TB Epidemiology and Intervention Research Unit
Current projects
Administration and Management
Principal Investigator: M vd Walt (MRC)
Project Leader: M vd Walt (MRC)
Objectives
To provide research direction, administrative and management support to baseline and externally funded projects, to secure external contracts and grants and to provide financial monitoring of projects.
Status
Ongoing and productive. General management and activities of the Unit was supported, 25 staff members and R491 722 (baseline) projects.
WHO Supranational Reference Laboratory
Principal Investigator: M vd Walt
Project Leader: P Mativandlela, NB Bapela
Objectives
- To provide bacteriological support to other research activities of the Unit,
- as SRL to provide (i) An external proficiency testing program (EPT) on drug susceptibility (DST) for first- and second line drugs for SADC countries, (ii) assistance to countries with drug-resistance surveys; (iii) training of laboratory staff from national and regional TB laboratories, to conduct site visits and conduct laboratory assessments, and (iv) participate in the development of an EPT program for line probe assays.
- Health monitoring of all staff (internal and external) involved in laboratory related tuberculosis projects.
- Maintenance of the Laboratory and animal facilities to ensure biosafety level II and III standards.
Research
- The PETTS project (Preserving Effective TB Treatment with Second-Line Drugs) received support regarding microscopy and culture.
- The MRC AIR facility in Witbank constantly receives bacteriological support in the form of microscopy, culture, identification, first and second line drug susceptibility tests.
- Drug susceptibility testing using the Hain line probe assay (LPA) was completed on cultures from all failure and death patients - DOTS Plus study.
- Collaboration with University of Norway and Stellenbosch is currently underway for molecular characterization of strains from our various culture collections
SRL
- Training: Nigeria, Botswana, Malawi, Zimbabwe and Swaziland.
- Regional country support: Botswana, Lesotho, Swaziland, Zimbabwe and Zambia
- Policy development: Review of requirements for second African SRL
- Proficiency testing: Line probe assay external proficiency testing program development.
(LPA EPT program)
Maintenance
A maintenance program is in place to ensure biosafety level II and III standards in the laboratories are maintained at all times. Calibration of equipment (biosafety cabinets, balances, microscopes etc) is performed bi-annually or annually (autoclaves, centrifuges, pH meters and freezers). These efforts are costly and accounts for the high financial burden with regards to the maintenance of the laboratory.
DOTS-Plus for MDR-TB patients in South Africa
Principal Investigator: M van der Walt (MRC)
Project leader: J Lancaster (MRC)
Objectives
To evaluate the efficacy and effectiveness of a standardised approach to the management of MDR-TB in South Africa.
Status
Ongoing and productive. A systematic evaluation of the effectiveness of the standardised MDR-TB regimen was carried out on 2079 patients enrolled between 2000 and 2004. A retrospective record review to determine the five-year follow-up status of the 2079 patients enrolled, started November 2008 and will continue till July 2011 403/2079 cases were not eligible for follow-up (367 died during treatment; 36 transferred) and 1676/2079 patients were eligible for follow-up (1066 were cured or completed treatment; 186 were treatment failures; 424 treatment defaulters). At five year follow-up data were available for 765/1676 (46%) patients who were eligible for follow-up, for 16% records could not be found, 11% died 1% transferred and 2% completed follow-up. All MDR centres were visited to determine the prevalence of MDR in all provinces for the period 2000 – 2010 as no formal national statistics are available. The data base of the NHLS will be used to identify any patients who had been enrolled in the study and had an outcome of treatment completion or treatment cure, who were again diagnosed with MDR-TB during the five year follow-up.
TB Drug evaluation
Principal Investigators: P Mativandlela
Project Leader: P Mativandlela, NB Bapela
Collaboration: University of Pretoria – Plant Science and Pharmacology Departments, CSIR (Modderfontein) - Biosciences
Objective
In vitro and in vivo evaluation of natural products or isolated compounds to determine anti –Mycobacterium tuberculosis activity.
