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Background Risk factors for coronavirus disease 2019 (COVID-19) death in sub-Saharan Africa and the effects of human immunodeficiency virus (HIV) and tuberculosis on COVID-19 outcomes are unknown. Methods We conducted a population cohort study using linked data from adults attending public-sector health facilities in the Western Cape, South Africa. We used Cox proportional hazards models, adjusted for age, sex, location, and comorbidities, to examine the associations between HIV, tuberculosis, and COVID-19 death from 1 March to 9 June 2020 among (1) public-sector “active patients” (≥1 visit in the 3 years before March 2020); (2) laboratory-diagnosed COVID-19 cases; and (3) hospitalized COVID-19 cases. We calculated the standardized mortality ratio (SMR) for COVID-19, comparing adults living with and without HIV using modeled population estimates. Results Among 3 460 932 patients (16% living with HIV), 22 308 were diagnosed with COVID-19, of whom 625 died. COVID-19 death was associated with male sex, increasing age, diabetes, hypertension, and chronic kidney disease. HIV was associated with COVID-19 mortality (adjusted hazard ratio [aHR], 2.14; 95% confidence interval [CI], 1.70–2.70), with similar risks across strata of viral loads and immunosuppression. Current and previous diagnoses of tuberculosis were associated with COVID-19 death (aHR, 2.70 [95% CI, 1.81–4.04] and 1.51 [95% CI, 1.18–1.93], respectively). The SMR for COVID-19 death associated with HIV was 2.39 (95% CI, 1.96–2.86); population attributable fraction 8.5% (95% CI, 6.1–11.1). Conclusions While our findings may overestimate HIV- and tuberculosis-associated COVID-19 mortality risks due to residual confounding, both living with HIV and having current tuberculosis were independently associated with increased COVID-19 mortality. The associations between age, sex, and other comorbidities and COVID-19 mortality were similar to those in other settings.

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.

It is important for health planners to have timeous and accurate data on deaths. The Department of Home Affairs is responsible for the registration of deaths and the City of Cape Town has a well-established system of collating the death statistics based on vital registration, but the completeness of the death registration has not been assessed previously. The completeness was assessed for the City of Cape Town by comparing their statistics with an estimate based on data obtained from adult deaths reported in the 2001 census. A second approach assessed the trend in completeness between 1996 and 2004 by identifying three rates of mortality considered to be stable over time (non-lung and non-oesophageal cancers, the 10-14 age group and the 60+ age group) and inspecting to observe whether there was any trend apparent over time. Since deaths in most cases are under reported, and the under reporting usually differs in completeness between children and adults, child deaths from the ASSA model projection assuming that they are more complete were compared with the child deaths from the vital registration between 1996 and 2004 to check for completeness of the child vital registration data in Cape Town and its eight health districts The results show high levels of completeness in the adult deaths for Cape Town as a whole in 2001, around 95 per cent, but varying levels in the health districts. The completeness of reporting of male deaths in Cape Town declines with age, whilst completeness for females is fairly level with respect to age, with similar trends being observed in the health districts. Completeness of child (0 -4) death registration averaged around 60 per cent, about 35 per cent lower than the completeness of adult deaths in Cape Town. Cape Town as a whole and most of its health districts revealed two levels of completeness in the registration of deaths, 1996-1999 and 2001-2004 with 2000 sometimes consistent with the first and sometimes with the second period or different from either period in some of the health districts. In conclusion, the completeness estimates obtained are more rigorous from 2001 onwards suggesting that they can be reliably used to monitor trends in the levels of mortality in the city of Cape Town.

