Planning for the implementation of new diagnostic tests

Transcription

1 Planning for the implementation of new diagnostic tests Dr Christopher Gilpin Laboratories, Diagnostics & Drug Resistance WHO Global TB Programme, Geneva GLOBAL TB PROGRAMME Workshop on the development of National Strategic Plans for TB Control 1 Divonne, France, February 18 th 2014

2 The Global Burden of TB Estimated number of cases Estimated number of deaths All forms of TB HIV-associated TB 8.6 ( ) million 1.3 ( ) million* 0.5 m in children in children 3 million 2.9 m cases in women missed in women 1.1 ( ) million (13%) 320,000 (300k-340k) Multidrug-resistant TB (300k-600k) 170,000 (102k-242k) Source: WHO Global Tuberculosis Report * Including deaths attributed to HIV/TB

3 Outline WHO requirements for evaluation of new TB diagnostics Diagnostic pipeline Levels of laboratory services Diagnostic tools what is necessary? Forecasting and quantification based on country specific edpidemiology Maintenance Technical assistance

4 Evidence required for WHO review of diagnostics Phase 5 Scale-up and policy refinement Phase 1 Research and Development Phase 4 Phased uptake and collection of evidence for scale-up Phase 2 Evaluation and Demonstration Phase 3 WHO evidence assessment GRADE

5 Pipeline for new TB diagnostics

6 PROGRESS AT A GLANCE 2013 Global Report Volatile Organic Compounds BreathLink, Menssana Research, USA Prototype breathanalyzer device, Next Dimensions Technology, USA Molecular Detection MTB and drug resistance Alere Q, Alere, USA B-SMART, LabCorp, USA Gendrive MTB/RIF ID, Epistem, UK LATE-PCR, Brandeis University, USA GeneXpert XDR cartridge, Cepheid, USA TruArray MDR-TB, Akkoni, USA INFINITIMTB Assay, AutoGenomics, USA Nonmolecular technologies TB Rapid Screen, Global BioDiagnostics, USA TBDx, Signature Mapping Medical Sciences, USA Culture-based technologies BNP Middlebrook, NanoLogix, USA MDR-XDR TB Color Test, FIND, Switzerland / Imperial College, UK TREK Sensititre MYCOTB MIC plate, Trek Diagnostic Systems/ Thermo Fisher Scientific, USA Molecular Detection MTB +/- drug resistance TB LAMP, Eiken, Japan Genotype MTBDRsl, Hain Lifescience, Germany Molecular Detection MTB and drug resistance icubate System, icubate, USA TB drug resistance array, Capital Bio, China NATeasy TB Diagnostic kit, Ustar Biotechnologies, China Truelab/Truenat MTB, Molbio/bigtec Diagnostics, India Nonmolecular technologies Alere Determine TB-LAM, Alere, USA Commercial serodiagnostics (ALL MANUFACTURERS) Interferon-gamma release assays for the detection of active TB (ALL SETTINGS) Molecular Detection of MTB and drug resistance Xpert MTB/RIF (pulmonary extrapulmonary and paediatric samples) Lineprobe assays for the detection of MTB and rifampicin resistance conferring mutations in AFB smear positive sputum or MTB cultures Microscopy Light and LED Microscopy Same-day -diagnosis Culture-based technologies Commercial liquid culture systems and rapid speciation Non-commercial culture and DST (MODS, NRA, CRI)

7 Technologies endorsed by WHO MTB and drug resistance Xpert MTB/RIF (pulmonary extrapulmonary and paediatric samples) Lineprobe assays for the detection of MTB and rifampicin resistance conferring mutations in AFB smear positive sputum or MTB cultures Microscopy Light and LED Microscopy Same-day -diagnosis Culture-based technologies Commercial liquid culture systems and rapid speciation Non-commercial culture and DST (MODS, NRA, CRI)

8 WHO recommended diagnostics for use at different levels of laboratory sophistication *Available at:

9 Biosafety Levels for TB Laboratories High TB risk precautions Culture, DST, LPA (cultures) Moderate TB risk precautions liquifying (processing) samples Low TB risk precautions Microscopy, Xpert

10 High TB Risk Precautions TB containment laboratory Double door airlock Separate air inlet Venting of BSC via thimble Aerosol containment Negative pressure monitoring Uni-directional airflow PPE Autoclave for waste disposal Necessary for performing culture and DST

11 Why perform culture? Culture in Liquid media up to six weeks Reference method Culture on solid media up to eight weeks Given the diagnostic delay culture is NOT a good diagnostic tool Essential for performing DST to second-line drugs Necessary for monitoring patient response to treatment