The project is also supporting a national research platform for drug development with particular focus on indigenous medicinal plants and synthesized compounds. Compounds received are subjected to the three levels of in vitro testing. Compounds found to be active in the in vitro testing model are further tested in vivo in a mouse and guinea pig models.
Status
Ongoing: Several compounds have been tested in this laboratory for the activity against Mycobacterium tuberculosis. Intracellular mechanisms of action on human cell lines, on potential antituberculosis compounds are also tested for their in vitro activity. Collaborations with national and international research groups are currently in the pipeline. Drs Mativandlela and Bapela attended training on animal models for TB at Colorado State University and also the NRF/DST Research Expertise Advancement Programme at Emory University.
Ongoing Projects: Contracts / Grants
Improving access to HIV care for tuberculosis patients in South Africa through a best-practices approach (PEPFAR Project) – Expansion to North West, Eastern Cape, Western Cape
Principal Investigator: M van der Walt (MRC)
Project Leader: M Uys (FPD)
Objectives
To expand the delivery of ART for TB patients in South Africa, using lessons learnt from the best-practice model approach.
Status
Ongoing and productive. Thus far several that’sit sites have been implemented across four provinces in South Africa. Activities at the sites are ongoing and on target (PEPFAR targets). Collaborative research between MRC/FPD/CDC to assess adherence of TB patients on dual therapy has been designed and will be initiated in the next budget period. Several conference posters and other outcomes have been generated by FPD staff.
Preserving the effectiveness of tuberculosis treatment with second-line drugs (PETTS Study)
Principal investigators: M van der Walt (MRC)
Project Leader: J Lancaster (MRC), J Brand (MRC), T Dalton (CDC), P Cegielski (CDC), M Wolfgang (CDC), R Odendaal (MRC)
Objectives
To assess whether MDR-TB treatment leads to amplification of second-line drug resistance and to determine the risk factors (if any) for amplification.
Status
Ongoing and productive. Enrolment of 539 patients has been completed June 2008 and data collection had been completed 30 June 2010. During preliminary data analysis it was found that 530 patients had been enrolled and had a final outcome, 54% was found to be HIV positive, 91% were treated before with first line drugs (FLD), 6% were never treated before with FLD and 3% were treated with SLD before. Classification of previous treatment: 20% were treated after cure, 33% were treatment failure, 6% defaulted treatment, 7% are chronic MDR-TB patients and 26% started treatment as FLD sensitive TB and were found to have MDR-TB during treatment period. On September 2010 the last of the specimens for genotyping were sent to CDC, and have been included among the 1562 baseline specimens from all sites investigated. Among these specimens MDR-TB was confirmed in 1320 isolates (all sites). 6% had XDR-TB at onset of treatment and prevalence of XDR in all eight sites range between 8% to 11.4%. DST and genotyping of follow-up isolates will allow assessing the frequency of acquired XDR-TB. To prevent worsening resistance, MDR-TB patients should be treated with ≥4 effective drugs based on DST and treatment history. Final Data cleaning is in progress for analysis to start 1 April 2011.
Implementation of a TB /HIV Infection Control and Prevention project at 6 TB hospitals and 10 primary health care centres of the Western Cape Department of Health
Principal investigators: M van der Walt (MRC), Jason E. Farley (Johns Hopkins University)
Project Leader: M Mphahlele (MRC)
Collaboration:Johns Hopkins University – Western Cape Department of Health
Objective
The objective of this study was to systematically evaluate the infection control (IC) and occupational health infrastructure of drug-resistant TB facilities and HCW IC knowledge, attitudes and practices in 6 MDR-TB hospitals and 10 primary health care centres the Western Cape. We enrolled over 100 healthcare workers from the province in the knowledge, attitudes and practice survey. Findings have identified numerous gaps in infection control practices throughout the province.
