to conduct an in-depth study, in a black Southern African population, of genes previously associated with susceptibility to developing HIV-SN (TNFA and surrounding genes and IL12B) and variations in pain susceptibility and intensity (GCH1, KCNS1, IL1B, IL6, CCL2 and CCR2) in other neuropathic pain states. Single nucleotide polymorphisms (SNPs) identified in the literature were supplemented with population appropriate tagSNPs to improve assessment of the genes in an African population. Genotyping of previously collected deoxyribonucleic acid (DNA) samples was carried out using a GoldenGate assay with VeraCode microbeads and data were read on an Illumina BeadXpress Reader. Data were statistically analysed to assess the association of the genetic variants with susceptibility to developing HIV-SN and pain and variability of pain intensity in those patients with painful HIV-SN. Although some SNPs and haplotypes in the genes investigated associated with HIV-SN susceptibility (TNFA region), pain susceptibility (TNFA region, IL12B, KCNS1, IL6 and CCR2) or pain intensity (TNFA region, KCNS1, IL1B and IL6), none of the results were consistent with that which has been found in previous studies in non-African populations. Reasons for this may be that associations are population-specific or model-specific. Limitations of the study included the use of a relatively small sample, the method of sampling (convenience sampling), genotyping failure and tagging inefficiency in some instances, and the fact that there is no Southern African population dataset to use for tagSNP selection. My findings emphasise the importance of conducting genetic association studies in separate ethnic groups.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements of the degree of Master of Science in Medicine in Pharmaceutical Affairs. / Many will be disappointed to learn that pharmacoeconomic evaluations provide information, not answers. Although pharmacoeconomics broadens the perspective taken in evaluating drug therapies, the final drug therapy decision is still influenced by clinician preferences, patient desires, and the working and politics of the healthcare delivery system”. 1 Globally and in South Africa there is an increasing pressure on healthcare resources. These pressures have exponents both in the supply and demand arms of the economic equation and have set the scene for the development of a new discipline in healthcare. Pharmacoeconomics can be defined as “the description and analysis of the cost of drug therapy of health care systems and society”. 2 Pharmacoeconomics assesses the ratio of the cost to the consequences of specific drug therapies using a technique called Cost Effective analysis which uses tools such as Cost Minimisation analysis, Cost Effective analysis and Cost Benefit analysis / IT2018

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of requirements for the degree of Master of Science in the School of Molecular and Cell Biology. Johannesburg, 2016. / Telomeres play significant roles in maintaining genome stability, regulating cell proliferation and apoptosis. The role of telomere biology and telomerase reactivation has been studied extensively in cancers. Telomerase has been previously associated with driving chronic kidney disease (CKD) advancement and most frequently due to HIV infection. However, the mechanism by which telomerase activation contributes towards disease progression beyond its canonical function of telomere maintenance is poorly understood. Telomerase is a ribonucleoprotein whose main function is telomere maintenance. Telomerase activity is dependent on expression of the rate-limiting human telomerase reverse transcriptase (hTERT) component. In addition to telomere maintenance, hTERT is implicated in other non-telomere related functions that promote cellular proliferation. Expression of hTERT is predominantly regulated at the transcription level where variation in promoter and minisatellite (MNS16A) sequences alter its expression. This variation has been implicated to confer susceptibility to diseases such as cancer and ageing disorders in non-African populations. Data on variation and pathogenicity of telomere-associated genes in African populations is limited and warrants further research. Thus bioinformatics analysis was performed to elucidate variation within the human TERT gene and promoter in different populations. The promoter, MNS16A and relative telomere length (RTL) were also evaluated in 159 African study participants with and without CKD. TERT common variants are equally distributed across populations with limited data on connection to the effects of the variants in African populations. Further bioinformatics analyses revealed significant difference (p<0.0001) in distribution of promoter variant rs2853669 between African and non-African populations. No common promoter mutations were identified in our study population. Interestingly, the long MNS16A variant suggested to increase TERT expression was significantly overrepresented in individuals with CKD regardless of HIV status. For the first time, a strong association of the long MNS16A variant with CKD regardless of HIV status is reported, implicating MNS16A as a potential risk factor in CKD.

