Browsing by Author "Cox, Helen"

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    Open Access
    “A very humiliating illness”: a qualitative study of patient-centered Care for Rifampicin-Resistant Tuberculosis in South Africa
    (2020-01-17) Furin, Jennifer; Loveday, Marian; Hlangu, Sindisiwe; Dickson-Hall, Lindy; le Roux, Sacha; Nicol, Mark; Cox, Helen
    Abstract Background Patient-centered care is pillar 1 of the “End TB” strategy, but little has been documented in the literature about what this means for people living with rifampicin-resistant (RR-TB). Optimizing care for such individuals requires a better understanding of the challenges they face and the support they need. Methods A qualitative study was done among persons living with RR-TB and members of their support network. A purposive sample was selected from a larger study population and open-ended interviews were conducted using a semi-standard interview guide. Interviews were recorded and transcribed and the content analyzed using an iterative thematic analysis based in grounded theory. Results 16 participants were interviewed from three different provinces. Four distinct periods in which support was needed were identified: 1) pre-diagnosis; 2) pre-treatment; 3) treatment; and 4) post-treatment. Challenges common in all four periods included: socioeconomic issues, centralized care, and the need for better counseling at multiple levels. Conclusions Beyond being a “very humiliating illness”, RR-TB robs people of their physical, social, economic, psychological, and emotional well-being far beyond the period when treatment is being administered. Efforts to tackle these issues are as important as new drugs and diagnostics in the fight against TB.
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    Barriers to implementation of Tuberculosis infection control amongst South African Health Care Workers
    (2012) Adeleke, Oluwatoyin; Rother, Andrea; Cox, Helen
    HIV co-infection and drug resistance worsen the burden of Tuberculosis in South Africa. Infectious TB cases, often undiagnosed and untreated, are commonly found in health facilities increasing the likelihood of health-care associated TB. Health Care Workers (HCWs; and clients) are particularly at risk of TB infection in health care facilities; such risk characterises TB as a dual public health threat; first as a communicable disease and second as an occupational health hazard. Tuberculosis infection control (TBIC) measures may reduce the risk of TB transmission in health care settings, yet HCWs face challenges implementing TBIC measures. There is a gap in operational research seeking to understand the barriers to TBIC implementation among HCWs. There is, therefore, an urgent need to generate qualitative data, using a behavioural and sociological approach that provides insight to TBIC implementation challenges among HCWs. This case study research explored the barriers to TBIC implementation among HCWs in Khayelitsha clinics. Among professional and lay HCWs, data was collected by direct observation, interviews, focus group discussions and review of previous TBIC clinic assessment reports. The data was analysed using thematic analysis and interpretive analysis. This minor dissertation is in four parts. The protocol (Part A) presents the concept note of the study and its methodology. A structured literature review (Part B) provides a background and broadly reviews previous research and findings on Tuberculosis infection control. The journal ready article (Part C) presents the study findings, while Part D presents the study tools and related resources (appendices). Although most HCWs recognise the importance of TBIC in preventing health-care associated TB, they commonly believed that the TB transmission risk is only significant in clinic areas where known TB patients are found, and as such emphasise TBIC measures in those areas. Measures such as use of respirators and masks are mostly prioritized by HCWs ahead of administrative and environmental measures that are potentially more effective in reducing TB infection. Barriers to TBIC implementation identified include: inadequate HCW training on TBIC, a non-responsive compensation policy and the perception that a busy clinic schedule leaves no time for TBIC implementation. Resource availability, adequate human resources and leadership were further identified as enablers for TBIC implementation.
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    Baseline prevalence and incidence and risk factors for new-onset drug induced hearing loss in adults receiving drug-resistant tuberculosis (DR-TB) treatment in Khayelitsha, South Africa
    (2013) Njuguna, Christine Wanjiku; Cox, Helen; Boulle, Andrew
    Treatment for drug-resistant tuberculosis (DR-TB) is longer and associated with more significant side-effects than drug susceptible TB. Second line injectable therapy using kanamycin, amikacin or capreomycin is associated with irreversible hearing loss. There is a scarcity of literature regarding the frequency of hearing loss as well as associated risk factors, particularly with long term use. This study aimed to determine the incidence and risk factors for hearing loss among patients receiving second line injectable drugs.