Status
Completed. Training for HCW was conducted in February 2010. This included further identification of barriers to implementation of IC practices in these settings and provided a hands-on training for evaluating UVGI fixtures and calculations of air exchanges in wards. Abstracts from this project have been presented at various meetings and conferences. A final project report was submitted to the WC National Department of Health in December 2010.
Results
Directly observed IC practices were incongruent with practices reported by key-informants in all settings. 128 HCW were surveyed in 6 M/XDR TB facilities in the Western Cape with more (79.7%) female participants than males. The mean years of experience in the current position was 10.2 (10.7) years (range 0 – 42 years). Of 5 (83.3%) facilities with UVGI only one had a maintenance plan. Only 49 (39.8%) HCWs who stated they receive annual TB symptom screening from the hospital. Five HCWs working in M(X)DR-TB facilities acknowledged being HIV+. Higher levels of training were associated with higher Infection Control knowledge.
Our study also revealed that only 2 of PHC centers had infection control plans specific to their facilities. There were adequate supplies of protective clothing in the majority 8 (80%) of facilities; the greatest need was for training and conducting TB risk assessments. There was no cohorting of TB patients and only 5 (50%) of the facilities had designated infection control officers on site.
International training and research center for MDR-TB/HIV and infection control
Principal Investigators: M van der Walt (MRC)
Project Leader: M van der Walt (MRC); L Podewills (CDC - Research) and P Jensen (CDC – Infection control)
Training
Training in Infection Control: Objectives
To develop a solid base of highly skilled professionals to lead the effort on control and management of M(X)DR-TB and HIV co-infection in the Sub-Saharan Africa region and to advance and accelerate training on infection control within the context of M(X)DR-TB.
Status
Ongoing. There had been limited activities over the past period. under separate funding from KNCV an infection control course had been developed.
TB-CAP/KNCV
Advanced Training Course on TB Infection control in Health Care Facilities
Principal Investigators: M van der Walt (MRC)
Project Leader: M Mphahlele (MRC); P Jensen (CDC), D Chemtob (WHO) and M Meis (TBCAP)
The purpose of the course was to improve TB infection control knowledge and practical skills on how to assess, plan, organize and implement, monitor and evaluate implementation of TB infection control at facility levels, within the framework of the Stop TB Strategy.This training also aimed at strengthening cooperation among different sectors involved in TB control.
Status
Ongoing. In total nineteen participants attended this training workshop (10 different countries-g 8 African countries, one from The Netherlands, Afghanistan). A project report was submitted in October 2010. An impact assessment will be done next month, to determine whether the training measured up and also to provide technical support.
Training in management of drug-resistant tuberculosis
Objectives
Assisting the National and Provincial Departments of Health in developing an appropriate response to the challenges of M(X)DR-TB and HIV by (i) providing technical assistance and national coordination to accomplish the MDR-TB goals of the Stop-TB Global Plan, and by (ii) assisting with capacity strengthening of health services and laboratory infrastructure in South Africa in order to allow sound diagnosis and treatment of M(X)DR-TB patients.
Status
Ongoing, a clinical management course for side effects due to MXDR-TB/HIV treatment has been developed, based on a need recognized among the provincial TB programmes. Two very successful courses were given in KwaZulu-Natal (May 2010 and January 2011). we have already been approached by other stakeholders for conducting the training in other provinces.
Training in Operational Research
Objectives
To address critical local and international priorities in TB, TB-HIV and MDR-TB control, aimed at development of evidence-based policies and procedures. These include searching for simple and effective infection control methods for low-income countries in an era of expanding HIV services, looking at ways to improve patient adherence when receiving treatment for MDR-TB and HIV, and exploring best-practice models for MDR-TB and HIV concomitant management.
Status
No activities over the past period.
Research
A KAP and Environmental Infrastructure Evaluation of Infection Control in MDR and XDR-TB Centres in South Africa
Principal investigators:
M van der Walt (MRC), Jason E. Farley (Johns Hopkins)
Project Leader: M Mphahlele (MRC)
Collaboration: Johns Hopkins University
Objective
The objective of this study was to perform a baseline assessment of infection control knowledge, attitudes, practices and environmental infrastructure among M(X)DR-TB Clinics in South Africa.
