Introduction Although HIV infection increases the likelihood of developing TB, evidence suggests that starting ART reduces the risk of TB incidence although not to the level of HIV negative people in the population. This study aims to determine the impact of ART on TB incidence in people living with HIV in the Western Cape Province of South Africa. Methods This is a retrospective cohort study using routinely collected data of HIV infected individuals aged 15 years and above from public health facilities in the Western Cape Province, South Africa, between 2007 and 2016. A Marginal Structural Model (MSM) with inverse probability of treatment weighting (IPTW) was used to estimate the effect of ART on TB incidence adjusting for measured time-dependent confounding by CD4 count. Results ART was associated with a 77.3% (95% CI, 76.7% – 78.0%) reduction in the risk of TB incidence in HIV infected patients. The overall TB incidence was 9 855 per 100 000 patient years (95% CI, 9 798 – 9 912). Patients on ART and those not on ART had a TB incidence of 3 939 and 15 329 per 100 000 patient years respectively. TB incidence was higher in males than females, and higher in patients with lower CD4 count at baseline and during follow-up. TB incidence declined with increasing ART duration and rising CD4 count but remained elevated compared to background incidence. Conclusion This study has shown that ART is highly effective at preventing TB in people living with HIV. The recent introduction of universal ART access for everyone living with HIV should contribute to further reducing TB incidence in South Africa and other high HIV and TB burden countries.

Includes bibliographical references. / Epidemiologic research shows that socioeconomic status influences different health outcomes including HIV/AIDS. Although poverty (low socioeconomic status (SES)) and HIV prevalence are correlated at the global level, the association between SES and HIV prevalence is rather mixed in sub-Saharan Africa. Differences in findings could be attributed to context and thus context specific evidence is needed to develop interventions that could have greater impact in those settings. However there are few studies that investigate the association between SES and HIV prevalence in Ethiopia. In 2011, the Central Statistics Agency (CSA) in collaboration with Federal Ministry of Health and ORC-MACRO collected a broad range of demographic, socioeconomic and health data on a representative sample of the population of Ethiopia. This included information on HIV status, demographic and socioeconomic variables (age, gender, religion, marital status, place of residence, household wealth, education, occupation and others) and behavioural risk factors. The present study took advantage of this dataset to describe the relationships between SES and demographic factors and HIV prevalence in the Ethiopian adult population, and to explore the relationship between household wealth and HIV prevalence. Part A of this dissertation (Protocol) describes the characteristics of the Ethiopian Demographic and Health Survey (EDHS2011) dataset, gives details on the sampling and data collection in the original study, and delineates the methodology of the secondary analysis. Part B (Literature review) illustrates the main findings of the conflicting epidemiological literature on the socioeconomic determinants of HIV/AIDS in sub-Saharan Africa and presents a summary of the major studies on wealth, education and place of residence as risk factors for HIV prevalence. Part C (Article) presents the methodological details, results, and possible interpretations of the analyses carried out on the EDHS2011 dataset. The estimated prevalence of HIV in the Ethiopian population aged between 15 to 49 years was 1.47% (95% CI: 1.25% to 1.68%). The analysis showed that household wealth and education were the main socioeconomic status determinants and were independently associated with higher HIV prevalence in Ethiopia, though having education beyond high school was protective against HIV. Data also suggested that living in urban areas, religion and age were the main demographic determinants of HIV prevalence in Ethiopia. Behavioural factors, especially having multiple sexual partners and condom use in the last 12 months were more prevalent both among HIV positive individuals and among more educated and relatively wealthier individuals. It is possible that these factors could be involved in the causal pathway between household wealth and HIV prevalence. The results confirm the pattern of association between education and HIV prevalence in sub-Saharan African countries undergoing epidemiological transition. Those with higher educational attainment had lower HIV prevalence compared to those with no education as the epidemic matured. The evidence generated in this study can be used to develop and update prevention strategies in order to target areas which have higher HIV prevalence.