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    Clinical deterioration during antituberculosis treatment in Africa: Incidence, causes and risk factors
    (BioMed Central Ltd, 2010) Pepper, Dominique; Marais, Suzaan; Wilkinson, Robert; Bhaijee, Feriyl; Maartens, Gary; McIlleron, Helen; De Azevedo, Virginia; Cox, Helen; McDermid, Cheryl; Sokhela, Simiso; Patel, Janisha; Meintjes, Graeme
    BACKGROUND:HIV-1 and Mycobacterium tuberculosis cause substantial morbidity and mortality. Despite the availability of antiretroviral and antituberculosis treatment in Africa, clinical deterioration during antituberculosis treatment remains a frequent reason for hospital admission. We therefore determined the incidence, causes and risk factors for clinical deterioration. METHODS: Prospective cohort study of 292 adults who initiated antituberculosis treatment during a 3-month period. We evaluated those with clinical deterioration over the following 24 weeks of treatment. RESULTS: Seventy-one percent (209/292) of patients were HIV-1 infected (median CD4+: 129 cells/muL [IQR:62-277]). At tuberculosis diagnosis, 23% (34/145) of HIV-1 infected patients qualifying for antiretroviral treatment (ART) were receiving ART; 6 months later, 75% (109/145) had received ART. Within 24 weeks of initiating antituberculosis treatment, 40% (117/292) of patients experienced clinical deterioration due to co-morbid illness (n = 70), tuberculosis related illness (n = 47), non AIDS-defining HIV-1 related infection (n = 25) and AIDS-defining illness (n = 21). Using HIV-1 uninfected patients as the referent group, HIV-1 infected patients had an increasing risk of clinical deterioration as CD4+ counts decreased [CD4+>350 cells/muL: RR = 1.4, 95% CI = 0.7-2.9; CD4+:200-350 cells/muL: RR = 2.0, 95% CI = 1.1-3.6; CD4+<200 cells/muL: RR = 3.0, 95% CI = 1.9-4.7]. During follow-up, 26% (30/117) of patients with clinical deterioration required hospital admission and 15% (17/117) died. Fifteen deaths were in HIV-1 infected patients with a CD4+<200 cells/muL. CONCLUSIONS: In multivariate analysis, HIV-1 infection and a low CD4+ count at tuberculosis diagnosis were significant risk factors for clinical deterioration and death. The initiation of ART at a CD4+ count of <350 cells/muL will likely reduce the high burden of clinical deterioration.
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    Conceptualising the right to enjoy benefits of scientific progress and exploring its potential to enhance access to effective diagnosis and treatment of drug-resistant tuberculosis in South Africa
    (2019) Shawa, Remmy Malama; London, Leslie; Coomans, Fons; Cox, Helen
    The lack of access to effective diagnosis and treatment of drug-resistant tuberculosis (DR-TB) remains a persistent global challenge. Human rights arguments for access to treatment mostly focus on the right to health. However, a key challenge in access to effective diagnosis and treatment is the glaring absence of scientific research in neglected diseases such as TB. This thesis sets out to elaborate the right to enjoy the benefits of scientific progress and explore its potential to increase scientific research in DR-TB and consequently enhance access to effective diagnosis and treatment in South Africa. This research project was conducted using three interrelated sub-studies; a legal analysis sub-study which examines the current conceptualisation of the REBSP in international law; a policy analysis sub-study which interrogates South Africa’s legal and policy efforts towards the realisation of the REBSP and access to diagnosis and treatment for DR-TB; and a qualitative sub-study which explores the South African context regarding research and development (R&D) in general, and in DR-TB in particular. The qualitative sub-study included 17 stakeholders who are active in TB R&D, advocacy and policy work, from human rights and research institutions, government agencies, civil society organisations, and donor agencies. This thesis finds