Summary:

Worldwide, tuberculosis bacillus (TB) has reached epidemic proportions, with rising infection rates calling out for immediate and effective action. Globally, approximately 2-3 million people die, and more than 7-8 million people develop active TB on a yearly basis.
Currently, no method exists to monitor successfully the efficacy of TB treatment. Upon diagnosis, patients are treated for TB with a course of medication lasting approximately six to nine months. Prior to the end of the treatment regime, there exists very little indication of the efficacy of the particular treatment. In the event that the individual is found resistant to primary treatment, a stringent and time-consuming analysis is undertaken to select the appropriate antibiotics effective for that particular patient as a second-line treatment.
It has previously been shown that the blood plasma protein suPAR (soluble urokinase Plasminogen Activator Receptor) is elevated in patients with active TB, carries prognostic value during the treatment period, and that suPAR levels decrease in patients that respond to therapy. This published data indicates that suPAR could possibly be used to guide clinical decision-making in HIV and TB management.
Guinea-Bissau has one of the highest incidences of TB in the world (about 470 cases for every 100 000 adults). However, as in other developing countries, markers of disease progression and/or treatment efficacy are difficult to find, especially if tests are to be inexpensive, technically simple and require very little advanced equipment.
The Bandim Health Project, a research programme holding a demographic health surveillance system covering five districts in Bissau (with a population of about 75 000) provides an optimal location to investigate if the serum level of suPAR is a useful marker for TB treatment efficacy. Amongst other objectives, the project aims to provide a basis for the monitoring of TB progression and TB treatment efficacy, as well as to provide TB treatment for study participants.

Background:

The focus of the proposal is to investigate the possibility of creating a novel approach to monitoring TB treatment efficacy in developing countries, which will in turn lead to a more rational use of drugs, at the same time reducing incidences of resistance to TB medication.

It has previously been shown that the blood plasma protein suPAR is elevated in patients with active TB, carries prognostic value during the treatment period, and that suPAR levels decrease in patients that respond to therapy.

(Eugen-Olsen J, Gustafson P, Sidenius N, Fischer TK, Parner J, Aaby P, Gomes VF, Lisse I. The serum level of soluble urokinase receptor is elevated in tuberculosis patients and predicts mortality during treatment: a community study from Guinea-Bissau. Int J Tuberc Lung Dis 2002 6(8): 686-92).

Aims:

The aims of this project are:

1. to investigate if suPAR levels are prognostic of TB treatment efficacy
2. to investigate if an elevated suPAR level is associated with increased mortality in TB patients
3. to determine suPAR measurements before and after TB treatment
4. to assess the risk factors associated with non-declining suPAR levels during TB treatment
5. to determine the prognostic value of suPAR in TB infected patients with or without HIV
6. to determine the prognostic value of suPAR in HIV positive individuals with or without TB
7. to assess the relevance of suPAR in relation to CD4 cell counts
8. to provide a basis for the monitoring of progression and impact of TB treatment efficacy and control programmes
9. to assess the concept of developing a suPAR-based assay to be used as a prognostic marker for TB disease progression and TB treatment efficacy
10. to provide a basis for the monitoring of TB progression and TB treatment efficacy
11. to develop common clinical laboratory standards, with emphasis on standardising protocols regarding sample collection, and data storage and analysis
12. to provide training for clinicians, nurse practitioners and students in clinical laboratory standards
13. to provide training for clinicians, nurse practitioners and students in disease monitoring techniques, such as measuring CD4 counts and suPAR levels
14. to provide TB treatment for study participants
15. to provide monitoring of TB and HIV infected individuals in a rural setting.

Expected results:

Should research follow according to previous publications, the findings are expected to show that the level of suPAR is elevated in TB-infected individuals compared to healthy controls, and that suPAR levels would decrease to a statistically significant level upon response to treatment, or remain at a high level if treatment proved inefficient.

Potential applications:

A suPAR-based TB treatment efficacy marker could possibly be used to guide clinical decisions in TB management. SuPAR is measurable in blood, serum, plasma and urine using the well-established and inexpensive ELISA method, thus this method not only allows for a high level of affordability and technical simplicity (requiring only simple reagents and an ELISA reader), but also allows the test to be widely transportable to the remotest of settings because suPAR is such a stable molecule.

Coordinator:

Partners:

Nº	Principal Scientific Participants	Official Address	Other Information
2	Peter Aaby Head of Bandim Health Project Professor Epidemiological Research Unit - State Serum Institute Denmark Member of Board of Scientific Advisors to ViroGates ApS	Bandim Health Project Apartado 862 1004 Bissau Codex Guinea Bissau	Tel: +245 255543 Fax: +245 201672