Ruth McNerney London School of Hygiene & Tropical Medicine

Progress and main challenges to development of POC test for active TB.

MSF Access Consultation 11th April 2008

‘ ‘Cambridge Group’Cambridge Group’

Last weekend a small group met in Cambridge, UKLast weekend a small group met in Cambridge, UKto discussto discuss rapid TB diagnostics.rapid TB diagnostics.

Brief report/statement to be producedBrief report/statement to be produced..

Convened by activists (TAG/AIDS Alliance), Convened by activists (TAG/AIDS Alliance), brought together people involved in a previous initiative brought together people involved in a previous initiative to develop low cost POC CD4 test with ‘TB experts’ to develop low cost POC CD4 test with ‘TB experts’ (program managers, NGOs, academics, FIND)(program managers, NGOs, academics, FIND)

First step towards developing an initiative to First step towards developing an initiative to develop POC test.develop POC test. Address funding gap for biomarker discovery/validation. Address funding gap for biomarker discovery/validation. Publish briefing document.Publish briefing document.

Estimated TB incidence rate, 2005

No estimate

0–24

50–99

100–299

300 or more

25–49

Estimated new TB cases (all forms) per 100 000 population

8 African countries with estimatedincidence >6 per 1,000Swaziland: 1.2 new cases per 100 persons.

WHO Global Report 2007

Estimated numbers of new cases, 2005

No estimate

0–999

10 000–99 999

100 000–999 999

1 000 000 or more

1000–9999

Estimated number of new TB cases (all forms)

The estimated number of new TB cases each year is over 9 million.

India: 1.8 million, China: 1.3 million, UK: 8,000

WHO Global Report 2007

Bovine tuberculosis is a disease of Bovine tuberculosis is a disease of zoonotic and economic importancezoonotic and economic importance..

TB in Cattle TB in Cattle During 12 months to Aug 2007 over During 12 months to Aug 2007 over 5 million tests5 million tests were performed in GB were performed in GB resulting the slaughter of resulting the slaughter of 25,47525,475 cattle. cattle. Defra National Statistics Nov 2007Defra National Statistics Nov 2007

Cough 3 weeks and/or haemoptysis Cough 3 weeks and/or haemoptysis

3 or 2 sputum exam (x-ray?)3 or 2 sputum exam (x-ray?) +ve+ve -ve -ve

TB treatmentTB treatment non TB antibiotic non TB antibiotic

No improvement ImprovementNo improvement Improvement 2nd antibiotic 2nd antibiotic Complete ABComplete AB treatmenttreatment No improvement ImprovementNo improvement Improvement

3x sputum 3x sputum Complete ABComplete AB +ve+ve -ve-ve treatment treatment TB treatmentTB treatment Chest x-ray Chest x-ray

Suggestive of TBSuggestive of TB ?? TB treatmentTB treatment

Diagnostic guidelines for endemic settings.Diagnostic guidelines for endemic settings.

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.

SALIVA

Sputum is the main diagnostic specimen

Challenge: finding the bacteria is very difficult.

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

Point of Collection: a test which can be performed at the site of Point of Collection: a test which can be performed at the site of specimen collection. In the context of TB this may be within specimen collection. In the context of TB this may be within a community or home setting, a clinic or at the bedsidea community or home setting, a clinic or at the bedside. .

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

Max 2-3 hours?Max 2-3 hours?

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.

BARRIER: BARRIER: Unrealistic expectationsUnrealistic expectations

that the test must be 100% accurate that the test must be 100% accurate in all populations, in all populations, in all settings,in all settings,and must cost less than the reagents and must cost less than the reagents for smear microscopy (0.5 USD)for smear microscopy (0.5 USD)

Discourages investment Discourages investment Discourages implementationDiscourages implementation

Technology?Technology?

5 min dip stick device5 min dip stick device

5 min bedside gadget 5 min bedside gadget

30 min kitchen gadget30 min kitchen gadget

2-3 hour kitchen test 2-3 hour kitchen test

Specimen?Specimen?

BreathBreath

SalivaSaliva

Urine Urine

BloodBlood

SputumSputum

Infrastructure?