that the REBSP essentially ensures two things, namely the production of science and access to the benefits of scientific progress. However, most countries including South Africa have systems, policies and resources aimed at advancing the production of science but lack similar systems, policies and resources to purposely ensure the enjoyment of the benefits from scientific progress. Internationally, there is no clear guidance on the interpretation of the REBSP, making it difficult for states to domesticate it in their national policies and framework laws. A General Comment by a UN human rights monitoring body is therefore urgently needed to secure global consensus on the interpretation of the REBSP. In the meanwhile, South Africa can still draw inspiration for the REBSP and together with the right to health, use it to advance access to DR-TB diagnosis and treatment alongside many other interventions. To enable better access to effective diagnosis and treatment of DR-TB, this thesis recommends that South Africa i) develops systems that would make scientific progress and results accessible, and affordable; ii) removes system and regulatory barriers that hinder the conduct of research or that delay registration of new drugs; iii) monitors and regulates the conduct of third parties and prevent them from exploiting communities; iv) encourages pharmaceutical companies to provide free access to successful treatment and tools in communities where trials are conducted; and v) mobilises financial and technical resources and allocates them to DR-TB researchfrom drug discovery through to implementation science.
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    Population Structure of Mixed Mycobacterium tuberculosis Infection Is Strain Genotype and Culture Medium Dependent
    (Public Library of Science, 2013) Hanekom, Madeleine; Streicher, Elizabeth M; Van de Berg, Doreen; Cox, Helen; McDermid, Cheryl; Bosman, Marlein; van Pittius, Nicolaas C Gey; Victor, Tommie C; Kidd, Martin; van Soolingen, Dick
    BACKGROUND: Molecular genotyping methods have shown infection with more than one Mycobacterium tuberculosis strain genotype in a single sputum culture, indicating mixed infection. Aim This study aimed to develop a PCR-based genotyping tool to determine the population structure of M. tuberculosis strain genotypes in primary Mycobacterial Growth Indicator Tubes (MGIT) and Löwenstein-Jensen (LJ) cultures to identify mixed infections and to establish whether the growth media influenced the recovery of certain strain genotypes. Method A convenience sample of 206 paired MGIT and LJ M. tuberculosis cultures from pulmonary tuberculosis patients resident in Khayelitsha, South Africa were genotyped using an in-house PCR-based method to detect defined M. tuberculosis strain genotypes. RESULTS: The sensitivity and specificity of the PCR-based method for detecting Beijing, Haarlem, S-family, and LAM genotypes was 100%, and 75% and 50% for detecting the Low Copy Clade, respectively. Thirty-one (15%) of the 206 cases showed the presence of more than one M. tuberculosis strain genotype. Strains of the Beijing and Haarlem genotypes were significantly more associated with a mixed infection (on both media) when compared to infections with a single strain (Beijing MGIT p = 0.02; LJ, p<0.01) and (Haarlem: MGIT p<0.01; LJ, p = 0.01). Strains with the Beijing genotype were less likely to be with "other genotype" strains (p<0.01) while LAM, Haarlem, S-family and LCC occurred independently with the Beijing genotype. CONCLUSION: The PCR-based method was able to identify mixed infection in at least 15% of the cases. LJ media was more sensitive in detecting mixed infections than MGIT media, implying that the growth characteristics of M. tuberculosis on different media may influence our ability to detect mixed infections. The Beijing and Haarlem genotypes were more likely to occur in a mixed infection than any of the other genotypes tested suggesting pathogen-pathogen compatibility.