Status
Completed. In 2009 a facility-based infection control audit of administrative, environmental and personal infection control measures as well as face-to-face interviews with key informants was conducted in all 24 M(XDR)TB facility throughout the country.
Results
Feedback to the individual TB Centers regarding their infection control practices in comparison to other M(X)DR-TB Centers has just been completed. We have identified several gaps in infection control practices throughout the country in these settings. Twenty four M(X)DR-TB facilities (100%) were enrolled. We identified the following facility level infrastructure: 19 (79%) facilities had an IC officer; 13 (54%) had a written TBIC plan; 14 (58%) had UVGI; 2 (.08%) had a UV maintenance plan; 23 (96%) had N-95 respirators, none offered fit testing; 15 (63%) had windows opened appropriately; 11 (46%) reassigned HIV positive staff. We enrolled 499 HCWs in the KAP evaluation; 42 (8.4%) physicians; 176 (35%) registered nurses; 125 (25%) enrolled nurses; 85 (17%) nurses aids; 72 (14%) other. Higher level of clinical training was associated with greater IC knowledge (p<0.001) and less time spent with coughing patients (p<0.001). Prior IC training had no impact on KAP for any level of non-physician staff. Among physicians, attending a recent facility specific IC training was associated with lower knowledge (p=.01). Attitudes toward IC were highly varied, 32% of individuals surveyed report it is an OK practice to collect sputum samples in the ward; 38% report not wearing their respirator. Further, we noted that having an occupational health officer increased the likelihood of receiving VCT and annual TB symptom screening.
Evaluation of Pheroid as delivery system for first-line TB drugs in a murine model of TB
Principal investigators: A Grobler (NWU), K Venter (MRC)
Project Leader: K Venter (MRC)
Objectives
- To assess the capacity of a Pheroid drug delivery system for four front-line TB drugs (isoniazid, rifampicin, pyrazinamide and ethambutol;
- to reduce duration of treatment and prevent TB relapse by mycobacterial enumeration from lungs of TB-infected mice that received treatment with combination drugs entrapped in Pheroids and TB-infected mice that received the standard combination treatment with free drugs.
Status
Completed. BALB/C mice were infected intravenously with MTB at a viable dose of 106 CFU’s/ mouse. Treatment commenced two weeks later and mice were treated daily by oral gavage (5 days per week for twelve weeks) with either Pheroid encapsulated first-line TB drugs or free combination first-line TB drugs. An untreated TB-infected control group was also included. Progression of disease in all groups of mice was determined by bacterial cultivation of lung homogenates on 7H10 agar plates and 7H9 broth MGIT tubes at two weekly intervals during a three month treatment period and at monthly intervals of a three month post treatment period and by comparing colony forming units on agar plates and time to detection of bacteria in MGIT tubes between the groups. CFU counts in lungs of the experimental group (PheroidTM) were significantly lower at 4, 6, 8 and 26 weeks after infection while longer time to detection values (and thus fewer organisms) were observed 4, 8, 12, 22 and 26 weeks post infection than that of the standard treatment group. The study was completed in 2009. A final report was submitted to NWU on March 15th 2010 and a manuscript has been published (see section 3).
Risk factors associated with failure from MDR-TB treatment
Principal investigators: J Farley (Johns Hopkins University, USA), M van der Walt (MRC)
Project Leader: J Lancaster (MRC)
Objectives
To identify factors associated with failure from standardised MDR-TB treatment in South Africa.
