Clinical And Biomedical Tuberculosis Research Unit
Current projects
Completed Projects
The below account represents current activity in the unit.
TB and HIV interaction: An evaluation of the impact of the interaction on the clinical outcome of HIV-related TB. This study focused on evaluating immunological parameters in conjunction with clinical and mycobacteriologic parameters longitudinally in a cohort of co infected patients and assessed the impact of these factors on treatment outcomes. The results are as follows:
At the time of TB diagnosis, HIV-1 prevalence was 66% and TB disease in HIV-1 infected individuals occurred across a broad spectrum of AIDS defining illness (ADI) and CD4 counts. TB disease rarely occurred in the absence of other ADI. Fifty percent of individuals were co-infected with intestinal parasites; there were no significant associations with HIV Viral Load (VL) and the presence or the successful treatment of intestinal parasitic infections at 6 months or 12 months respectively. Moreover, while CD4 T-cells differed statistically significantly by HIV status (p=0.0006) and improved by over 100 cells in the HIV negative group, there was no significant associations with CD4 T-cells and the presence or the treatment of intestinal parasitic infections at 6 or 12 months respectively. The overall TB cure rate after 6 months of TB DOT was 75.8% (97/128). A similar proportion of individuals from the HIV positive group (9.4%) and HIV negative group (9.3%) interrupted treatment. HIV positive subjects had a slightly increased risk of treatment failure (RR=1.14) and 6 HIV positive subjects (7.1%) died during TB treatment, while no HIV negative subject died. One year after the end of TB treatment 3 subjects had relapse, 2 HIV positive subjects (2.4%) and 1 HIV negative subject (2.3%). Among HIV positive patients the viral load remained high and unchanged during TB therapy. The mean CD4 counts, increased for the HIV-negative individuals by 173 (at 18 months) and was approximately unchanged for the HIV positive individuals. A sub-study investigated changes in naïve T-cells and activated T-cells in response to 6 months anti-TB therapy. Changes in blood dendritic cells were also assessed using the flow cytometry. Significantly lower proportion of CD4+ and CD8+ naïve T-cells were observed in subjects co-infected with TB and HIV-1 indicating greater immune degradation in this group. The data also shows an increased proportion of chronically activated CD4+ and CD8+ T-cells in the co-infected group which persisted during anti-TB therapy and thereafter for six months. In contrast the proportion of activated T-cells decreased in the TB only infected subjects. Therefore the data indicates that persistent HIV-1 infection overrides immune quiescence after TB treatment. HIV-1 RNA levels were not reduced during TB treatment; thus, viral replication drives immune activation. This study provided an opportunity to study the immune responses relevant to our population. Further, the high rates of HIV among those with active tuberculosis provides an efficient approach for identifying individuals with HIV who are likely to benefit most from interventions designed at HIV/AIDS care and management. The lack of evidence for immune-reconstitution highlights the opportunity to introduce anti-retrovirals to these patients. This study therefore informs the timing of antiretroviral therapy initiation by describing the spectrum of CD4 levels and concomitant AIDS related illnesses in dually infected individuals particularly in resource poor settings where it is recommended that ARV is commenced later in the course of HIV disease as determined by CD4 T-cell counts.
The research project was a collaborative effort between researchers at the South African Medical Research Council (Unit for Clinical and Biomedical TB Research); the National Institute of Virology, Johannesburg, South Africa; and the Nelson R Mandela School of Medicine.
Funding: in part from a DACTS grant and by the National Institute of Communicable Diseases.
Principal Investigator: Roxana Rustomjee
Other Investigators: PC Onyebujoh, C Gray, J Levin and P Sangweni
Time span: 15 August 2000 - 13 May 2003
Status: Submission for publication
Related sub-study
Immune responses in individuals infected with Mycobacterium tuberculosis and HIV-1 before and after TB treatment.
T cell responses to Mycobacterium tuberculosis antigen Esat-6 were evaluated using the Elispot assay. Intracellular Cytokine Assay and CD4+ and CD8+ depletions Assay were used determine whether these responses were CD4+ or CD8+ T cell mediated. The data indicated that subjects infected with TB have higher IFN-γ responses compared to healthy controls. There was a decrease in anti-TB responses overtime indicating that these responses are antigen driven responses. Both CD8+ and CD4+ T cells produced IFN-γ in response to Esat-6 indicating that CD8+ T cells also play an important role in immune response to TB.
