Background In 2006, South Africa documented its first outbreak of extensively drug-resistant (XDR-TB) in Tugela Ferry, Kwa-Zulu Natal. Delayed diagnosis of XDR-TB increases mortality, emphasizing the need or rapid diagnostics. The MTBDRsl assay rapidly identifies resistance to fluoroquinolones (FLQ) and aminoglycosides/capreomycin (AG/CP). Hospitalization provides the ideal opportunity for nosocomial infections of TB, including M/XDR-TB, with its associated morbidity and mortality. Occupational exposures amongst healthcare workers are also of concern. Rapid knowledge of second-line resistance patterns of these in-patients would allow for quick stratification and administration of individualized anti-chemotherapy treatment by clinicians, thereby reducing morbidity and mortality within this population. Methods ` A prospective cohort study was performed from admission sputum specimens collected from patients admitted to Sizwe Tropical Disease Hospital (Sizwe Hospital), the only M/XDR-TB referral hospital in Gauteng, South Africa. MTBDRplus (version 1) and MTBDRsl line probe assays (LPAs) were performed on all sputa, irrespective of smear positivity and subsequently on Mycobacteria Growth Indicator Tube (MGIT) isolates. The results from the LPAs were compared to the gold standard MGIT 960 culture and direct susceptibility testing (DST) results. Results From April 2011 to January 2012, 150 participants were recruited. Seventy-five (50.0%) were female, 91 (60.7%) were HIV-positive and 9 (6.00%) had an unknown HIV status. Of the MGIT cultures performed 71 (47.3%) were positive for Mycobacterium tuberculosis (MTB), 31 (20.7%) negative, 40 (26.7%) were contaminated and 8 (5.63%) were inadvertently discarded by the routinen laboratory. The proportion of smear-negative specimens in HIV- positive patients was not statistically significantly different to the smear-negatives in HIV-negative patients (57.1% vs. 46.0%; p=0.139). On phenotypic drug susceptibility testing, 47 (66.2%) were resistant to only isoniazid and rifampicin (MDR-TB), 10 (14.0%) were MDR-TB with added resistance to ofloxacin (pre-XDR-TB FLQ), 4 (5.63%) were MDR-TB with added resistance to kanamycin (pre-XDR-TB AG/CP), 4 (5.63%) were MDR-TB with added resistance to both ofloxacin and kanamycin (XDR-TB), 3 (4.23%) were mono-isoniazid resistant, 2 (2.82%) mono-rifampicin resistant, and 1 (1.41%) was TB-drug sensitive. No TB drug-sensitive sputum specimens were collected and used as a control group for the MTBDRplus (version 1) assay, thus only sensitivity indices and positive predictive values (PPVs) could be interpreted.All specimens collected were used as an inherent control group for the performance of the MTBDRsl assay, thus sensitivity and specificity indices together with the PPVs and NPVs, were calculated. From all sputum samples collected, including both smear-positives and smear-negative specimens, the sensitivity of the MTBDRplus (version 1) for RIF and INH was 98.1% for both drugs. Overall sensitivity for the MTBDRsl assay to detect ofloxacin (OFX) and kanamycin (KAN) resistance was 90.9% and 42.9%, respectively. The specificity was 100.0% and 95.7%, respectively. From smear-positive specimens, the sensitivity for OFX and KAN was 100.0% and 50.0%, respectively. The specificity was 100.0% and 96.8%, respectively. From smear-negative specimens the sensitivity was 50.0% and 33.3%, respectively. The specificity was 100.0% and 92.9%, respectively. From MGIT culture isolates, sensitivity for RIF and INH was 98.2% and 94.5% respectively. The sensitivity for OFX and KAN were 100.0% and 42.9%, respectively, whereas the specificity was 95.6% and 100.0%, respectively. Conclusion The performances of both LPAs correlate with other local and international publications. On direct, smear-positive sputa both LPAs perform well. From these, the MTBDRsl assay is a good rule-out test for detection of resistance to FLQ and AG/CP. For FLQ, it’s a good rule-in test: this indicates that the MTBDRsl assay can be used as a rapid screen for the onset of XDR-TB. As predicted, MTBDRsl does not perform well on smear-negative specimens, whereas the MTBDRplus (version 1) does. On cultures, both LPAs perform well.