Background: Globally, tuberculosis (TB) continues to be a major health problem. In the most recent World Health Organisation (WHO) Global Tuberculosis Report of 2019, TB was ranked as the leading cause of death from an infectious disease ahead of the human immunodeficiency virus (HIV) and acquired immune-deficiency syndrome (AIDS). In the 2019 WHO Global Report on TB, there is little information relating to TB post-cure effects and management. Although there is evidence that successful completion of TB treatment does not equate to normal lung function, there is growing need for research, both during and after TB treatment, on the extent of lung function abnormalities and how these impact on the individual's quality of life (QoL). Pulmonary rehabilitation programmes may provide a continuum of care for individuals with TB to address both lung function abnormalities as well as positively impacting on QoL. Objectives: The present PhD thesis aimed to provide insight into the extent of pulmonary disease in individuals with pulmonary TB during and near completion of TB treatment as well as to establish whether provision of a pulmonary rehabilitation programme (PRP) could address the research gap. To achieve this, three linked studies were undertaken in the form of observational (prevalence) study (Study 1), a systematic review (Study 2), and a randomised control trial (Study 3). Study One: Observational Study Objectives: The overall aim of the present observational study was to ascertain the prevalence of lung function abnormalities in first time, drug sensitive individuals living with TB, with or without HIV coinfection, at near completion (at least four months) of TB treatment. The specific objectives were to determine: i) baseline clinical and socio-economic profile, ii) baseline information pertaining to the QoL outcome measures of EQ-5D-3L and the St George's Respiratory Questionnaire (SGRQ), iii) measure lung function parameters, iv) establish the proportion of participants with normal or abnormal (obstructive, restrictive, or mixed) lung function and the severity of these, v) whether a correlation of lung function abnormalities with chest x-ray (CXR) abnormalities exist, vi) establish whether a relationship exists between lung function and QoL measures, and vii) identify the predictors of lung function abnormality in individuals being treated for active TB. Methods: A cross-sectional observational study using a sample of convenience was conducted. Inclusion criteria included all adult male and females between the age of 18-80 years with confirmed (smear positive or by CXR) drug-susceptible TB who were receiving treatment, with or without HIV coinfection, for at least four months (16 weeks). ii Participants were excluded from Study 1 if they were adult patients who had had previous TB episodes, recent severe chest trauma (within the previous three months), a recent history of pneumonia, known atopic asthma, chronic bronchitis, emphysema, bronchiectasis prior to TB diagnosis, cardiac failure, or any other unrelated respiratory disease as reported in their medical folder. Participants completed two QoL questionnaires (EQ-5D-3L and SGRQ), a self-designed clinical research form to collect descriptive data, a six-minute walk test (6MWT), CXR, and spirometry once off. Results: The sample of 305 participants were predominantly male (n=168:55; 1%), had a median age of 36 years (IQR:28-43), and had median time of 19 weeks (IQR:18-22) on TB treatment. Overall, 32% of the sample presented with abnormal lung function (obstructive=11%, restrictive=15%, and mixed=6%). Only 2.2% of the total sample had two or more co-morbidities. There was no statistically significant difference (p=0.29) in distance covered by participants who had obstructive compared to restrictive lung function abnormality. After logistic regression analysis of clinical and sociodemographic variables (multi-variate), only being older (56–65 years old) and being obese were statistically significant (p=0.02 and p=0.04 respectively). When considering QoL, only the domain of mobility for the EQ-5D-3L questionnaire was statistically associated with abnormal lung function (p=0.02). Linear regression modelling for continuous variables of lung function (FEV1, FVC, FEV1/FVC and percentage predicted of FEV1, FVC, and FEV1/FVC) with SGRQ, 6MWD, and CXR scores yielded no predictor. Conclusion: Overall, 32% of participants presented with abnormal lung function, which is lower than comparator studies investigating lung function in TB populations. Quality of life measures for most participants was considered good at the time of assessment. Limitations to Study 1 related to the absence of normative data for a healthy population relating to lung function and 6MWD to compare the findings in this TB population. Recommendations for future research would be to establish normative data for these outcome measures. Regarding lung function testing, it is recommended that training of correct execution of the spirometry techniques is performed prior to assessment as the technique may be unfamiliar compared to the routine tests done at clinic visits for individuals receiving TB treatment. iii Study Two: Systematic Narrative Review A systematic review was conducted to establish the evidence of the impact of non-pharmacological intervention programmes (pulmonary rehabilitation) in the rehabilitation of individuals living with TB on lung function outcomes. Methods: MEDLINE via Pubmed, CENTRAL, CINAHL, PEDro, Web of Science, Scopus, Science Direct, and African Index Medicus, including Google Scholar were searched (from January 1995 to December 2016 with an updated search in November 2018) for randomised control trials, quasi-experimental and pre-post-test studies on PRPsfor adult individuals with TB specifically with lung function measures as primary outcome. Results: In