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    Rifampicin-resistant tuberculosis in Botswana: barriers and risk factors influencing patient outcomes, case detection, and linkage to effective care and treatment
    (2019) Boyd, Rosanna M; Cox, Helen
    Background: Botswana reports high treatment success for rifampicin-resistant tuberculosis (RR-TB), but many challenges remain. Case detection is lower than expected and varies by year, and mortality rates are high. Research aims included identifying: factors associated with mortality, access to culture and drug susceptibility testing (DST) for patients at risk of RR-TB, access to first- and second-line DST among RR-TB patients, time to RRTB treatment, and patient and provider experiences with RR-TB management. Methods: Retrospective data (multiple cohorts across 2006-2014) were extracted from Botswana national registers and information systems, with additional data collected by standardized, qualitative interviews (2017). Data analyses (Cox proportional hazards regression, survival and hazards curves, logistic regression) were conducted to describe significant associations. A systematic review and meta-analysis was conducted. Thematic analysis was performed for qualitative research. Results: There was low access (42%) to culture testing among patients at risk of RR-TB (previously-treated TB patients); particularly associated with rural residence and having previous successful TB treatment, compared to previous treatment failure. While confirmation of first-line drug resistance was available for 85% of patients initiating RR-TB treatment, access to second-line DST was poor (24%), impacted by limited in-country laboratory capacity. Genotypic DST by Xpert MTB/RIF at peripheral laboratories was associated with faster time to treatment from diagnosis compared to phenotypic DST at the centralized national lab, 5 versus 22 days (median, p<0.001), consistent with systematic review findings of time to RR-TB treatment. Risk factors for mortality during treatment included unconfirmed RR-TB (aHR 2.9), Pre/XDR-TB (aHR 2.5), HIV positivity without ART (aHR 3.6) and receiving treatment at two (of five) specific facilities (aHR 2.6 and 2.3). Qualitative interviews confirmed inconsistent adherence to national policies and identified additional challenges including frequent medication and reagent stock-outs, misperceptions about disease transmission from both providers and patients, and inadequate national level support for the RR-TB program. Conclusion: Several clinical and demographic factors negatively influencing case detection and RR-TB mortality in Botswana were identified. General health system dysfunction and poor political commitment to the RR-TB program also contributed. Recommendations include increased focus on: early diagnosis through universal DST, consistent access to effective drugs, and overall adherence to policies.
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    The Epidemiology and Evolution of Rifampicin Mono Resistant Tuberculosis in Khayelitsha, Cape Town, South Africa
    (2021) Salaam-Dreyer, Zubeida; Cox, Helen
    Background: According to the World Health Organization Global TB report 2018, rifampicin monoresistant tuberculosis (RMR-TB) comprises 22% and 38% of all rifampicin-resistant TB (RR-TB) globally, and within South Africa, respectively. National surveys from South Africa show an increasing proportion of RMR-TB among TB cases compared to multi-drug resistant tuberculosis (MDR-TB) from 2001-02 (0.4% vs 2.9%) to 2012-14 (1.7% vs 2.8%). Data from the 2012-14 survey showed considerable variation in RMR-TB prevalence throughout the nine provinces of South Africa. Despite the above, factors associated with the rise in RMR-TB are unknown; and research is limited. This thesis aims to describe RMR-TB in more detail, by investigating the emergence and transmission of RR-TB strains in Khayelitsha, Western Cape Province, South Africa. This included: conducting a systematic review on temporal trends, transmission and risk factors associated with RMR-TB; describing the overall prevalence of RMR-TB among RR-TB; assessing the relative risk of RMR-TB versus MDR-TB among RRTB patients by HIV status during prior TB treatment; describing the distribution of rpoB mutations among RR-TB strains and assessing minimum inhibitory concentration (MIC) values in RR-TB strains with particular rifampicin-resistance (RIF R) conferring mutations; and investigating potential transmission through whole genome sequence (WGS) derived clusters among RR-TB strains. Methods: Routinely diagnosed RR-TB isolates are stored in a biobank at Stellenbosch University (SU). Clinical data (Médecins sans Frontières and additional data requested from the Western Cape