Background: There is widespread concern about the rise of drug-resistant TB because treatment outcomes of affected patients remain poor and treatment options are limited. After more than a forty-year gap without any breakthrough discovery, several new (bedaquiline and delamanid) and repurposed drugs (linezolid) are increasingly becoming available for use. However, data regarding the efficacy and safety of these drugs in drug-resistant TB patients, with or without HIV infection, from a real-life programmatic setting are lacking. This thesis aims to address that knowledge gap and provide information for management of drug-resistant TB in countries with high disease burden. Methods: A total of 326 drug resistant TB patients were prospectively followed up between January 2008 and April 2018. The efficacy and safety of two new drugs (bedaquiline and delamanid) and one repurposed drug (linezolid) was determined in these patients in three studies. In the first study, 24 months treatment outcomes and adverse event profiles were compared between extensively drug resistant (XDR) TB patients who received programmatic treatment regimens with the backbone of second line injectables and fluoroquinolones (nonbedaquiline-based) and those who received a bedaquiline- and/ or linezolid-based treatment regimen. The second study determined the frequency of system-specific adverse events associated with linezolid. The third study interrogated the safety and effectiveness of a strengthened treatment regimen containing a combination of delamanid and bedaquiline in patients with poor prognostic features compared to bedaquiline-based regimen. Results: In the first study, patients who received a bedaquiline-based treatment regimen had a significantly greater favourable outcome rate (66.2% vs 13.2%; p<0.001) ), more than a fourfold reduction in treatment failure rate (5.9% vs 26%; p<0.001 ) and less than a half of mortality rate compared to patients who received a non-bedaquiline-based regimen. The bedaquiline survival and favourable outcome effect remained significant in HIV-infected patients (p<0.001). The second study showed that linezolid interruption was common in patients receiving a bedaquiline-based treatment regimen, and that system-specific toxicity occurred within predictable time frames. It also showed that anaemia (77.3% versus 7.3%; p<0.001), peripheral neuropathy (63.6% versus 14.6%; p=0.003), and optic neuritis (18.2% versus 9.8%; p=0.34) occurred more frequently in linezolid interrupters than in non-interrupters. The third study showed that the use of delamanid-bedaquiline combination regimen was safe and efficacious in drug resistant TB patients with poor prognosis when compared with outcomes in the less sick patients who received a bedaquiline-based regimen. It also showed no significant difference in culture conversion rate at 6 months (92.5% versus 81.8%; p=0.26) or favourable treatment outcome rate (63.4% versus 67.5%; p=0.66) between the two groups. Although patients who received the combination regimen had more frequent occurrence of QTcF prolongation greater than 60 ms from baseline (p=0.001) and more episodes of QTcF greater than 450 ms during treatment (p=0.001), none of them were symptomatic or had delamanid or bedaquiline withdrawn from their regimen. Conclusion: These data demonstrated that new and repurposed drugs remarkably improved treatment outcomes in patients with drug-resistant TB. Although linezolid, which is an important component of the bedaquiline-based treatment regimen, is often associated with system-specific adverse events, these occurred at predictable time frames thereby guiding physicians to make informed management decisions. Lastly, drug resistant TB patients with poor prognosis may benefit from a regimen containing delamanid and bedaquiline which seems relatively safe from an adverse event perspective. These data, despite some limitations, make a case for a widespread and accelerated roll-out of new and repurposed drugs for the treatment of drug resistant TB.

The study aimed to explore and describe the experiences of people treated for multidrug resistant tuberculosis (MDR-TB) in Omaheke region, Namibia in order to make relevant recommendations regarding their management. A descriptive qualitative design approach was used. Data was collected using in-depth individual interviews with six participants. The interview transcripts were analysed using thematic content analysis. Three themes emerged namely (1) Stressors related to MDR-TB diagnosis and treatment which involved nature of disease and compulsory hospitalisation (2) Impact of being treated for MDR-TB which related to emotional , social , spiritual and financial impact (3) Support structures for people treated for MDR-TB which included family members, health care professionals and friends. Systemic practical patient-centred, staff-centred and community-centred recommendations are suggested as well as recommendations for future research and an appraisal of the limitations of this study. / Health Studies / M.A. (Public Health)

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in part fulfillment of the requirements for the degree of MSc (Med) (Pharmaceutical Affairs) Johannesburg, 25 March 2013 / The emergence of resistant forms of tuberculosis (TB) has not only caused continuous challenges on the world populations’ health, but has also attracted increased costs of primary health care for the infected and society at large. In 2005, when the South African public came to learn about another resistant form of TB other than multi-drug resistant (MDR), 53 patients had just died in a rural hospital in KwaZulu-Natal (KZN). The reports (SA DoH, 2006) came to announce this form of TB as extreme drug resistant tuberculosis (XDR-TB).