Results
A total of 1023 patients were enrolled in the MDR-TB program between 2001 and 2004. HIV infection was present at baseline in 287 patients (27%), and has a lower mean age than HIV-uninfected patients (34.8 years vs. 37.4 years; p<0.001) and were more likely to be male (52.5 vs. 46.2). The overall treatment success was 47%, the failure rate of second-line therapy was 11% and the mortality rare was 22%. Patients with HIV infection were less likely to be cured/complete therapy (40% vs. 49%; p<0.01) than those without HIV and more likely to die during treatment (35% vs. 17%; p=<0.0001). Twenty-two percent of patients were lost to follow-up, with no differences by HIV status. The odds of death increased significantly as baseline weight declined among both HIV positive and HIV negative subjects.
Conclusions
Overall treatment outcomes were poor in this program, with fewer than half of patients successfully treated. HIV infection and low body weight were associated with increased mortality. Interventions to improve adherence, detect and manage extensive drug resistance, and antiretroviral therapy for HIV infected patients with MDR-TB would likely improve outcomes.
Status
Completed. Follow up research from this project were funded under a separate agreement (see project 2290).
US-XDR Awareness Materials
Principal investigators: M van der Walt (MRC)
Project Leader: JL Lancaster (MRC), Janus Snyders (MRC)
Objectives
Evaluation of health information on M(X)DR-TB by assessing the information needs and seeking of professional health care givers providing care to patients presenting with M(X)DR-TB and developing appropriate materials
Status
Completed in collaboration with Web and Media Technologies Platform Unit of the MRC.
Project outcomes
One article per month (4 article in total) had been published in DENOSA Nursing Update magazine and SAMA Insider with the nursing and other medical professions as target audience. The publications covered the period from March 2010 to June 2010. The themes for the articles covered the following:
- M(X)DR-TB background
- Treatment and prevention
- Infection control
- Personal protection for the HCW
- Research in the field of TB
The articles were translated into the five identified languages and to be distributed to community health workers. Brochures for each article had been developed and presented to MDR centres and at the South African TB conference in June 2010. A final report had been delivered to the Office of International Health at the US embassy in Pretoria.
Demonstration Project to determine the effectiveness of rapid assays for rifampicin resistance for presumptive MDR-TB diagnosis in smear-positive specimens from patients in high TB burden countries
Principal investigators: M van der Walt (MRC)
Co-Investigators: G Coetzee (NHLS), H Albert (FIND), Tuberculosis Control Programme (National, Provincial – Western Cape, KwaZulu-Natal, Northern Cape, Gauteng, North West)
Project Leader: M Sewpersadh (MRC)
Objectives
To assess the feasibility and impact of rapid tests for detecting MDR-TB in individuals at risk of MDR-TB in a high MDR-TB-HIV burden setting. The feasibility of implementation, cost, cost-effectiveness, and clinical impact of the assay under National Tuberculosis Control Programme (NTCP) conditions will be determined, and thereby providing evidence to the NTCP how the test may be best applied in diagnostic algorithms and confirm the benefits (including financial) from implementation.
Status
Ongoing and active: Data analysis completed and the final project progress report was submitted to the data and safety committee in January 2011. MDR TB cultures of MDR TB patients were collected and stored in our culture collection. The recording sheets of LPAs were re-read to assess inter-reader variability and to assess transcribing errors. Limited variability or subscribing errors were found. Collections on the clinical data of MDR patients are currently underway.
Novel TB Prevention Regimens for HIV-Infected Adults
Principal investigators: M van der Walt (MRC), Jason Farley
Project Leader: Jeannette Brand (MRC)
Objective
Drug-sensitivity testing to determine the prevalence of resistance towards second-line drugs and determining the association with poor treatment outcomes
Status
Ongoing and productive. LPA drug-sensitivity testing for second-line drugs on isolates from patients is underway. Poster displays accepted at 2nd TB conference in Durban, June 2010 and IUTLD, Germany, November 2010.
Molecular Characterization and drug susceptibility of isolates from MDR-TB patients in the Eastern Cape and North West provinces of South Africa
Principal investigators: M Mphahlele (MRC)
Project Leader: M Mphahlele (MRC)
Collaboration: University of Stellenbosch
Objectives
- To study the prevailing and evolving genetic characteristics (genetic fingerprints, mutations) and drug susceptibility profiles of MDR-MTB isolates in two provinces in South Africa through time and correlate these with clinical outcomes associated with strain-specific MTB isolates.
