1 |

Dr Karin Weyer

Stop TB Department Geneva, Switzerland

Strategic guidance on the useof laboratory technologies

Strategic guidance on the useof laboratory technologies

DEWG Meeting, Geneva: 13 October 2009

2 |

OutlineOutline

Outline of diagnostic and laboratory gaps

Addressing these gaps

WHO policy development process

Policy framework for use of new WHO-endorsed technologies

Urgent actions needed at global and country level

3 |

Latest global TB estimates - 2007Latest global TB estimates - 2007

Estimated number of

cases

Estimated number of

deaths

1.77 million1.77 million(27 per (27 per 100,000)100,000)

9.27 million9.27 million(139 per (139 per 100,000)100,000)

150,000 511,000

All forms of TB Greatest number of cases in Asia; greatest rates per capita in Africa

Multidrug-resistant TB (MDR-TB)

Extensively drug-resistant TB (XDR-TB)

50,000 30,000

HIV-associated TB 1.4 million

456,000

(Updated February 2009)

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Overall problem: MDR-TB diagnostic and treatment levels far too lowOverall problem: MDR-TB diagnostic and treatment levels far too low

511,000 estimated cases annually

Diagnosed and treated in Green Light Committee programmes

Countries report diagnosis and treatment, standard unknown

No diagnosis and treatment reported. Some treatment probably obtained, quality unknown

3%

5 |

DOTS expansion needsDOTS expansion needs

• Increased case detection towards universal access

• HIV- associated and drug resistant TB integrated into routine NTP programmes

Increased managerial and programmatic capacity

Increased access to affordable quality-assured anti-TB drugs

Models of care based on innovative frameworks

underpinned by

Laboratory strengthening

6 |2010 2012 2015

Required expansion of Culture and DST capacity: from 10 to 60 million p/a

# of tests required (million) USD funding

required (million)

2500

2000

1500

1000

500

Required expansion of Smear capacity: fro

m 80 to 200 million p/a

Global laboratory capacity gap:Gap of 120 million smears, 50 million cultures and 5 million drug susceptibility investigations

must be met by 2015, requiring increased investment in laboratory infrastructureand annual variable cost

USD 6.1 billion required by 2015

2008

Urg

ent

MD

G T

argets

200

150

100

50

2,000 biosafety level 3 labs20,000 newly trained technicians

7 |

Meeting the diagnostic gapMeeting the diagnostic gap

Challenges

Weak health systems Inadequate human resources Lack of recognition of laboratory importance in TB control and weak

communication between NTP and laboratory services, requiring rapid policy change

Biosafety concerns Insufficient financial resources Problems of laboratory availability and accessibility Delay in technology transfer to resource-limited settings No or minimal interaction with private-sector

8 |

Diagnostic pipeline accelerated Diagnostic pipeline accelerated

Recent developments:

At least 20 new technologies in various stages of development and evaluation

Distinct target areas for drug-resistant TB being addressed– Growth and resistance detection– Molecular-based assays

Liquid culture, rapid speciation and line probe assays endorsed by WHO 2007-2008; LED microscopy and selected non-commercial culture and drug susceptibility testing methods expected in 2009

9 |

Need for new diagnostics at each levelNeed for new diagnostics at each level

10 |

Establishing strong partnerships is keyChallenges of implementing new diagnosticsEstablishing strong partnerships is keyChallenges of implementing new diagnostics

Feasibility, contract, development phases

Demonstrationphase

Global Impact

Evaluationphase Access phase

• Evidence for regulatory approval

• Evidence for making policy

• Evidence for scaling up

• Evidence for measuring impact

Moving from demonstration to access and impact requires that new diagnostic tools are integrated into functional laboratory services

Additional components to ensure quality diagnostic services

Essential instruments, reagents, supplies

• Global Policy

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Global Laboratory Initiative

Mission: To serve as a platform of coordination and communication, providing the required infrastructure, focused on TB laboratory strengthening, in the areas of:

Global policy guidance, norms, standards, best practices

Laboratory capacity development Interface with other laboratory networks, enabling integration

Standardised laboratory quality assurance

Facilitating technical assistance

Effective knowledge sharing

Advocacy and resource mobilisation

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Identifying the need

for policy change

Reviewing the evidence

Convening an Expert Panel

Assessing draft policyand guidelines

Formulating anddisseminating policy

WHO policy formulation process

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Recent WHO laboratory policiesRecent WHO laboratory policies

Automated liquid culture and DST (2007): Use of liquid culture systems in the context of a comprehensive country plan for strengthening TB laboratory capacity; in a phased manner starting at national/central reference laboratory level

Rapid speciation (2007): Strip speciation for rapid Mycobacterium tuberculosis from non-tuberculous mycobacteria; established at regional or central reference laboratory level in combination with liquid culture

Line probe assays (2008): Use of line probe assays for rapid detection of R resistance within the context of country plans for MDR-TB management, including development of country-specific screening algorithms and timely access to quality-assured second-line anti-tuberculosis drugs; do not eliminate the need for conventional culture and DST capability; should be phased in, starting at national/central reference laboratory or those with proven molecular capability

Second-line drug susceptibility testing (2008): Reliable and reproducible for injectables and fluoroquinolones; to be conducted in supranational or national/central reference laboratories using standardised methodology and drug concentrations

Available at: http://www.who.int/tb/dots/laboratory/policy/en/print.html

14 |

Policy framework at country levelPolicy framework at country level

• Local epidemiology (TB, HIV, MDR-TB)

• Priorities for case detection

• Local laboratory capacity and networks

• Local laboratory human resources and skills base

• Local treatment policies for MDR-TB

• Financial resources

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Analytical processAnalytical process

• Quantify or estimate TB, TB-HIV and MDR-TB burden

• Identify and target specific patient risk groups

• Quantify or estimate diagnostic need to identify risk groups-Number of suspects to be screened-Number and type of laboratories at each service level

• Estimate budget for comprehensive laboratory services-All core components-Capacity for diagnostic and monitoring-Ancillary laboratory services (eg. biochemistry, haematology)

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Phase 1: Laboratory preparedness– Assessment of TB laboratory networks and diagnostic policies

– Upgrade of laboratory infrastructure and biosafety

– Development and implementation of GLP, SOPS, QA, etc.

