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Review of WHO TB diagnostics Review of WHO TB diagnostics
1 |
Karin Weyer
Laboratories, Diagnostics and Drug Resistance Unit
Review of WHO TB diagnostics
policy development
Review of WHO TB diagnostics
policy development
GLI Meeting: Les Pensièrees, Annecy, France : 17 -19
Review of WHO TB diagnostics Review of WHO TB diagnostics
Karin Weyer
Laboratories, Diagnostics and Drug Resistance Unit
Review of WHO TB diagnostics
policy development
Review of WHO TB diagnostics
policy development
19 April 2012
Outline
• WHO TB diagnostics policy formulation process
• Current WHO-endorsed TB diagnostics/approaches
• Policy transfer and uptake
• Policy impact
Policy innovation • Policy innovation
Outline
WHO TB diagnostics policy formulation process
endorsed TB diagnostics/approaches
Outline
• WHO TB diagnostics policy formulation process
• Current WHO-endorsed TB diagnostics/approaches
• Policy transfer and uptake
• Policy impact
Policy innovation • Policy innovation
Outline
WHO TB diagnostics policy formulation process
endorsed TB diagnostics/approaches
Identifying the needfor policy change
Reviewing the evidence
WHO TB diagnostics polic
• WH
• Partners (researchers, industry, etc)
• Body of evidence available
• Commissioning of systematic reviews
• QU
• Meta
• Experts, methodologists, end
• Guidelines Review CommitteeConvening an Expert Group
Assessing policy proposal
and recommendations
Formulating and
disseminating policy
• Guidelines Review Committee
• GRADE process for evidence synthesis
• Strategic and Technical Advisory Group
• Endorsement/revision/addition
• Advise to WHO to proceed/not with policy
• Guidelines Review Committee
• Dissemination to Member States
• Promotion with stakeholders & funders
• Phased implementation & scale
policy formulation process
HO strategic monitoring of country needs
Partners (researchers, industry, etc)
Body of evidence available
Commissioning of systematic reviews
UADAS or other diagnostic accuracy tool
Meta-analyses (where feasible)
Experts, methodologists, end-users
Guidelines Review CommitteeGuidelines Review Committee
GRADE process for evidence synthesis
Strategic and Technical Advisory Group
Endorsement/revision/addition
Advise to WHO to proceed/not with policy
Guidelines Review Committee
Dissemination to Member States
Promotion with stakeholders & funders
Phased implementation & scale-up plan
GRADE evaluation
Clear separation:
• Recommendationstrong or conditional/optional/weak (for or against an intervention)– Benefits and downsides, values and preferences, impact, resource use
balanced with
*Grades of Recommendation Assessment,
balanced with
• Quality of evidence
⊕⊕⊕⊕ (High), ⊕⊕⊕�(Moderate), ⊕⊕��
– Methodological quality of evidence– Likelihood of bias– By outcome and across outcomes
• GRC review cycle 3 to 5 years
GRADE evaluation
/optional/weak (for or against an intervention)Benefits and downsides, values and preferences, impact, resource use
with
ssessment, Development and Evaluation
with
��(Low), ⊕���(Very low)
Methodological quality of evidence
Example of GRADE for
1. Xpert MTB/RIF should be used as the initia
of having MDR-TB or HIV-associated TB. (
2. Xpert MTB/RIF may be considered as a follow
where MDR-TB or HIV is of lesser concern, especially in further testing of smear
negative specimens. (Conditional recomme
implications)
Remarks:
6
Remarks:
These recommendations apply to the use of Xpert MTB/RIF
decontaminated specimens). Data on the utility of Xpert
limited;
These recommendations support the use of one sputum specimen for diagnostic testing
that multiple specimens increase the sensitivity of Xpert
These recommendations also apply to children, based on the generalisation of data from adults and
acknowledging the limitations of microbiological diagnosis of TB (including MDR
Access to conventional microscopy, culture and DST is still needed
surveys and/or surveillance, and for recovering isolate
including second-line anti-TB drugs).