total, 1 705 studies were obtained from the search. Once duplicate studies were removed, 1 220 studies remained. The titles and abstracts of these studies were screened resulting in 1 210 studies being excluded. Therefore, 10 studies were potentially eligible. Once the full-text articles were assessed, four studies met the inclusion criteria. Of the included studies, only one was a randomised control trial, two studies were single arm before and after studies, and one study was a prospective non-randomised open trial (two arms). In total, there were 178 participants in these studies, with sample sizes ranging from 10 to 67 participants. All four selected studies had both male and female participants; however, overall, male participants were the majority with 69% versus 21% females. The mean age across the studies was 70 years. No statistically significant difference (p>0.05) was found regarding lung function parameters and the PRPs. No meta-analysis could be performed as data could not be pooled due to the differences in study characteristics and outcome measures. Conclusion: This review was unable to support or negate the use of pulmonary rehabilitation for individuals with TB primarily due to the lack of well-designed and executed randomised control trials. The studies showed that no effect on FEV1 was demonstrated. The researchers recommended that future research investigates the extent of pulmonary sequelae in patients after completion of TB chemotherapy in large-scale studies. Long-term follow-up in those who have had TB without surgical intervention should be prioritised to see the extent of lung function disorders in this population, particularly in countries on the high-burden list for the disease. A further recommendation is that well executed randomised control trials that control for biases to investigate pulmonary rehabilitation in populations of individuals with TB should be prioritised as there is a need to develop an evidencebased continuum of care. iv Study Three: Randomised Controlled Trial Objectives: The overall objective of study three was to determine what the impact of a contextually relevant PRP would have on individuals living with TB, with or without HIV co-infection, on outcomes related to lung function, functional capacity, and QoL. Methods: A pilot randomised, single blinded, pre-test-post-test design was used. Inclusion criteria were all adult males and females between 18-65 years with TB confirmed by Gene Xpert, irrespective of number of TB episodes, HIV status, or having chronic obstructive pulmonary disease. Participants had to be within their first week of TB treatment. Participants with only extra-pulmonary TB, recent severe chest trauma (within the last three months), a recent history of pneumonia (within one month), known atopic asthma, cardiac failure, or any other unrelated respiratory disease as reported in their medical folders or who had defaulted on their treatment were excluded. In addition to this, if participants failed the pre-participation health screening and were non-ambulate due to paralysis or amputation, they were also excluded. Fifty-eight participants were randomised into a control group (CG) receiving only pharmacological therapy and the intervention group (IG) who received pulmonary rehabilitation in addition to pharmacological therapy. The PRP was held for 12 weeks and consisted of two weekly sessions with a duration of 45 minutes each, which was delivered at a community centre. Participants completed two QoL questionnaires (EQ-5D-3L and SGRQ), a self-designed clinical research form to collect descriptive data, a three-minute step test, and spirometry at three time points (enrolment, at six weeks, and at 12 weeks). T-tests were conducted to determine the difference between means of the CG and IG for lung function parameters, functional capacity, and QoL outcomes. Results: There were 29 participants in each group. Regarding sex, age, and number of co-morbidities the two groups were well matched. Regarding HIV status, the CG had more participants that were HIV positive (n=22) and on anti-retroviral therapy (n=11) than their IG counterparts (n=13 and n=5 respectively). Nearly half of the participants had a first time TB diagnosis, with the participants in the IG having reported more recurring TB incidences overall (n=16 vs. n=13). A t-test for difference between means showed no statistical significance for the CG and IG regarding FEV1, FVC, and FEV1/FVC ratio for absolute or percentage predicted values. Forty-three percent of participants in the total sample had normal lung function at baseline, with the remaining participants being classified as having either obstructive (26%), restrictive (21%), or mixed (10%) lung function. At baseline, 48% of participants in the CG had abnormal lung function compared to 67% in the IG. At six weeks there was no change in the CG regarding lung abnormalities. However, the IG only had 33% abnormal lung function at the same time point. v Although there was no statistical significance for any of the lung function categories, there was a 42% improvement in normal lung function at six weeks in the IG compared to the CG at baseline. The median baseline number of steps taken by the CG was 79 steps (IQR:42-134) compared to 117 steps by the IG (IQR:84-154). A t-test conducted to test the difference between means for the CG and IG was statistically significant for the step test (p=0.002) at six weeks for the IG, but not at 12 weeks (p=0.13). No correlation was found between the SGRQ (QoL parameter) and any lung function parameter (p>0.05) at 12 weeks. Conclusion: Although the changes in lung function, functional capacity, and QoL did not reach statistical significance at completion of the PRP for the IG, the continued improvement in all the outcomes for the IG from 0 weeks to 12 weeks holds potential clinical significance.