Over the last few years the World Health Organization (WHO) has endorsed several tests for the rapid detection of multidrug-resistant tuberculosis (MDR-TB) in resource-poor settings. The objective of this study was to compare the cost-effectiveness of a line probe assay test (less than one week for results) to conventional (bacterial culture) drug susceptibility testing (one month for results) for the detection of MDR-TB in an HIV-positive South African population by estimating the incremental cost-effectiveness ratio (ICER) per disability-adjusted life-year (DALY) averted. Costs of testing, drug treatment, hospitalization, as well as estimates for mortality, treatment success, and failure rates were obtained from literature sources, the South African Department of Health, the WHO, the Foundation of Innovative Diagnostics (FIND), and expert opinion. The willingness-to-pay threshold for a DALY averted was pre-set at 3 times the 2009 GDP per capita (about $17,400) for South Africa. In the base-case scenario for a prevalence of 30% of MDR-TB among HIV-positive patients, the average cost per person for the line probe assay testing strategy was $3,539/0.458 DALY averted and the conventional testing approach was $3,011/0.430 DALY averted. The base-line ICER was about $18,800 per DALY averted – about $1,400 above the pre-set threshold. In sensitivity analyses, the model was robust to changes in prevalence (+ 50%); costs (+ 10%), and probabilities of death, success and failure (+ 20%). However, when the treatment success rate for the line probe assay test was increased to 60% (one of the targets set by WHO in TB treatment) the ICER was below the willingness-to-pay level (i.e., cost-effective). The probabilistic sensitivity analysis showed there is a 70% chance that the additional cost of the line probe assay, compared with conventional testing, was less than $30,000 per DALY averted. However, the model may have underestimated the benefits of the line probe assay because it did not account for a decrease in the transmission of the disease due to earlier treatment nor did it measure any benefits more than a year after testing. / text

The study aimed to explore and describe the experiences of people treated for multidrug resistant tuberculosis (MDR-TB) in Omaheke region, Namibia in order to make relevant recommendations regarding their management. A descriptive qualitative design approach was used. Data was collected using in-depth individual interviews with six participants. The interview transcripts were analysed using thematic content analysis. Three themes emerged namely (1) Stressors related to MDR-TB diagnosis and treatment which involved nature of disease and compulsory hospitalisation (2) Impact of being treated for MDR-TB which related to emotional , social , spiritual and financial impact (3) Support structures for people treated for MDR-TB which included family members, health care professionals and friends. Systemic practical patient-centred, staff-centred and community-centred recommendations are suggested as well as recommendations for future research and an appraisal of the limitations of this study. / Health Studies / M.A. (Public Health)

Background: Pulmonary Tuberculosis (PTB) is considered a disease of the past but it remains a major cause of mortality among immune compromised patients and continues to be a significant threat to public health globally. Notably, the prevalence of diabetes mellitus (DM) has increased over the years. The biological link of TB and DM has been reported in numerous literature with DM attributed to three folds increase in the risk of TB and linked to Drug Resistant TB, especially amongst aged diabetic patients. The aim of the study was to examine the distribution of DM among TB patients and explore the risk of Drug resistant TB in Diabetics infected with TB Methods: The study employed a retrospective cross-sectional descriptive case based study involving 3638 patients diagnosed with pulmonary TB in the State of Florida, USA, 2009-2014. A comparative analysis of TB cases with DM and cases without DM adjusted for age was conducted. The risk of Drug resistant TB associated with DM was estimated through logistic regression analysis. Odds Ratios of TB/DM comorbidity were calculated and adjusted for Age using 5-year intervals from 40 years to above 70 years. Ninety-five percent (95%) confidence intervals were used and the accepted level of error was 0.05. Results: There were 3836 cases of Pulmonary TB in Florida for the period of 2009-2014. The majority of cases (65%) were males and likely unemployed (59.1%). The prevalence of DM was 12 % but when adjusted for age the prevalence of DM was 3.9% amongst patients aged below 40 years and 16.7 % in patients aged above 40 years. An estimated 469 cases had TB/DM comorbidity (12.2%). The majority of TB/DM cases were above 40 years amongst the patients with DM, 44/469 (9.4%) had drug resistant TB and a majority were resistant to Rifampin. Population density did not influence the distribution of TB in this study. Conclusion: Diabetes Mellitus, Aging, and low immunity are linked with increased rates of progressing from latent TB infection to active disease. To achieve the goal of TB elimination it is important to fully understand and identify known TB comorbidities for proper diagnosis and early initiation to care. There is a positive correlation between high DM burden and increased TB prevalence. Therefore, it is recommended that prevention of DM, hyperglycemia and comprehensive management of DM be intensified to prevent TB, improve TB treatment outcomes and reduce the risk of drug resistant TB in Florida, USA.