Introduction: In South Africa postpartum women have been shown to be at high risk of disengagement from HIV care and postpartum mobility may be related to disruptions in care. This study aimed to describe patterns of mobility, and explore associations with viral suppression and retention in the postpartum period. Methods: This study used data from a prospective cohort study that enrolled women who initiated life-long antiretroviral therapy (ART) during their pregnancy in Gugulethu, Cape Town (March 2013 -June 2014), and an additional follow-up study at approximately 4 years postpartum. Patterns of self-reported mobility between delivery and the 4 year measurement visit were examined. Logbinomial models were used to explore the association between mobility (moving in the 3, 6 or 12 months prior to the study visit) and i) viral suppression (viral load (VL) ≤50 and ≤1000 copies/mL measured at the 12 month and 4 year measurement visit) and ii) retention in care (based on routine medical record data at approximately 12 months and 4 years postpartum). Results: Among the 353 women in this analysis, 98 (28%) reported having ever moved between delivery and 4 years postpartum. Mobility was more likely to occur soon after delivery with 50% of the moves occurring within the first year following delivery; the most common reason for moving being to live with and receive support from family (44%). Moving within 3 months of the viral load measurement at 12 months postpartum was associated with having a VL≤50 copies/mL (aRR=1.61, 95% CI: 1.17-2.21). Moving in any window prior to the 12 month or 4 year postpartum viral load was not associated with viral suppression. Retention in care at both 12 months and 4 years postpartum was not associated with mobility. Conclusions: These results demonstrate that movement following delivery is a common occurrence among postpartum women, but this movement did not seem to disrupt engagement in HIV care. There is a need for further research to understand the impact of this movement on postpartum women's viral suppression and retention in care, as well as on ways to support continued engagement in HIV care after delivery.

Antibiotic resistance (ABR), alternately referred to as antimicrobial resistance, has been labelled as the next big global health crisis. If current levels of ABR continue along the same trajectories, by 2050 ABR will cost the lives of 10 million people a year, ABR cannot be stopped but it can be slowed down. ABR occurs because the bacteria evolve to protect themselves from antibiotics. One of the main causes of ABR is the misuse and over prescription of antibiotics. The primary objective of the study is to ascertain the level of knowledge, attitudes and perceptions of appropriate antibiotic use and ABR, among prescribers and patients in private health care in South Africa. The secondary objective of the study is to explore associations between knowledge, attitudes and perceptions of prescribers and patients regarding antibiotic use and resistance. This project consists of three main sections, a proposal, literature review and a journal ready article. All sections focus on ABR. The proposal lays a foundation for the need for the research, and explains how the research will be conducted. The literature review explores the existing evidence on the topic, and the final section is a secondary analysis of cross sectional study data, in which private practice patients and prescribers in South Africa completed a once-off anonymous survey. Data was analysed using Stata,T-tests, chi-squared tests and logistic regression models were used to assess associations between knowledge, attitudes and perceptions of both patients and prescribers. We found that mean knowledge scores among patients (n=403, mean 9 out of 14, standard deviation [SD] 3) and providers (n=175, median 5 maximum 7, IQR 4, 6), were suboptimal and that poor knowledge was associated with perceptions and behaviours as well as prescribing practices that could lead to ABR. Associations between knowledge, attitudes and perceptions of patients and prescribers were explored in multivariate logistic regression models. After adjusting for education and sex, a 1-unit increase in patient knowledge score was associated with the belief that antibiotics will work less well in future if we over-use them now (aOR 1.3; 95% CI: 1.18, 1.43; pvalue <0.001). Prescribers with higher knowledge scores were less likely to report that they prescribe antibiotics when not necessary as antibiotics cannot harm the patient (aOR 0.55; 95% CI: 0.33, 0.91; pvalue 0.02). We also identified a large proportion (58%) of patients who were interested in alternatives to antibiotics and a large proportion (91%) of prescribers wanting educational material to facilitate conversations about resistance with patients. Our study demonstrates gaps in patient and prescriber knowledge that are associated with potentially harmful perceptions and destructive behaviours regarding antibiotic use. These associations, together with our finding that patients and prescribers would like more education on ABR, suggest that educational tools and patient-provider communication tools could promote rational antibiotic use.