M.Sc.(Med.) (Population Based Field Epidemiology) / Background Assessing HIV incidence over time in a rural population, largely characterized by high levels of migration and poverty is important to understand the dynamics of the spread of HIV infection. Understanding patterns of HIV infection is a key to defining the appropriate strategies for prevention of the disease especially in areas where information on HIV incidence is scarce, such as in Africa and South Africa in particular. Objectives and methods The main objective of this study is to measure the association between migration history and newly acquired HIV infection by sex. The specific objectives are to: (i) quantify median distance of migration by members of the cohort during the period of observation; (ii) measure the association between migration status and acquisition of HIV infection among males and females study participants. The current analysis is based on secondary data collected at the Africa Centre Demographic Surveillance System (DSS) in South Africa. Women aged 15-49 years and men aged 15-54 years were enrolled in the study and tested for HIV between 2003/5 and 2008. A Weibull survival model was used to determine the probability of HIV infection, subject to migration and possible confounders. Results For external migration, the median of external in-migration distance was 53.9 km, with a lower quartile of 27 km and upper quartile of 204 km while the median of external out-migration distance was 104.7 km, with a lower quartile of 52 km and upper quartile of 204 km. The total migration rate among males is 8.8 and for females the rate is 8.2 per 100 person-years (PYO). The majority of external migrants moved to Durban, which appeared to be the most important origin and destination for most migrants. Of the 9300 individuals enrolled in this study, 699 sero-converted. The HIV incidence rate among non-migrants males was 2.0/100 PYO (95% CI, 1.7 – 2.3) and for non-migrants females was 4.1/100 PYO (95% CI, 3.8 – 4.5) while the HIV incidence rates among migrants were higher for females in all categories: 2.0/100 PYO (95% CI, 1.3- 3.1) among internal migrants, 3.8/100 PYO (95% CI, 1.7- 8.5) for external in-migrant and among external out-migrants the HIV incidence rate was 3.2/100 PYO (95% CI, 2.3 – 4.5). For both genders, except internal migration showed a significant risk of HIV acquisition, other types of migration showed no significant association with HIV acquisition. Among other predictors, males who were in the age group 25-29 had the highest hazard of 3.75 times increased risk of HIV acquisition compared to the age group 15-19 [HR = 3.75, 95% CI (2.30 – 6.32), P < 0.001]. Females aged 20-24 years had 43% increased risk of HIV acquisition compared to the those aged 15-19 years [HR = 1.43, 95% CI (1.13 – 1.79), P = 0.002]. For marital status, females who had never been married and not engaged had 71% increased risk of HIV acquisition compared to those who were married, [HR = 1.71, 95% CI (1.09 – 2.68), P = 0.019]. Females with conjugal partners who were always resident and females with conjugal partners who were partial resident had a reduced risk of HIV acquisition of 41% [HR = 0.59, 95% CI (0.36 – 0.95), P = 0.031] and 38% [HR = 0.62, 95% CI (0.40 – 0.96), P = 0.034] respectively. Conclusion Rates of migration vary by age and gender in this cohort of repeat-testers of HIV. Younger individuals migrated more often and the majority of migrants moved to urban centres close to the study area. In terms of HIV incidence, for all covariates, females had higher rates of HIV acquisition than males. External migration does not appear to increase HIV acquisition for this cohort of repeat-testers of HIV, and those who internally migrated had a reduced risk of HIV acquisition. Based on these findings, public health efforts aimed at controlling the spread of HIV infection in this cohort should target at socio-economic condition, sexual behaviour and empowering of women in particular.