Background: In low- and middle-income countries where SARS-CoV-2 testing is limited, seroprevalence studies can characterise the scale and determinants of the pandemic, as well as elucidate protection conferred by prior exposure., Methods: We conducted repeated cross-sectional serosurveys (July 2020 - November 2021) using residual plasma from routine convenient blood samples from patients with non-COVID-19 conditions from Cape Town, South Africa. SARS-CoV-2 anti-nucleocapsid antibodies and linked clinical information were used to investigate: (1) seroprevalence over time and risk factors associated with seropositivity, (2) ecological comparison of seroprevalence between subdistricts, (3) case ascertainment rates, and (4) the relative protection against COVID-19 associated with seropositivity and vaccination statuses, to estimate variant disease severity., Findings: Among the subset sampled, seroprevalence of SARS-CoV-2 in Cape Town increased from 39.2% in July 2020 to 67.8% in November 2021. Poorer communities had both higher seroprevalence and COVID-19 mortality. Only 10% of seropositive individuals had a recorded positive SARS-CoV-2 test. Antibody positivity before the start of the Omicron BA.1 wave (28 November 2021) was strongly protective for severe disease (adjusted odds ratio [aOR] 0.15; 95%CI 0.05-0.46), with additional benefit in those who were also vaccinated (aOR 0.07, 95%CI 0.01-0.35)., Interpretation: The high population seroprevalence in Cape Town was attained at the cost of substantial COVID-19 mortality. At the individual level, seropositivity was highly protective against subsequent infections and severe COVID-19., Funding: Wellcome Trust, National Health Laboratory Service, the Division of Intramural Research, NIAID, NIH (ADR) and Western Cape Government Health.

Introduction: While a large proportion of people with HIV (PWH) have experienced SARS-CoV-2 infections, there is uncertainty about the role of HIV disease severity on COVID-19 outcomes, especially in lower income settings. We studied the association between mortality and characteristics of HIV severity and management, and vaccination, among adult PWH., Methods: We analysed observational cohort data on all PWH aged ≥15 years experiencing a diagnosed SARS-CoV-2 infection (until March 2022), who accessed public sector healthcare in the Western Cape province of South Africa. Logistic regression was used to study the association of mortality with CD4 cell count, viral load, evidence of ART, time since first HIV evidence, and vaccination, adjusting for demographic characteristics, comorbidities, admission pressure, location and time period., Results: Mortality occurred in 5.7% (95% CI: 5.3,6.0) of 17 831 first diagnosed infections. Higher mortality was associated with lower recent CD4, no evidence of ART collection, high or unknown recent viral load (among those with ART evidence), and recent first HIV evidence, differentially by age. Vaccination was protective. The burden of comorbidities was high, and tuberculosis, chronic kidney disease, diabetes and hypertension were associated with higher mortality, more strongly in younger adults., Conclusions: Mortality was strongly associated with suboptimal HIV control, and prevalence of these risk factors increased in later COVID-19 waves. It remains a public health priority to ensure PWH are on suppressive ART and vaccinated, and manage any disruptions in care that occurred during the pandemic. The diagnosis and management of comorbidities, including for tuberculosis, should be optimised., Competing Interests: Conflicts of interest: None Competing interests There are no competing interests.