– Training of core laboratory staff

– Initiating NTP policy reform on diagnostics

Phase 2: Introduction of new diagnostics– Integration of new diagnostics into NTP policies and procedures

– Procurement and installation of instruments, reagents, and other essential supplies

– Validation of new tools and laboratory performance

Phase 3: Impact assessment– Continued mentoring, technical support and oversight of technology transfer

– Assessment of impact of new diagnostics

Phased approach

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Laboratory algorithmLaboratory algorithm

Starts with

• Screening policy for suspects

• Microscopy services as entry point

Positive Negative

MICROSCOPY(ZN or Fluorescence)

CULTURE(Solid or Liquid)

No result

DRUG SUSCEPTIBILITY TESTING-1st LINE(Solid or Liquid)

No resultPositive Negative

MDR

DRUG SUSCEPTIBILITY TESTING-2nd LINE(Solid or liquid)

XDR

Susceptible No result

Not XDR, resistant other drugs Susceptible

Not MDR, resistant other drugs

No result

Dis

tric

t N

RL

/re

gio

nal

SR

L/

NR

L

IDENTIFICATION (SPECIATION)(Conventional/Commercial)

AFB

TB/NTM

Positive Negative

MICROSCOPY(ZN or Fluorescence)

CULTURE(Solid or Liquid)

No result

DRUG SUSCEPTIBILITY TESTING-1st LINE(Solid or Liquid)

No resultPositive Negative

MDR

DRUG SUSCEPTIBILITY TESTING-2nd LINE(Solid or liquid)

XDR

Susceptible No result

Not XDR, resistant other drugs Susceptible

Not MDR, resistant other drugs

No result

Dis

tric

t N

RL

/re

gio

nal

SR

L/

NR

L

IDENTIFICATION (SPECIATION)(Conventional/Commercial)

AFB

TB/NTM

LINE PROBE ASSAY

Solid culture

6-8w

1st line DST

3-4w

2nd line DST

3-4w

Microscopy

24h

Liquid culture

2-3w

1st line DST

1-3w

2nd line DST

1-2w

Microscopy

24h

Microscopy

24h

Line probe assay

24h

MDR-TB diagnosis using conventional solid culture and DST

MDR-TB diagnosis using liquid culture and DST

2nd line DST

1-2w

1st line DST

1-2w

MDR-TB diagnosis using line probe assay, liquid culture and DST

Line probe assay

24h

+

- 2nd line DST

1-2w

1st line DST

1-3w

Liquid culture

2-3w

MDR-TB diagnosisafter 9 to 12 weeks

MDR-TB diagnosisafter 1 to 2 days

MDR-TB diagnosisafter 3 to 5 weeks

MDR-TB diagnosisafter 3 to 5 weeks

Solid culture

6-8w

1st line DST

3-4w

2nd line DST

3-4w

Microscopy

24h

Liquid culture

2-3w

1st line DST

1-3w

2nd line DST

1-2w

Microscopy

24h

Microscopy

24h

LPA

24h

XDR-TB diagnosis using conventional solid culture and DST

XDR-TB diagnosis using liquid culture and DST

2nd line DST

1-2w

1st line DST

1-2w

XDR-TB diagnosis using line probe assay, liquid culture and DST

LPA

24h

+

- 2nd line DST

1-2w

1st line DST

1-3w

Liquid culture

2-3w

XDR-TB diagnosisafter 12 to 16 weeks

XDR-TB diagnosisafter 4 to 9 weeks

2nd line DST*

3-4w

* Methods not validated or standardised

2nd line DST

1-3w

2nd line DST

1-3w

Liquid culture

2-3w

2nd line DST

1-3w

2nd line DST

1-3w

XDR-TB diagnosisafter 4 to 9 weeks

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Policy considerations Policy considerations Current technologies not mutually exclusive

– Conventional culture capacity required for SM- specimens– Conventional DST capacity required to detect XDR-TB

Liquid culture and line probe assay considered as gold standards, to be phased in without loss of existing solid culture and DST capacity

LED microscopy as alternative for both fluorescence and conventional light microscopy (pending STAG endorsement)

Selected non-commercial culture and DST methods not alternatives for gold standards, but may provide interim solution (pending STAG endorsement)

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Urgent actions needed Urgent actions needed

Increased political commitment

Accelerated policy change (with lab expert involvement)

National laboratory strategic plans

Laboratory human resource plans

Increased and sustained donor funding

Novel approaches to technical assistance

Increased research to develop point of care tests

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‘From unimaginable…to indispensable’

Strengthening TB laboratoriesStrengthening TB laboratories

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• WHO-STB laboratory staff

• WHO Expert Groups

• WHO Strategic and Technical Advisory Group for TB (STAG-TB)

• Global Laboratory Initiative (GLI) Core Group

• GLI Technical Working Groups

• GLI Partners involved in laboratory strengthening

• FIND

AcknowledgementsAcknowledgements