Provincial Health Data Centre), together with stored RR-TB isolates from the biobank across 2013-15 inclusive were used to address research questions in Khayelitsha. To describe the overall prevalence of RMR-TB among all RR-TB over time, epidemiological data from 2008-17 were used. Laboratory techniques (sub-culturing of stored frozen cultures into mycobacterial growth indicator tubes [MGITs] for DNA extraction and quantitative phenotypic DST [q pDST]) involving the handling of live Mycobacterium tuberculosis cultures, were done in a Biosafety Level 3 laboratory at SU. Extracted DNA was sent to the University of Basel in Switzerland for library preparation and whole genome sequencing (WGS) on the Illumina HiSeq. The raw fastq WGS data files of the sequenced DNA were securely transferred to UCT. TB profiler was used to identify RIF R conferring mutations in rpoB and strain lineages. rpoB mutations were classified as high/moderate and minimal confidence in conferring rifampicin-resistance. q pDST (MGIT) was performed for isolates with minimal, moderate and rpoB confidence level mutations that were not classified. q pDST was also performed on isolates found to be rifampicin susceptible TB (RS-TB using WGS) [no RIF R conferring rpoB mutations detected] but were isolated from patients routinely diagnosed with RR-TB. A combination of software packages was used, as well as in-house developed scripts to compile a pipeline for WGS transmission cluster analysis. Computations were performed using facilities provided by UCTs ICTS High Performance Computing (HPC) team. Clusters were identified with Clusterpicker and by generating a single nucleotide polymorphism (SNP) distance matrix (SNP differences found between genomes) using R software; a SNP threshold of 12 was used to suggest recent transmission. Results: i) The overall prevalence of RMR-TB among all RR-TB remained relatively stable (17-31%) with no major temporal trend observed during 2008-17 in Khayelitsha. ii) The proportion of RMR-TB among all RR-TB was significantly higher among patients who were HIV positive during previous TB treatment compared to those who were HIV negative. iii) A high proportion (11%) of discordance was found among RIF R routinely diagnosed RR-TB patients (43% RMR-TB; 57% MDR-TB); resulting from possible mixed infections (43%), false-positive RIF R (18%) or both (39%). iv) The WGS-based DR-TB profile for rpoB mutations were distinctly different between RMR- and MDR-TB strains. The proportion of high/moderate vs minimal confidence levels for rpoB mutations was significantly higher among MDRTB (high confidence rpoB S531L mutation - Lineage 2) than for RMR-TB. v) Among RMR-TB strains, rpoB L511P (described as a disputed mutation, conferring minimal confidence for RIF R or low-level RIF R) was predominantly found among RMR-TB strains compared to MDR-TB strains. All rpoB L511P mutations (including RMR- and MDR-TB) tested phenotypically susceptible to rifampicin with MGIT; causing discrepancies between WGS and q pDST. All RMR-TB strains, including those with rpoB L511P mutations, had no other mutations conferring resistance to any of the other TB drugs. vi) Clustering was higher among MDR-TB strains compared to RMR-TB and more MDR-TB strains were clustered among strains with the rpoB S531L mutation compared to RMR-TB with the same mutation. In contrast, among strains with the rpoB L511P mutation, more RMR-TB strains were clustered compared to no clustering found among MDR-TB strains with the same mutation. Clinical data showed that RMRTB rpoB L511P clusters were due to closely related community acquired or nosocomial transmission; and SNP differences were < 5, suggesting direct transmission between RMR-TB rpoB L511P patients. Conclusion: In Khayelitsha, lower clustering of RMR-TB strains suggests reduced transmission compared to MDR-TB and along with a different rpoB mutation profile, suggests a different evolutionary mechanism of RIF R. Additionally, RMR-TB appears to be associated with HIV positivity during previous TB treatment, suggesting a role for HIV in the generation of RMR-TB. Given the association of rpoB L511P with low-level RIF R among RMR-TB strains, it is possible that different treatment approaches could be effective for these patients, as there are also no clinical trials to optimise treatment of these patients. WGS is beneficial, not only for understanding transmission of RR-TB strains, but also to be used in combination with MIC testing for individualised patient treatment regimens, in order to accurately diagnose RR-TB in future. Recommendations for preventing M.tb transmission; irrespective of HIV status; include early diagnosis and treatment initiation, and implementation of infection control programmes in various settings.