- To identify gene profiles for MDR-TB strains that are most prevalent amongst HIV+ patients by molecular characterization of MDR-strains isolated from MDR-TB patients, to study the infectiousness of these strains in guinea pigs by measuring the infection kinetics in lungs, mediastinal lymph nodes & spleen and histopathological assessment of tubercular lesions and correlate these data with the treatment outcome in the patients
Status
On-going and productive. The project leader spent 3 months of training in 2010 at Harvard University, Epidemiology Department to analyze the clinical data of the project. A manuscript on data analyzed at Harvard is in progress. Drug-sensitivity testing for second-line drugs and molecular investigation (spoligotyping) on isolates from patients in both provinces is in progress.
Evaluation of Surgical Face Mask Usage as a Tool for Infection Control
Principal investigators: M Mphahlele (MRC), M van der Walt (MRC),
Co-investigators: E Nardell (Harvard University), M First (Harvard University), P Jensen (CDC), A Dharmadhikari (Harvard University), K Venter (MRC)
Project leader: M Mphahlele (MRC)
Collaboration: MRC Centre for Molecular and Cellular Biology
Objective
This experiment is a sub-study of the project titled “Testing Interventions to Human Generated Occupational Airborne Infections” which covers three experiments 1) The effect of upper room germicidal ultraviolet irradiation (UVGI) in reducing airborne transmission 2) Evaluation of Surgical Face Mask Usage as a Tool for Infection Control 3) Efficacy of In-room Air Filtration Units Usage in Preventing Transmission of MDR-TB (project 2304 (b)). The first experiment has been completed. The objective of this particular study was to determine if surgical masks on individuals with airborne infections are at least 50% effective in reducing transmission.
Status: Bacteriology component of the experiment is ongoing. Face masks were well tolerated by patients for 12hrs of continuous use every other day. At the end of 4 month exposure; 36 guinea pigs were infected in the intervention room whereas 69 guinea pigs were infected in the control room. Guinea pigs in the control group had a 2.3 fold increased risk of becoming infected compared to guinea pigs in the intervention group. This intervention demonstrated a more than 50% efficacy in the intervention arm.
Bacteriology and molecular investigations of bacterial isolates from both patients and animal specimens are underway.
The major finding of this research is the evidence that patients’ wearing of simple surgical masks is effective in reducing airborne infection.
Efficacy of In-room Air Filtration Units Usage in Preventing Transmission of MDR-TB
Principal investigators: M Mphahlele (MRC), M van der Walt (MRC)
Co-investigators: E Nardell (Harvard University), M First (Harvard University), P Jensen (CDC), A Dharmadhikari (Harvard University), K Venter (MRC)
Project leader: M Mphahlele (MRC)
Collaboration: MRC Centre for Molecular and Cellular Biology
Objective
To determine if in-room air filtration units are at least 50% effective in reducing transmission of natural MDR-TB infections.
Status
Ongoing. Approval has been obtained from both the MRC and the Provincial Ethics Committee for human studies. Our protocol has also been approved by the MRC Ethics Committee for Research on Animals. Experiment is scheduled to start end of February 2011.
Nanoparticle drug release in mice
Principal Investigators: H. Swai (CSIR)
Project Leader: K. Venter (MRC)
Objectives
The proposed study forms part of a long term study whose objectives are to establish the in vivo mechanism of uptake, tissue distribution and degradation of drug-loaded nanoparticles (NPs) and drug release profiles in mice animal models. This aspect will comprise phase one of the study. The second phase will seeks to establish pharmacokinetics, chemotherapeutic efficacy, bioavailability/bioequivalence and toxicological effects of encapsulated TB drugs compared to that of free drugs, within the macrophages, blood and tissues of TB-infected mice. Finally efficacy of combination therapy of nano-particle loaded first-line TB drugs will be tested in a murine model of tuberculosis.