Sleep deprivation and insomnia may be risk factors for obesity due to decreased energy expenditure and increased caloric intake. The relationship between sleep duration, insomnia and weight and fat mass was assessed in postmenopausal women (N=92,706) in the Women’s Health Initiative Observational Study from 1993-2005. Baseline sleep duration and insomnia status, and annual weight information were collected by questionnaire. Body mass index (BMI) was calculated annually from height and weight measurements. Fat mass percent was assessed at baseline and every 3 years by dual-energy x-ray absorptiometry. After multivariable adjustment, baseline cross-sectional analyses demonstrated a significant relationship between sleeping 6 hours (β = 0.19, 95% CI: 0.10, 0.29) and 8 hours (β = 0.16, 95% CI: 0.06, 0.26) but not ≤ 5 or ≥ 9 hours and BMI (reference = 7 hours). After multivariable adjustment, baseline insomnia was associated with significantly lower BMI (β = -0.31, 95% CI: -0.39, -0.23). No association was observed between baseline sleep duration, insomnia status and fat mass percent. Prospectively, baseline sleep duration was not significantly associated with weight change or change in fat mass percent. Similarly, baseline insomnia status was not associated with change in weight or change in fat mass percent over time. As the prevalence of obesity increases, it is necessary to identify modifiable risk factors. Our findings suggest that sleep duration is not a factor for weight gain in post-menopausal women.

The majority of evidence used by the World Health Organization (WHO) to inform guidelines for the treatment of multidrug-resistant tuberculosis (MDR-TB) is based on findings from observational cohort studies. Observational cohort studies have important limitations when interpreting estimates as causal effects, in contrast to randomized controlled trials (RCTs), the gold standard for assessing efficacy. Specifically, observational cohort studies are at greater risk of common threats to validity, such as selection bias and confounding. The consequences of residual bias in observational cohort studies of MDR-TB patients would be substantial, given WHO guidelines inform the treatment approach for the 500,000 patients estimated to fall sick with MDR-TB globally each year. The goals of this dissertation are to: assess the comparative effectiveness of adding delamanid to MDR-TB regimens (Aim 1), scrutinize the potential for selection bias when using different approaches to defining the subcohort of MDR-TB patients eligible for studies using sputum culture conversion outcomes (Aim 2), and evaluate differences in the interpretation and estimates of the comparative effectiveness of adding delamanid (as explored in Aim 1) when the time-varying nature of MDR-TB treatment is and is not accounted for (Aim 3). In all aims, we use data from the observational cohort of the endTB initiative. The endTB initiative was launched in 2015 to rapidly expand access to two new drugs for MDR-TB, bedaquiline and delamanid, for over 2,700 patients in 17 countries. In partnership with national TB programs, a consortium of non-governmental organizations leads the initiative: Partners In Health, Médecins Sans Frontières, and Interactive Research and Development. Participants are treated in accordance with guidelines of WHO and their respective countries under routine programmatic conditions. Study activities are directed by a common protocol, data are collected using standardized forms, and adverse events (AE) are monitored through a unified pharmacovigilance system, which facilitates data consistency across sites. In Aim 1, we investigate whether adding delamanid to MDR-TB regimens comprised of three drugs likely to be effective improves two- and six-month culture conversion. We apply a censoring approach using inverse probability weighting that accounts for MDR-TB regimen changes over the course of treatment to estimate the observational analogue of the per-protocol effect. We did not identify a difference in two- or six-month culture conversion between participants with delamanid added to their regimen and participants without delamanid. We hypothesize that delamanid did not provide a contribution to effectiveness because regimens already contained multiple efficacious drugs (e.g. linezolid, moxifloxacin/levofloxacin, bedaquiline). In Aim 2, we used simulated data and data from the endTB observational cohort to evaluate whether extending the allowable baseline sputum culture collection interval past treatment initiation is a source of selection bias in studies using culture conversion outcomes. Two of the most influential factors that increased bias were the proportion of the cohort with a missing pre-treatment culture and the occurrence of death and loss to follow up (LTFU) in this group. These occurred infrequently in the endTB observational cohort; thus we did not observe meaningful differences when the baseline culture definition was extended past treatment initiation. In cohorts with an excess of missing pre-treatment culture data and early non-conversion events such as death and LTFU, extending the allowable interval past treatment initiation may introduce bias. Investigators should scrutinize whether extending the baseline sputum culture collection interval will inadvertently exclude these patients who may have been eligible for inclusion had they had pre-treatment sputum culture data. In Aim 3, we used the clinical research question from Aim 1 to investigate whether implementing inverse probability of censoring weights to account for the time-varying nature of MDR-TB treatment generated results that were different from those generated through baseline-adjusted analytic approaches. Results were similar using the two types of approaches. This similarity is likely a consequence of the relative modest frequency of regimen changes and the distribution of participants with regimen changes across exposure groups and the outcome. We hypothesize that estimates may differ meaningfully for research questions where treatment changes are highly concentrated in one exposure group and these treatment changes are highly associated with the outcome.