Magister Public Health - MPH / Namibia is currently coping with a dual burden of human immunodeficiency (HIV) and HIV-associated tuberculosis (TB). In 2010, HIV prevalence was 18.8%, the TB case notification rate was 634 per 100,000 population, while TB/HIV co-infection was 58% in 2009. There were 372 reported cases of drug-resistant TB (DR-TB) in 2009. This study assessed the prevalence, profile and outcome of adverse events (AEs) associated with the treatment of DR-TB, and risk factors for the adverse events. The researcher used a cross-sectional design. Data was collected from the treatment records of all patients treated for DR-TB (N = 59) at the study facility between January 2008 and February 2010. Descriptive statistics were used to describe the frequency of the adverse events and logistic regression to analyse the association between possible risk factors and (specific) adverse events, with stratification (sub-group analysis) and multivariate analysis to adjust for measured confounders. Results of logistic regression analysis are reported as odds ratio (OR), 95% confidence interval (CI) and p-value, where p<0.05 was considered to be statistically significant. A total of 141 adverse events were experienced by 90% (53/59) of patients in the sample. HIV-associated TB occurred in 31 (53%) of the sample. The prevalence of gastrointestinal tract (GIT) adverse events was 64%, tinnitus 45%, joint pain 28% and decreased hearing 25%. Abdominal pain, rash, nausea, decreased hearing and joint pain were found to be more common in people living with HIV than in HIV-negative patients. Moderate-to-severe adverse events were mostly experienced after four weeks of DR-TB treatment (OR 6.4; 95% CI 1.6 – 25.6, p= 0.01). Drug-resistant TB patients who were coinfected with HIV were more prone to experiencing three or more adverse events (OR 3.9; 95% CI 1.2 – 13.6, p= 0.03). Patients treated with zidovudine-based ART were at an increased risk of experiencing nausea (OR 7.5; 95% CI 1.1 -51.5, p=0.04). Females were associated with an increased risk of skin rash (OR 15.7; 95% CI 1.7 – 143.7, p=0.01). The use of cycloserine-based DR-TB regimens was associated with joint pain (OR 6.5; 95% CI 1.6 – 25.8, p=0.01), while the risk of ototoxicity was associated with the use of amikacin-containing regimens (OR 12.0; 95% CI 1.3 – 111.3, p=0.03). Adverse events were found to be more common among patients treated for DR-TB (90% prevalence), particularly during the intensive phase of TB therapy. Most of these adverse events were mild and tolerable. Some adverse events were more common among DR-TB patients who were co-infected with HIV than in HIV-negative patients. The characteristics and risk factors of the serious adverse events need further research. The use of cycloserine-based DR-TB regimens was associated with joint pain. Findings of the risk factor analysis are inconclusive because of the small sample size, which severely limited the power of the study. Clinicians should invest more time in the prevention and management of adverse events, and should pay greater attention to the needs of HIV co-infected DR-TB patients who are using second-line anti-TB medications, especially those who are concomitantly undergoing treatment using antiretroviral medicines.

Master of Public Health - MPH / Decentralisation of multi-drug resistant tuberculosis (MDR-TB) services has resulted in improved access to care, with community-based treatment of MDR-TB shown to be more effective than centralised hospital-based care. Furthermore, increasing bed shortages resulted in the National Department of Health establishing MDR-TB policy guidelines in 2011. However, the extent to which this policy has been implemented by the decentralised MDR- TB sites and the factors influencing implementation of the policy from a management perspective were not well described. The aim of this study was therefore to explore and compare the actual and ascribed roles and responsibilities of key management-level role players at the decentralised MDR-TB sites, and to explore the factors influencing implementation of the MDR-TB decentralisation policy (2011).

Doctor Pharmaceuticae - DPharm / Introduction: Drug-resistant tuberculosis remains a major world health problem and one of the leading cause of death worldwide. Despite adequate adherence to antituberculosis drugs by patients, the emergence of drug-resistance tuberculosis still occurs. This fact implies other factors leading to the emergence of resistant strains of Mycobacterium tuberculosis. A multidrug treatment regimen, which may consist of five to seven different drugs including terizidone, is used in the treatment of drugresistance tuberculosis. Terizidone is part of the multidrug regimen whose pharmacokinetics is scarce in literature and plasma concentration profile unknown. Two molecules of cycloserine joined by terephtalaldehyde moiety makes up a molecule of terizidone, which is thought to undergo complete metabolism into cycloserine in vivo. Additionally, the current literature report that terizidone and cycloserine can be used interchangeably as they are thought to be equivalent. The aim of this thesis was first to develop and validate bioanalytical methods for determination of terizidone and cycloserine in patients’ plasma samples. Secondly, to model population pharmacokinetics of terizidone and cycloserine. Thirdly, to determine the amount of cycloserine resulting from metabolism of terizidone.