Status
Ongoing. The effects of nanoparticles (NP) on macrophage activation and cytokine stimulation were determined by means of Fluorescence Activated Cell Sorting (FACS) that was performed on peritoneal exudate cells (PECS) derived from BALB/C mice after oral and intraperitoneal administration. Biodistribution of NP in the tissues of the main target organs after single oral administration were determined and histology of tissue sections from various organs is in progress to test for presence of toxic effects. Isoniazid and Rifampicin were encapsulated in nanoparticle compounds. Pharmacokinetic (PK) NP-encapsulated drugs parameters were evaluated in BALB/C mice by HPLC analysis of plasma collected at various time points after single oral administration and compared to those obtained from BALB/C mice treated with the free drugs. Extensive toxicity tests were performed in 2009 during which effect of various doses of nano-particles was determined on cytokine production and potential damage to target organs was investigated by histopathology. Rifampicin is one of the most documented inducers of CYP3A4 and CYP2C9 enzymes which result in neverapine metabolism. This induction has been found to be at the root of neverapine catabolism in HIV positive patients on TB medication. Sub consequently the effect of Rifampicin encapsulated Nanoparticles on activation of these enzymes is currently investigated to see whether encapsulation of Rifampicin can prevent this detrimental effect. In addition the biodistribution of NP encapsulated Isoniazid and Rifampicin will be compared to that of the free drugs.
Challenges of Stop-TB
Principal Investigator: M van der Walt (MRC)
Project leader: M van der Walt, C Kvasvnovsky (CDC/Emory University)
Objectives
- To assist National and Provincial Departments of Health in SA in developing an appropriate response to the challenges of M(X)DR-TB and HIV,
- To provide technical assistance and national coordination to accomplish the MDR-TB goals of the Stop-TB Global Plan, and (iii) To assist with capacity strengthening of health services and laboratory infrastructure in Southern Africa in order to allow sound diagnosis and treatment of M(X)DR-TB patients.
Status
Completed.
Outcomes in XDR-TB patients Eastern Cape Province, South Africa
Objectives
To assess interim treatment outcomes in patients 12 and 24 months after diagnosis of XDR-TB in Eastern Cape Province and to assess treatment regimens for XDR-TB, as well as the description of clinical features and co-morbidities of patients with XDR-TB. The study is a retrospective analysis of all patients diagnosed with XDR-TB from October 2006-January 2008.
Status
Completed. Final data collection will be conducted in March 2011. Preliminary results were presented at the 2010 International Union Against TB and Lung Disease Conference. These findings are in press (see section 3). South African TB conference in June findings on the high levels of resistance to injectable second-line drugs in patients starting treatment for MDR-TB in Eastern Cape were presented. To take the findings of this project further, an additional cohort of patients are to be enrolled. Protocol development is underway, and if successful, will be continued under the ITRC as research. The article on Extensively drug-resistant TB in Eastern-Cape, South Africa: High Mortality in HIV Negative and HIV positive patients. written by C Kvasnovsky, M vd Walt, KK Thomas, R Erasmus, O Siwisa is in press.
New Projects
Pharmacokinetics, toxicity and efficacy of spray dried clofazimine used for TB treatment via oral route in a murine model of pulmonary tuberculosis
Principal investigators: Dr André Germishuizen (MEND), K Venter (MRC)
Project Leader: K Venter (MRC)
Objectives
To indicate that oral administration of spray-dried clofazimine in mice results in improved bioavailability; improved Biodistribution reduced toxicity; and improved efficacy against tuberculosis infection when compared to oral administration of native clofazimine. If the experiments suggest that spray drying of clofazimine results in reduced gastro-intestinal toxicity, improved bioavailability-and-biodistribution and improved efficacy against TB, spray-dried clofazimine can be considered for clinical trials in treatment of MDR-TB and leprosy. The results of the study will also provide insight into the dose range that can be studied in the under mentioned guinea pig study
Status
In vitro testing of the spray dried clofazimine is almost completed. Approval is obtained from the MRC’s Ethics Committee for Research on Animals.