Funding: Piggy-backed on DACTS Grant
Principal Investigator: Clive Gray (NICD)
Investigator: Phumelele Sangweni (MRC) - Master of Med Science (Virology)
Status: Manuscript Preparation
Rifapentine Early Bactericidal Activity (EBA): Randomized Clinical Trial
A study comparing the early bactericidal activities of a range of dose sizes of rifampicin and rifapentine was carried out on 123 patients at Durban and Cape Town. Patients received either daily doses of 600, 300 or 150 mg rifampicin for 5 days or one dose of 300, 600, 900 or 1200 mg rifapentine. Sputum was collected before treatment and after treatment for 2 and 5 days. EBAs were calculated as the daily fall in the colony forming units of tubercle bacilli in the sputum over the first 2 days, the last 3 days or the entire 5 days of treatment. The response of both rifamycins was similar with a linear relationship to log dose size at lower doses and a curvilinear relationship at the higher doses, such that there was a plateau at a dose size of 1136 mg rifapentine. While this result suggested that 900 mg rifapentine might be the optimal dose size, further evidence, particularly from the curve obtained during the last 3 days of treatment, suggested that it would be wise to conclude that the optimal dose should be 1200 mg rifapentine once weekly.
Principal Investigator: F. A. Sirgel
Collaborators Nesri Padayatchi, P.R. Donald, P. B. Fourie, J. Levin, G. Roscigno, D.A. Mitchison and the Rifapentine EBA Collaborative Study Group
Status: Data ready for publication
Funding: Aventis
Principal Investigator: Nesri Padayatchi / B Fourie
Other Investigators: I Master, A Ramjee, G Osburn, R Rustomjee, F Sirgel
Time span: October 2001 - November 2002
Status: Manuscript submission
Being analysed
A Comparative Study Of The Bactericidal And Sterilising Activity Of Three Fluoroquinolones: Gatifloxacin, Moxifloxacin And Ofloxacin; Substituted For Ethambutol In The 2-Month Initial Phase Of The Standard Anti-Tuberculosis Treatment Regimen Containing Also Rifampicin, Isoniazid And Pyrazinamide.
In an attempt to reduce further the duration of treatment, several drugs have been proposed, including the quinolones. Currently, it takes at least six months to treat and cure a case of tuberculosis. In many cases, patients find it difficult to maintain the schedule of daily chemotherapy for such a long period of time, default from treatment, and in most instances then experience recurrent disease with tuberculosis-causing organisms that might be multi-drug resistant. Courses of treatment significantly shorter than 6 months would have major operational advantages, and would save greatly on expenditure associated with patient monitoring, and tracing of lost cases. This study aims to evaluate a potential treatment-shortening regimen containing the fluoroquinolone, gatifloxacin. The quinolones, gatifloxacin and moxifloxacin have MIC’s (minimum inhibition concentration) 4 times lower that the MIC of ofloxacin against Mycobacterium Tuberculosis. There is a need to assess the comparative activity of these quinolones in tuberculosis. Serial sputum viable counts can measure the penetration and the activity of the 3-flouroquinolone containing regimens and a non-flouroquinolone containing control regimen on active bacilli in cavities over the initial phase of 8 weeks of treatment. The therapeutic margin is the best estimate of how well the drug penetrates and whether it can be expected to be active in all lesions in which there may be different degrees of drug penetration. Statistical methods will assess the bactericidal and sterilising potencies of the drugs. Participant recruitment began in July 2004.
Funding: WHO/TDR and European Communities Commission
Project Leader: B Fourie
Principal Investigator: R Rustomjee
Co-Investigators: JB Levin; N Padayatchi; A Ramjee; S Bamber; J Allen; F Sirgel; Professor Sturm
Time span: 2003-2006
WHO/TDR Survey of TB Diagnostic Test Prices, Practices and Preferences in 7 High Burden Countries
This project is carried out in collaboration with The Tuberculosis Diagnostics Initiative (TBDI), academic investigators, public health experts, disease control programs and their associated laboratory networks, and with the diagnostic industry at different centers around the world. The mission of TBDI is to facilitate the discovery, development, evaluation and appropriate deployment of diagnostic tools to support TB control in endemic settings. This project aims to make a comprehensive assessment of the market for TB diagnostic tests must examine the range of public sector and retail prices and diagnostic practices applied in a sample of laboratories, health facilities and physicians in public and private sectors of high and low-burden countries.