The relationship between malnutrition and tuberculosis disease (TB) severity is understudied. This study analyzed data collected by a large cohort study to investigate the effect malnutrition, measured by BMI, had on TB mycobacterial burden. A study population of 538 subjects was utilized for this secondary data analysis. Multivariate negative binomial regression was used to evaluate relationships between body mass index (BMI) categories and mycobacterial growth indicator tube (MGIT) days to positive. Of the 538 subjects, 79% were male and 21% were female. The median age was 45 years of age. One subject was HIV seropositive and was excluded from the final analysis. There were incomplete outcome data for 63 subjects, who were excluded from the final analysis. BMI was categorized as severe malnutrition (BMI<16.5 kg/m2), malnutrition (16.5≤BMI<18.5), normal (18.5≤BMI<25), and overweight/obese (BMI≥25), with 27%, 32%, 36%, and 5% of the population comprising these categories, respectively. The median MGIT days to positive was 8 days. After adjusting for confounders, individuals who had severe malnutrition or malnutrition had an adjusted RR of 1.05 (95% CI, 0.90–1.23) and 1.08 (95% CI, 0.94, 1.24), neither measure was significant for the association between TB disease burden and MGIT. Overweight/obese individuals had an 8% decreased risk (RR=0.92, 95% CI, 0.79–1.19) of shorter time to result compared to those with normal BMI, after adjusting for confounders. The results of this study indicate that there is no significant association between BMI and MGIT in an adjusted model. However, there are several limitations to this result including, lack of cavitation data and failure to account for collinearity in the final model.

Includes abstract. / Includes bibliographical references. / We hypothesized that the increased burden of TB disease among young females in Cape Town is primarily due to HIV infection in this age group. During 2009, City of Cape Town TB clinics prospectively collected routine notification data on 29,478 new TB cases. The objectives of this analysis were to describe the 2009 Cape Town TB case population by gender, age, and HIV; explore associations between gender, clinical characteristics, and HIV in TB cases; and estimate age-specific TB notification rates by gender and HIV.

Includes abstract. / Includes bibliographical references. / The aim of this analysis was to determine the effects of HIV exposure on child growth and nutritional status in children less than two years of age in the Free State (FS) and Western Cape (WC) Provinces, South Africa.

Includes abstract. Includes bibliographical references.