Formulating Clofazimine for pulmonary delivery in the treatment of DR-TB in a guinea pig model of pulmonary tuberculosis
Principal investigators: Dr André Germishuizen (MEND), K Venter (MRC)
Project Leader:K Venter (MRC)
Objectives
The aim of this project is to develop an aerosol delivery approach to improve the efficacy and reduce the toxic side effects of clofazimine in the treatment of MDR-TB. A clofazimine formulation will be developed using spray drying to optimize the physical properties required for pulmonary delivery. Initial studies will focus on the optimization of the clofazimine formulation and its stability, and an in vitro test will be used to study efficacy of the formulation against the laboratory strain MTB H37Rv. A suitable candidate aerosol formulation will be tested further in pharmacokinetic, pharmacodynamic and efficacy studies on a guinea pig model.
Status
In vitro testing of the formulation is in progress. Ethics committee approval is obtained for pharmacokinetic, pharmacodynamic and efficacy studies in a guinea pig model of pulmonary tuberculosis.
Characterization of the immune response induced by atypical mycobacteria isolated on the efficacy of BCG vaccination in M. bovis infected mice
Principal investigators: Dr Akinbowale Jenkins (Dept of Veterinary Tropical Diseases, Faculty of Veterinary Science, University of Pretoria), K Venter (MRC)
Project Leader: K Venter (MRC)
Objectives
To determine how pre exposure to non tuberculous mycobacteria effects BGC vaccination against Mycobacterium bovis infection in a murine model of pulmonary infection.
Status
Approval is obtained from the MRC’s Ethics Committee for Research on Animals. Two groups of mice were exposed via oral administration respectively to M. fortuitum and M kansasii at baseline and two weekly intervals for a month while a negative group received sham exposure. After a month of rest half of the mice in each group were vaccinated with BCG. half of the mice in each group (equal numbers of BCG vaccinated and non vaccinated mice) were sacrificed to determine cytokine levels in serums and lymphocyte populations in spleens. All the remaining mice were infected via aerosol inhalation with M. bovis. Four weeks later these mice were sacrificed for determination of cytokine levels (serum), lymphocyte populations (spleen) and bacterial enumeration (lungs).
Improving the quality of health services for people living with HIV/AIDS and TB through providing technical support to strengthen Swaziland’s TB laboratory service
Principal investigators: NB Bapela
Project Leader: J Brand, N Matlhola, M Sewpersadh
Objectives
- To strengthen laboratory quality assurance, quality management systems and to expand both HIV/AIDS and TB diagnostic services at all levels within the Swaziland health system.
- To enhance laboratory testing practices and strengthen the quality of laboratory testing services in order to improve the effectiveness of HIV/AIDS prevention, care and treatment services and interventions
Status: The MOU and the budget have been agreed upon by both URC and MRC and the sub-agreement is now legal. The project started in January 2011.
Regional Capacity Building and Knowledge Sharing in Strengthening Health Systems
Principal Investigators: M van der Walt (MRC), M Schneidman (World Bank)
Project Leader: P Mativandlela (MRC)
Objective
To assist the SA-MRC to build regional capacity through the transfer of knowledge and expertise in setting up quality assured tuberculosis (TB) diagnostic services in the high burden participating countries (Botswana, Lesotho, Namibia and Swaziland). The project aims to enhance diagnosis of TB, including multi-drug resistant TB, to develop operational research agenda, and thereby control the threat posed by the spread of drug resistant TB in the sub-region.
Status
The IDF Grant, endorsement letters from SA-MRC and SA-Treasury have been agreed upon by both World Bank, SA-MRC and SA-Treasury. The World Bank’s General Procurement and Expression of Interest Notice are published on the UN Development Business. The project will be implemented after completion of SA-MRC procurement procedures. |