Funding /Source: WHO/TDR
Start/End Date: November 2003/2004
PI: Roxana Rustomjee
Current studies
A Randomised Open-Label Controlled Trial Of A 4 Month Gatifloxacin-Containing Regimen vs Standard 6 Month Regimen For The Treatment Of Adult Patients With Pulmonary Tuberculosis
This proposal seeks to assess the bacteriological and clinical efficacy of a gatifloxacin-containing short-course regimen for the treatment of pulmonary TB. It is a multi-centre randomised control trial that will be conducted jointly in 5 anglophone and francophone countries in Africa, with the collaboration and support of 5 European institutions. The study aims to (i) compare the efficacy and sterilising activities of gatifloxacin-containing four-month combined regimen in the treatment of pulmonary TB in comparison with a standard 6-month short-course regimen; (ii) develop research capacities to conduct clinical trials in developing countries and provide the necessary infrastructure to enable it through appropriate training and technology transfer; (iv) reinforce structures aiming at conducting clinical trials in developing countries with the aim of developing a clinical trial centres network based around sites of excellence for field research and (v) form a platform for the clinical assessment of new drugs or vaccines for the treatment or prevention of tuberculosis, and collaborating centres will be able to mount their own research projects and participate to further international multi-centre trials of drugs or vaccines.
Funding: European Communities Commission
Project Leader: B Fourie
Principal Investigator: R Rustomjee, (South Africa)
Time span: 2003-2006
Ongoing
WHO/TDR Tuberculosis Specimen Bank
The purpose of the WHO/TDR Tuberculosis Specimen Bank is to assemble a source of well-characterized clinical specimens from patients suspected of having tuberculosis from distinct geographical sites around the world. These specimens will be used to assist in the development and evaluation of new products for the diagnosis of tuberculosis appropriate for use in low-income countries.
In the long term this project will assist in promoting product comparisons, facilitating quality control and encouraging investment in TB diagnostics by providing reliable reference materials.
Funding: WHO/TDR
Principal Investigator: R Rustomjee
Co-Investigators: Ms Thuli Mthiyane
Ongoing
New projects
TB Treatment and HAART: An evaluation of the impact of early initiation of HAART on TB treatment outcomes for TB patients co-infected with HIV
The high rates of HIV among those with active tuberculosis provides an efficient approach for identifying individuals with HIV who are likely to benefit most from interventions designed at HIV/AIDS care and management. The lack of evidence for immune-reconstitution highlights the opportunity to introduce anti-retrovirals to these patients. This study therefore informs the timing of antiretroviral therapy initiation by describing the spectrum of CD4 levels and concomitant AIDS related illnesses in dually infected individuals particularly in resource poor settings where it is recommended that ARV is commenced later in the course of HIV disease as determined by CD4 T-cell counts. In the light of this, further research has been developed to provide the evidence for optimizing and improving the management of TB in high HIV prevalent settings and two grant applications have been successful viz. to introduce HAART concomitantly with TB treatment for individuals with a range in CD4 T cell levels in order to study pharmacokinetic interactions as well as to determine the optimal timing for the introduction of ARVs.
Funding: WHO/TDR
Principal Investigator: R Rustomjee
Co-Investigators: Ms Thuli Mthiyane; PC Onyebujoh A Zumla, J Levin
Time span: 2005-2008
Submitted to ethics
Bioavailability of the fixed dose formulation rifafour containing isoniazid rifampicin pyrazinamide and ethambutol administered to new TB patients at different levels of immunosupression
This study proposes to assess the bioavailability of Fixed drug combination antituberculosis (TB) drugs (Rifafour) containing rifampicin, isoniazid, pyrazinamide and ethambutol in treatment naive TB patients with and without HIV (stratified into groups dependent upon CD4 counts) and to determine the extent and effect of malabsorption of these drugs measured repeatedly in the blood and in the urine post trial drug administration. This study is a collaborative project between the WHO Tropical Disease Research, Medical Research Council's Unit for Clinical and Biomedical TB Research Programme, Durban, KwaZulu Natal, South Africa and the Department of Pharmacology at the University of Cape Town.