Example of GRADE for Xpert MTB/RIF
nitial diagnostic test in individuals suspected
associated TB. (Strong recommendation)
MTB/RIF may be considered as a follow-on test to microscopy in settings
TB or HIV is of lesser concern, especially in further testing of smear-
mmendation, acknowledging major resource
6
MTB/RIF in sputum specimens (including pellets from
Xpert MTB/RIF in extra-pulmonary specimens are still
one sputum specimen for diagnostic testing, acknowledging
Xpert MTB/RIF but have major resource implications;
, based on the generalisation of data from adults and
acknowledging the limitations of microbiological diagnosis of TB (including MDR-TB) in children;
Access to conventional microscopy, culture and DST is still needed for monitoring of therapy, for prevalence
lates for drug susceptibility testing other than rifampicin
Outline
• WHO TB diagnostics policy formulation process
• Current WHO-endorsed TB diagnostics/approaches
• Policy transfer and uptake
• Policy impact
Policy innovation • Policy innovation
Outline
WHO TB diagnostics policy formulation process
endorsed TB diagnostics/approaches
Acceleration
• Tools development: At least 20stages of development and evaluation in last 10 years
• WHO policy formulation*- 2007 : New SS+ case definition, two
culture, rapid speciation- 2008 : Line probe assay- 2008 : Line probe assay- 2009 : LED microscopy, ‘same-day diagnosis’, selected non
commercial culture and drug susceptibility testing methods- 2010 : Xpert MTB-RIF- 2011 : IGRAs, commercial serodiagnostics
• Access to new diagnostics and and EXPAND-TB)
*Available at: http://www.who.int/tb/dots/laboratory/policy/en
Acceleration
st 20 new technologies in various stages of development and evaluation in last 10 years
New SS+ case definition, two-specimen approach, liquid culture, rapid speciation
day diagnosis’, selected non-commercial culture and drug susceptibility testing methods
serodiagnostics
and laboratory strengthening (GLI
http://www.who.int/tb/dots/laboratory/policy/en
Tools/methods not recommended
• Evidence base too weak, to be reassessed
– 2009: Sputum processing methods
– 2009: TLA method for rapid DST
– 2010: LPA for XDR-TB – 2010: LPA for XDR-TB
• ‘Negative’ policy (do-not
– 2011: Commercial serodiagnostics
– 2011: IGRAs (high TB or HIV burden settings)
Tools/methods not recommended
Evidence base too weak, to be reassessed
Sputum processing methods
TLA method for rapid DST
not-use)
Commercial serodiagnostics
IGRAs (high TB or HIV burden settings)
Diagnostics pipelineDiagnostics pipeline
Policy pipeline 2012
• Laboratory biosafety
– Procedure (risk)-based, minimum requirements
• Guidance on drug susceptibility testing
– Update on 2008 guidance– Update on 2008 guidance
• LPA update
– New 2nd-line LPA (XDR)
• Evaluation of new technologies
– LAMP assay
Policy pipeline 2012
based, minimum requirements
Guidance on drug susceptibility testing
guidanceguidance
line LPA (XDR)
Evaluation of new technologies
Outline
• WHO TB diagnostics policy formulation process
• Current WHO-endorsed TB diagnostics/approaches
• Policy transfer and uptake
• Policy impact
Policy innovation • Policy innovation
Outline
WHO TB diagnostics policy formulation process
endorsed TB diagnostics/approaches
Surveillance
Reference methods
Network supervision
Tools in tiered heath services
National
Reference
Level
Central
Reference
Level
Case finding
TreatmentDistrict &
Sub-district Level
Community Level
District &
Sub-district Level
Community LevelScreening
Referral
Tools in tiered heath services
National
Reference
Level
Central
Reference
Level
District &
district Level
Community Level
District &
district Level
Community Level
Year Technology
Before 2007ZN microscopy
Solid Culture
early diagnosis & care smear-negative TB rapid resistance detection
Tools in combination
2007Liquid Culture / DST
Rapid speciation
2008Line Probe Assay
(1st line, Rif & INH)
2009LED-based FM
2009
In house DST
(MODS, CRI, NRA)
2010
Xpert MTB/RIF
(TB, R resistance
Technology Turnaround timeSensitivity
gain
ZN microscopy
Solid Culture
2-3 days
30-60 daysBaseline
negative TB rapid resistance detection
Tools in combination