No cold chainNo electricity

Intermittent electricity

Specialist training

Cold chainConstant electricity

Specialist supervision

SAFETYSAFETY

TEST SPECIFICATIONS

Current rapid tests:Current rapid tests: Clinical assessment Clinical assessment Smear microscopySmear microscopy??

There are no “approved” POC tests for active TB.There are no “approved” POC tests for active TB.

There are a number of POC tests on the market being There are a number of POC tests on the market being sold to private labs in unregulated countries.sold to private labs in unregulated countries.

These tests are not well validated. They appear to have These tests are not well validated. They appear to have disappointing performance, particularly in HIV co-infecteddisappointing performance, particularly in HIV co-infected..

POC tests in development POC tests in development using known biomarkers using known biomarkers

Antigen detectionAntigen detection e.g. LAM urine test.e.g. LAM urine test.

Antibody detectionAntibody detection

Sensitivity disappointing so far.Sensitivity disappointing so far.

Biomarker discoveryBiomarker discoveryLooking for Looking for characteristic metabolites, characteristic metabolites, immunogenic markers, immunogenic markers, host response,host response,volatile compounds.volatile compounds.

Complaints from academics of funding gap.Complaints from academics of funding gap.

HippocratesHippocrates Greek physician, 460-410 BCGreek physician, 460-410 BC

““In persons affected with phthisis, if the sputa which In persons affected with phthisis, if the sputa which they cough up have they cough up have a heavy smella heavy smell when poured upon when poured upon coals, and if the hairs of the head fall off, the case willcoals, and if the hairs of the head fall off, the case will prove fatalprove fatal.”.”

Caelius AureliusCaelius Aurelius Roman physician 130 B.C. Roman physician 130 B.C.

““Many subject the purulent sputa to diagnostic tests Many subject the purulent sputa to diagnostic tests they place the phlegm over hot coals and note its odor they place the phlegm over hot coals and note its odor when it has burned; for a when it has burned; for a foul odorfoul odor always characterizes always characterizes the product of physical decompositionthe product of physical decomposition.”.”

Several competing groups investigating volatile biomakers and various technologies.

Need for IP to lever funding is preventing co-ordination of efforts.

New technologiesNew technologies.. Nucleic acid detection e.g. LAMPNucleic acid detection e.g. LAMP

Translation of tools from military/space race Translation of tools from military/space race

““If you can build instruments rugged If you can build instruments rugged enough to look for life elsewhere in the enough to look for life elsewhere in the Solar System, you should be able to crack Solar System, you should be able to crack the problem of detecting TB bacteria in the problem of detecting TB bacteria in the lung of a patient”the lung of a patient”

Ted Bianco, Wellcome Trust.Ted Bianco, Wellcome Trust. November 2007November 2007

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 MedicineBiomedical Training Inst and various clinics in Harare, Zimbabwe.

TBSA = Tuberculostearic acid

ChallengesChallengesLack of basic research Lack of basic research

Biological/geographic variationBiological/geographic variation

Uncertain fundingUncertain fundingDiagnostics not sexy or lucrative Diagnostics not sexy or lucrative Poor career structurePoor career structureRAE – drive to publishRAE – drive to publish

Access to cat 3 facilitiesAccess to cat 3 facilities

Inadequate fundingInadequate funding

IP barriers to co-operationIP barriers to co-operation

Lack of memory – re-inventing the wheelLack of memory – re-inventing the wheel

Existing tests:Existing tests:Lack of evaluation in different populationsLack of evaluation in different populationsLack of communication with private sectorLack of communication with private sector

Translational research:Translational research:Lack of funding opportunitiesLack of funding opportunitiesLack of expertise/awareness in academiaLack of expertise/awareness in academiaSMEs – uncertain funding, SMEs – uncertain funding, Poor exchange of informationPoor exchange of informationAccess to specimens/field sitesAccess to specimens/field sites

Lack of commitment from large companies Lack of commitment from large companies

The Gates EffectThe Gates Effect

Discourages involvement of other funding bodies.Discourages involvement of other funding bodies.

Limited gateway distorts marketLimited gateway distorts market not conducive to new players.not conducive to new players.

Discussion Discussion . . .. . .