Funding: WHO/TDR
Project Leader: Mrs J. Allen
Principal Investigator: R Rustomjee
Co-Investigators: Dr H McIlleron, Dr P Smith, Dr J Levin, Mrs J Allen
Time span: 2005-2008.
Submitted to ethics
Rapid Evaluation Of Moxifloxacin In The Treatment Of Sputum Smear Positive Tuberculosis: REMoxTB
Principal Investigator: Dr R Rustomjee
Project Leader: Professor Stephen Gillespie
Moxifloxacin, an 8-methoxyquinolone has been identified in in vitro and in vivo studies as an agent with the potential to shorten the duration of chemotherapy in tuberculosis. We argue that if treatment is to be shortened significantly the new regimen should produce a more rapid sputum conversion than the currently recommended four drug regimen. This novel approach to clinical trial monitoring will permit new drugs to be evaluated more rapidly and will be the essential prelude to trials of four month regimens. Earlier studies have suggested that some of the components of the current therapeutic regimen may be antagonistic so in this study we propose to investigate the ability of moxifloxacin to substitute for either ethambutol or isoniazid. This will also reveal how quinolones should be used when managing patients with resistance to these agents. Our proposed study will build on three established tuberculosis clinical trials sites conducted at University College London, Kibon’goto National Tuberculosis Hospital and Tumaini University, Tanzania, the University Teaching Hospital, Lusaka, Zambia and SAMRC Tuberculosis Programme, Durban, South Africa. The enrolment period will be 24 months
The capacity strengthening component of this application will improve the physical and human resources capacity to trial new agents in the future. The study described here is linked to the ongoing tuberculosis clinical studies at each site. This study will also be supported by the work of the Nuffield Foundation Programme Grant “Science training and institutional strengthening”. It will also link to plans being finalised by the Liverpool School of Tropical Medicine, UCL and the WHO standards laboratory in Lyons to develop Masters programmes in three sub-Saharan countries.
Funding: European and Development Countries Clinical Trials Partnership (EDCTP)
Time span: 2005-2007
Submitted to ethics and MCC
Studies On Surrogate Markers Of Drug Efficacy, Disease Activity And Relapse In Tuberculosis
Principal Investigator: Dr R Rustomjee (South African site)
Project Leader: Prof. Ali Zumla (University College London)
This proposal involves a multi-country partnership involving 8 African partners (Zambia, Tanzania x2, South Africa, Senegal, Madagascar, Ethiopia and Gambia) and 5 European partners (United Kingdom x2, Germany, Denmark and France). The African sites represent all corners of sub-Saharan Africa. It is planned to perform trials of surrogate markers of drug/treatment efficacy, emphasizing non-clinical predictors of sterilizing activity and relapse following anti-TB therapy. We propose to setup two major cohorts of patients: a) newly diagnosed adult patients (HIV-positive and HIV-negative) with tuberculosis followed-up over time, and b) contacts of tuberculosis patients (HIV-positive and HIV-negative) without tuberculosis who proceed to developing tuberculosis on follow-up. (four of our African partners on EU-funded VACSIS project have already established these cohorts). The following surrogate markers of disease activity and drug efficacy will be studied in these study groups: a) bacterial load: sputum colony counts, LAM in urine, blood and sputum, DNA in urine, b) biochemical and molecular parameters: CRP, ESR, TNF, apoptotic markers; and c) immunological markers: serological, cytokines, micro-array and ELISPOT. These data will be studied on all cohorts at all sites and correlated with treatment success, relapse and disease activity. We anticipate that all sites, as far as possible, will perform all assays in parallel. Those newer markers being currently developed will be applied to stored samples from the study groups. These studies are of relevance and will affect policy and practice in Africa. This proposal incorporates training, capacity and infrastructure development aspects.
Funding: WHO/TDR
Time span: 2006-2007
Updated: 31 July, 2006 |