Liquid Culture / DST
Rapid speciation15-30 days
+10% compared
to LJ
Line Probe Assay
(1st line, Rif & INH)2-4 days S+ only
based FM 1-2 days+10% compared
to ZN
In house DST
(MODS, CRI, NRA)15-30 days 1st line only
MTB/RIF
resistance)100 minutes
+40% compared
to ZN
Tools in different algorithms
One size no longer fits all
Tools in different algorithms
One size no longer fits all
Policy uptake at country level
• Rapid uptake
– SS+ case definition
• Limited or no uptake
– Two-specimen strategy
– Same-day-diagnosis – Same-day-diagnosis
– Non-commercial culture and DST methods
• Gradual uptake
– LED microscopy
– Liquid culture and DST
– Rapid speciation
– Line probe assay
Policy uptake at country level (1)
commercial culture and DST methods
Policy uptake at country level (2)
HIGH TB BURDEN
HIGH MDR-TB BURDEN
GLOBAL
Source: 2011 WHO TB Control Report
Policy uptake at country level (2)
Source: 2011 WHO TB Control Report
Policy uptake at country level (
HIGH TB BURDEN
HIGH MDR-TB BURDEN
GLOBAL
Source: 2011 WHO TB Control Report
Policy uptake at country level (3)
Source: 2011 WHO TB Control Report
Outline
• WHO TB diagnostics policy formulation process
• Current WHO-endorsed TB diagnostics/approaches
• Policy transfer and uptake
• Policy impact
Policy innovation • Policy innovation
Outline
WHO TB diagnostics policy formulation process
endorsed TB diagnostics/approaches
Policy impact (1)
460 GXP machines and 591,450
procured in 47 countries
Dec 2010 Dec 2011
Policy impact (1)
460 GXP machines and 591,450 Xpert MTB/RIF cartridges
procured in 47 countries
2011
Policy impact (2)
First ’negative’ policy guidance by WHO
Unprecedented p
Policy impact (2)
First ’negative’ policy guidance by WHO
d political commitment by India
Outline
• WHO TB diagnostics policy formulation process
• Current WHO-endorsed TB diagnostics/approaches
• Policy transfer and uptake
• Policy impact
Policy innovation • Policy innovation
Outline
WHO TB diagnostics policy formulation process
endorsed TB diagnostics/approaches
Guidance documents
• GLI Roadmap, Tools Set, Accreditation Guide
• WHO Policy Framework for Im
• WHO Fact Sheets
• ‘How to’ documents and online tracking
• Xpert MTB/RIF Rapid Implementation Document• Xpert MTB/RIF Rapid Implementation Document
• Xpert MTB/RIF Checklist
• Xpert MTB/RIF Website and Online Data Collection Tool
Guidance documents
Roadmap, Tools Set, Accreditation Guide
or Implementing TB Diagnostics
‘How to’ documents and online tracking
MTB/RIF Rapid Implementation DocumentMTB/RIF Rapid Implementation Document
Online Data Collection Tool
GRADE evolution for TB Diagnostics
• Refined quality assessment tools
• Refined statistical methodology for meta
• Standardised proxies for patient
• Cost-effectiveness modeling
• But: Test-specific recommendations necessary• But: Test-specific recommendations necessary
• Different technologies, targets, performance characteristics
GRADE evolution for TB Diagnostics
Refined quality assessment tools (eg. QUADAS-2)
Refined statistical methodology for meta-analyses
proxies for patient- and public health impact
modeling
specific recommendations necessaryspecific recommendations necessary
Different technologies, targets, performance characteristics
Dynamic policy refinement
New product successfully implemented in routine diagnostic services in early implementers’ laboratories in high disease endemic countries
Dynamic policy refinement
New product successfully implemented in routine diagnostic services in early implementers’ laboratories in high disease endemic countries
New technology rolled out in high disease endemic countries
Acknowledgements
• WHO/STB/TBL staff
C Gilpin, F Mirzayev, W van Gemert, J Iragena
• Systematic reviewers
K Steingart, A Cattamanchi, J MetcaA Zwerling, M Pai, A Date
• GRADE Working Group Chair: Holger
• Expert Group members
• WHO STAG members
• Funding: USAID, WHO, TDR, TREATTB/The Union
• FIND: Evaluation studies and reports
Acknowledgements
C Gilpin, F Mirzayev, W van Gemert, J Iragena
etcalf, A Detjen, R Menzies, L Rangaka,
Holger Schünemann
Funding: USAID, WHO, TDR, TREATTB/The Union
FIND: Evaluation studies and reports