Progress and Challenges in Developing POC Test for Active TB

1. Progress and main challenges to development of POC test for active TB. Ruth McNerney London School of Hygiene & Tropical Medicine MSF Access Consultation 11th April 2008

2. ‘Cambridge Group’ Last weekend a small group met in Cambridge, UK to discussrapid TB diagnostics. Brief report/statement to be produced. Convened by activists (TAG/AIDS Alliance), brought together people involved in a previous initiative to develop low cost POC CD4 test with ‘TB experts’ (program managers, NGOs, academics, FIND) First step towards developing an initiative to develop POC test. Address funding gap for biomarker discovery/validation. Publish briefing document.

3. Estimated new TB cases (all forms) per 100 000 population No estimate 0–24 25–49 50–99 100–299 300 or more Estimated TB incidence rate, 2005 8 African countries with estimated incidence >6 per 1,000 Swaziland: 1.2 new cases per 100 persons. WHO Global Report 2007

4. Estimated numbers of new cases, 2005 Estimated number of new TB cases (all forms) India: 1.8 million, China: 1.3 million, UK: 8,000 No estimate 0–999 1000–9999 10 000–99 999 100 000–999 999 The estimated number of new TB cases each year is over 9 million. 1 000 000 or more WHO Global Report 2007

5. Bovine tuberculosis is a disease of zoonotic and economic importance. TB in Cattle During 12 months to Aug 2007 over 5 million tests were performed in GB resulting the slaughter of 25,475 cattle. Defra National Statistics Nov 2007

6. Diagnostic guidelines for endemic settings. Cough 3 weeks and/or haemoptysis 3 or 2 sputum exam (x-ray?) +ve -ve TB treatment non TB antibiotic No improvement Improvement 2nd antibiotic Complete AB treatment No improvement Improvement 3x sputum Complete AB +ve-ve treatment TB treatment Chest x-ray Suggestive of TB? TB treatment

7. Smear microscopy the frontline TB test is insensitive, slow, requires at least 2 expectorated sputum specimens, is labour intensive, has a subjective readout and requires external QA.

8. Challenge: finding the bacteria is very difficult. SALIVA Sputum is the main diagnostic specimen

9. What are POC tests? Point Of Care: a test which can be performed at the site at which care is provided with immediate results, without referral to a specialist laboratory. In the context of TB this may be a clinic, health centre or hospital setting. Point of Collection: a test which can be performed at the site of specimen collection. In the context of TB this may be within a community or home setting, a clinic or at the bedside.

10. What are rapid tests? In the context of TB this is a test device where the result is available within the duration of a single visit to the health care provider and does not require a second visit at a later date. Max 2-3 hours?

11. We need a test to improve access to treatment Particularly for the poor, vulnerable and isolated, including children and those with non-pulmonary forms of disease.

12. BARRIER: Unrealistic expectations that the test must be 100% accurate in all populations, in all settings, and must cost less than the reagents for smear microscopy (0.5 USD) Discourages investment Discourages implementation

13. TEST SPECIFICATIONS SAFETY Technology? 5 min dip stick device 5 min bedside gadget 30 min kitchen gadget 2-3 hour kitchen test Specimen? Breath Saliva Urine Blood Sputum Infrastructure? No cold chain No electricity Intermittent electricity Specialist training Cold chain Constant electricity Specialist supervision

14. Current rapid tests: Clinical assessment Smear microscopy? There are no “approved” POC tests for active TB. There are a number of POC tests on the market being sold to private labs in unregulated countries. These tests are not well validated. They appear to have disappointing performance, particularly in HIV co-infected.

15. POC tests in development using known biomarkers Antigen detection e.g. LAM urine test. Antibody detection Sensitivity disappointing so far.

16. Biomarker discovery Looking for characteristic metabolites, immunogenic markers, host response, volatile compounds. Complaints from academics of funding gap.

17. Hippocrates Greek physician, 460-410 BC “In persons affected with phthisis, if the sputa which they cough up have a heavy smell when poured upon coals, and if the hairs of the head fall off, the case will prove fatal.” Caelius Aurelius Roman physician 130 B.C. “Many subject the purulent sputa to diagnostic tests they place the phlegm over hot coals and note its odor when it has burned; for a foul odor always characterizes the product of physical decomposition.”

18. Several competing groups investigating volatile biomakers and various technologies. Need for IP to lever funding is preventing co-ordination of efforts.

19. New technologies. Nucleic acid detection e.g. LAMP Translation of tools from military/space race “If you can build instruments rugged enough to look for life elsewhere in the Solar System, you should be able to crack the problem of detecting TB bacteria in the lung of a patient” Ted Bianco, Wellcome Trust. November 2007

20. Detection of cell wall component (TBSA) by field deployable mass spectrometry. £1.3 million (US$ 2.6) over two years Planetary Sciences Institute, Open University. London School of Hygeine & Tropical Medicine Biomedical Training Inst and various clinics in Harare, Zimbabwe. TBSA = Tuberculostearic acid

21. Challenges Lack of basic research Biological/geographic variation Uncertain funding Diagnostics not sexy or lucrative Poor career structure RAE – drive to publish Access to cat 3 facilities Inadequate funding IP barriers to co-operation Lack of memory – re-inventing the wheel

22. Translational research: Lack of funding opportunities Lack of expertise/awareness in academia SMEs – uncertain funding, Poor exchange of information Access to specimens/field sites Lack of commitment from large companies Existing tests: Lack of evaluation in different populations Lack of communication with private sector

23. The Gates Effect Discourages involvement of other funding bodies. Limited gateway distorts market not conducive to new players. Discussion . . .