1 |1 | Dr Karin Weyer Stop TB Department Geneva, Switzerland Strategic guidance on the use of laboratory technologies DEWG Meeting, Geneva: 13 October 2009

2 |2 | Outline 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 |3 | Latest global TB estimates Estimated number of cases Estimated number of deaths 1.77 million (27 per 100,000) 9.27 million (139 per 100,000) 150, ,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)

4 |4 | Overall 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 |5 | DOTS 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 |6 | Required expansion of Culture and DST capacity: from 10 to 60 million p/a # of tests required (million) USD funding required (million) Required expansion of Smear capacity: from 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 infrastructure and annual variable cost USD 6.1 billion required by Urgent MDG Targets  2,000 biosafety level 3 labs  20,000 newly trained technicians

7 |7 | Meeting 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 |8 | 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 ; LED microscopy and selected non-commercial culture and drug susceptibility testing methods expected in 2009

9 |9 | Need for new diagnostics at each level

10 | Establishing strong partnerships is key Challenges of implementing new diagnostics Feasibility, contract, development phases Demonstrati on phase Glob al Impa ct Evaluatio n phase 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 Logistics and supplies Human Resources (Guidelines Technology transfer) InfrastructureQuality Assurance Linked referral systems and reporting Additional components to ensure quality diagnostic services Essential instruments, reagents, supplies Global Policy

11 | 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

12 | Identifying the need for policy change Reviewing the evidence Convening an Expert Panel Assessing draft policy and guidelines Formulating and disseminating policy WHO policy formulation process

13 | Recent 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:

14 | Policy 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

15 | Analytical 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)

16 | 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

17 | Laboratory 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-1 st LINE (Solid or Liquid) No result Positive Negative MDR DRUG SUSCEPTIBILITY TESTING-2 nd LINE (Solid or liquid) XDR SusceptibleNo result Not XDR, resistant other drugsSusceptible Not MDR, resistant other drugs No result District NRL/regional SRL/NRL IDENTIFICATION (SPECIATION) (Conventional/Commercial) AFB TB/NTM

Positive Negative MICROSCOPY (ZN or Fluorescence) CULTURE (Solid or Liquid) No result DRUG SUSCEPTIBILITY TESTING-1 st LINE (Solid or Liquid) No result Positive Negative MDR DRUG SUSCEPTIBILITY TESTING-2 nd LINE (Solid or liquid) XDR SusceptibleNo result Not XDR, resistant other drugsSusceptible Not MDR, resistant other drugs No result District NRL/regional SRL/NRL 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 diagnosis after 9 to 12 weeks MDR-TB diagnosis after 1 to 2 days MDR-TB diagnosis after 3 to 5 weeks MDR-TB diagnosis after 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 diagnosis after 12 to 16 weeks XDR-TB diagnosis after 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 diagnosis after 4 to 9 weeks

22 | Policy c onsiderations 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)

23 | 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

24 | ‘From unimaginable…to indispensable’ Strengthening TB laboratories

25 | 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 Acknowledgements