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    Whole genome sequencing reveals complex evolution patterns of multidrug-resistant Mycobacterium tuberculosis Beijing strains in patients
    (Public Library of Science, 2013) Merker, Matthias; Kohl, Thomas A; Roetzer, Andreas; Truebe, Leona; Richter, Elvira; Rüsch-Gerdes, Sabine; Fattorini, Lanfranco; Oggioni, Marco R; Cox, Helen; Varaine, Francis
    Multidrug-resistant (MDR) Mycobacterium tuberculosis complex (MTBC) strains represent a major threat for tuberculosis (TB) control. Treatment of MDR-TB patients is long and less effective, resulting in a significant number of treatment failures. The development of further resistances leads to extensively drug-resistant (XDR) variants. However, data on the individual reasons for treatment failure, e.g. an induced mutational burst, and on the evolution of bacteria in the patient are only sparsely available. To address this question, we investigated the intra-patient evolution of serial MTBC isolates obtained from three MDR-TB patients undergoing longitudinal treatment, finally leading to XDR-TB. Sequential isolates displayed identical IS 6110 fingerprint patterns, suggesting the absence of exogenous re-infection. We utilized whole genome sequencing (WGS) to screen for variations in three isolates from Patient A and four isolates from Patient B and C, respectively. Acquired polymorphisms were subsequently validated in up to 15 serial isolates by Sanger sequencing. We determined eight (Patient A) and nine (Patient B) polymorphisms, which occurred in a stepwise manner during the course of the therapy and were linked to resistance or a potential compensatory mechanism. For both patients, our analysis revealed the long-term co-existence of clonal subpopulations that displayed different drug resistance allele combinations. Out of these, the most resistant clone was fixed in the population. In contrast, baseline and follow-up isolates of Patient C were distinguished each by eleven unique polymorphisms, indicating an exogenous re-infection with an XDR strain not detected by IS 6110 RFLP typing. Our study demonstrates that intra-patient microevolution of MDR-MTBC strains under longitudinal treatment is more complex than previously anticipated. However, a mutator phenotype was not detected. The presence of different subpopulations might confound phenotypic and molecular drug resistance tests. Furthermore, high resolution WGS analysis is necessary to accurately detect exogenous re-infection as classical genotyping lacks discriminatory power in high incidence settings.
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    Wind-driven roof turbines: a novel way to improve ventilation for TB infection control in health facilities
    (Public Library of Science, 2012) Cox, Helen; Escombe, Rod; McDermid, Cheryl; Mtshemla, Yolanda; Spelman, Tim; Azevedo, Virginia; London, Leslie
    Objective Tuberculosis transmission in healthcare facilities contributes significantly to the TB epidemic, particularly in high HIV settings. Although improving ventilation may reduce transmission, there is a lack of evidence to support low-cost practical interventions. We assessed the efficacy of wind-driven roof turbines to achieve recommended ventilation rates, compared to current recommended practices for natural ventilation (opening windows), in primary care clinic rooms in Khayelitsha, South Africa. METHODS: Room ventilation was assessed (CO 2 gas tracer technique) in 4 rooms where roof turbines and air-intake grates were installed, across three scenarios: turbine, grate and window closed, only window open, and only turbine and grate open, with concurrent wind speed measurement. 332 measurements were conducted over 24 months. FINDINGS: For all 4 rooms combined, median air changes per hour (ACH) increased with wind speed quartiles across all scenarios. Higher median ACH were recorded with open roof turbines and grates, compared to open windows across all wind speed quartiles. Ventilation with open turbine and grate exceeded WHO-recommended levels (60 Litres/second/patient) for 95% or more of measurements in 3 of the 4 rooms; 47% in the remaining room, where wind speeds were lower and a smaller diameter turbine was installed. CONCLUSION: High room ventilation rates, meeting recommended thresholds, may be achieved using wind-driven roof turbines and grates, even at low wind speeds. Roof turbines and air-intake grates are not easily closed by staff, allowing continued ventilation through colder periods. This simple, low-cost technology represents an important addition to our tools for TB infection control.