MSc (Med) Population-Based Field Epidemiology, Faculty of Health Sciences, University of the Witwatersrand, 2009 / Background: Sub-Saharan Africa continues to bear the brunt of the global HIV epidemic, with the epicentre located in Southern Africa. Of all the adult and children living with HIV globally in 2006, two-thirds (63%) were in sub-Saharan Africa.1 The epicenter of the HIV/AIDS epidemic in South Africa is located in the KwaZulu Natal province, where HIV incidence and prevalence continue to remain high and this has serious implications for HIV prevention and control programmes. Objectives i. To profile individuals who sero-converted during the period 2003-2007 in order to better target interventions. ii. To estimate the incidence rate for HIV during the period 2003 to 2007. iii. To identify factors associated with HIV infection at individual and household levels in Kwazulu-Natal. Methods This involved analysis data of a dynamic cohort study. The follow-up period was 2003-2007, and the study was a household-based HIV sero-prevalence survey of a population in Kwazulu Natal, South Africa, conducted by the Africa Centre for Health and Population Studies. The cohort comprised females aged 15 to 49 and males 15 to 54 years who participated in the baseline HIV sero-prevalence survey in 2003 and/ or subsequent surveys in 2005, 2006 and 2007. Individuals who participated in at least two surveys and had a negative HIV result on first enrolment were included in the analysis. Selected demographic, socio-economic, behavioural and geographic variables of the participants were obtained from the demographic surveillance system (DSS) database of the Africa Centre Demographic and Information System (ACDIS) for analysis. Profiles of recently HIV sero-converters were based on these variables and descriptive statistics used to compare the differences in sero-conversion between the different strata of each variable. Multiple logistic regression was used to investigate the association between variables of key interest. Results A total of 39, 738 individuals were surveyed for the four annual sero-prevalence surveys conducted from 2003-2007. Of these, 41.5% (n=16,491) were HIV negative on their first enrolment into the study, 11.6% (n=4610) were HIV positive on first enrolment, while 46.9% (n=18,637) had either participated in just one out of the four surveys, or were non-resident at baseline. These two categories of participants as well as those who tested HIV positive on first enrolment were dropped from the analysis. The final sample size used for analysis was 16,491 individuals and comprised 8,425(51.1%) females aged 15-49 years old and 8,066 (48.9%) males aged 15-54 years old. The incidence rate for HIV sero-conversion among the 16, 491 individuals included in the final analysis was 11.5 per 1000PYs during the follow-up period. In other words, 539 individuals sero-converted during 46818.15 person-years (PYs) at risk from 2003-2007. A significant proportion of the new HIV acquisitions (69.8%) occurred in households without any recently or previously infected household member, and women had a significantly greater risk of HIV infection(IR= 16.9 per 1000PYs; 95% CI: 15.33-18.640) compared to men(IR=5.9; 95% CI: 4.95-6.94) in this study area. Conclusion The younger age bracket (24-30 years old) was associated with significantly higher risk of HIV infection compared to the older age category. However, the age group 20-24 years bears the greatest burden of HIV pandemic in this community. Majority of seroconverters were rural dwellers but peri-urban dwellers had the greatest risk of HIV acquisition. The study also showed that attendance of a school or a training facility on a full-time basis during the follow-up period was protective for HIV acquisition compared. Also, attainment of standard 10 to 12 level of education was associated with a greater risk of HIV seroconversion. This can be attributed to the age of individuals at these levels of education and the associated high risk profile of this group. Living in close proximity to primary or secondary roads was also associated with a risk of HIV infection compared to those living far from major roads. This could be due to the ease of mobility and potential exposure multiple sex partners. This may be due to a desire for modern social amenities which requires financial wherewithal, which in turn facilitates transactional sex.

Published work submitted to the Faculty of Medicine, University of the Witwatersrand, Johannesburg, for the degree Doctor of Science in Medicine. / Andrew Chakane 2018

MSc (Med), Faculty of Health Sciences, University of the Witwatersrand, 2011 / Despite being a fulminant pathogen, Neisseria meningitidis (meningococcus) is part of the commensal flora of the human nasopharynx. Globally, five meningococcal serogroups (A, B, C, Y and W135) cause the majority of invasive disease. Most serogroup B cases occur sporadically but may be endemic or epidemic within a geographic region. In South Africa, there are limited data on invasive serogroup B clones and the antigenic diversity of certain meningococcal outer membrane proteins. This study examined the molecular epidemiology of serogroup B meningococci in South Africa from 2002 through 2006. Invasive meningococcal isolates were submitted to a national laboratory-based surveillance system. For this study, serogroup B isolates were characterised by pulsed-field gel electrophoresis (PFGE), PorA, FetA and multilocus sequence (MLST) typing. PorA, FetA and multilocus sequence (MLST) typing were performed on all 2005 isolates (n=58) and randomly selected isolates from other years (n=25). A total of 2144 invasive cases were reported over the study period. Of these, 76% (1627/2144) had viable isolates available for serogrouping and 307 (19%) were serogroup B. Serogroup B cases were reported from across the country however the majority were from the Western Cape province. The highest incidence of serogroup B was in children less than 5 years of age. Isolates displayed a high level of diversity by PFGE. Despite this diversity the majority of serogroup B meningococci collected over the 5-year period could be grouped into several clonal clusters representative of global invasive MLST clonal complexes. Overall, the most predominant MLST clones in South Africa were ST-32/ET-5 and ST-41/44/lineage 3. In addition, at least 19 PorA types and 16 FetA types were determined among selected isolates. Globally invasive serogroup B disease is caused by heterogeneous strains however, prolonged outbreaks in several countries have been due to strains of the ST-32/ET-5 and ST-41/44/lineage 3 clonal complexes. At present, serogroup B disease in South Africa is not dominated by an epidemic clone, however, global clonal complexes ST-32/ET-5 and ST-41/44/lineage 3 are circulating in Western Cape and Gauteng, respectively.