12 Complexity of performing sputum culture and line probe assays 1. Liquefaction 2. Sample decanted 3. Decontamination NaOH 4. Vortex 5. Phosphate Buffer 6. Centrifugation 7. Decant 8. Re-suspend 9. Inoculation 12

13 Why perform LPA? LPA can be used to detect rifampicin and isoniazid conferring mutations in AFB smear positive specimens Positive TB cultures Results can be available in 24 hrs Secondline LPA NOT recommended Needs sophisticated laboratory Needs good referral mechanisms Suitable for high throughput testing at Central or Regional laboratory level

14 CC AC TUB rpob rpob rpob rpob rpob rpob rpob rpob rpob rpob rpob rpob rpob WT1 WT2 WT3 WT4 WT5 WT6 WT7 WT8 MUT1 MUT2A MUT2B MUT3 katg katg WT katg MUT1 katg MUT2 inha inha inha inha inha inha inha TUB WT1 WT2 MUT1 MUT2 MUT3A MUT3B rpob MUT katg WT katg MUT inha WT inha MUT sensitive resistant sensitive resistant Additional infrastructure for LPA 1. Laboratory infrastructure to address biosafety and contamination control 1. Containment laboratory for DNA extraction 2. At least two additional rooms needed for DNA pre-amplification and post-amplification processes 2. Appropriately well train staff supervised by experience technologists in molecular biology 3. Multiple pieces of equipment 4. Stringent laboratory protocols needed SOPs, Internal QC, External QA, # katg RMP INH rpob inha

15 Why perform Xpert MTB/RIF 1. Laboratory infrastructure similar to that for microscopy is required 2. Can be de-centralised for testing at lower levels of the laboratory network 3. Suitable for the diagnosis of TB and rifampicin resistance in AFB smear-negative and smear-positive individuals 4. New WHO policy recommendations issued for use in adults children and extrapulmonary TB

16 Individuals to test using Xpert MTB/RIF All individuals presumed to have TB Initial TB diagnostic test Xpert MTB/RIF should be used rather than conventional microscopy, culture and DST as the All individuals at initial diagnostic test in adults presumed to have MDR-TB or HIV-associated TB risk of MDR-TB (TB A. (strong recommendation, high-quality Strong recommendation evidence). confirmed and TB Xpert MTB/RIF Xpert suspected) MTB/RIF should be used rather than conventional microscopy, culture and DST as the initial diagnostic test in children presumed to have MDR-TB or HIV-associated TB (strong recommendation, very low-quality evidence). HIV (+) individuals Xpert (or MTB/RIF HIV unknown may be used in rather than conventional microscopy and culture as the initial diagnostic Xpert MTB/RIF B. high test HIV in settings) all adults presumed Strong recommendation to have TB (conditional recommendation acknowledging resource suspected implications, of high-quality evidence). Xpert having MTB/RIF TB may be used rather than conventional microscopy and culture as the initial diagnostic test in all children presumed to have TB (conditional recommendation acknowledging resource implications, very low-quality evidence). Conditional recommendation Xpert Adults MTB/RIF presumed may be used to as a follow-on test to microscopy in adults presumed to have TB C. but not have at risk TB of but MDR-TB not at or HIV Conditional associated TB, especially Smear in further Smear testing of smear-negative microscopy neg. Xpert MTB/RIF specimens risk of (conditional MDR-TB or recommendation acknowledging resource implications, high-quality evidence). HIV associated TB

17 Interpretation of test results Xpert MTB/RIF assay TB not detected In groups with high risk of MDR-TB TB detected; Rif resistant TB detected; Rif sensitive WHO recommended regimen for MDR-TB with INH; Registration as RR-TB DST to at least INH; Quinolones; SL injectable In groups with low risk of MDR-TB Repeat Xpert MTB/RIF WHO recommended first-line treatment; Registration as bacteriologically confirmed TB Modify treatment based on the DST results; Update registration TB detected; Rif resistant TB detected; Rif sensitive WHO recommended regimen for MDR-TB with INH; Registration as RR-TB DST to at least RIF; INH; Quinolones; SL injectable Modify treatment based on the DST results; Update registration In case of discordance on Rif result refer sample for sequencing If TB still suspected Further investigation (CXR, repeat Xpert MTB/RIF, culture, etc..)

18 National strategy and objectives Which diagnostic algorithm will be implemented? Procurement planning is directly linked to the National TB Plan What infrastructure needs to be established or upgraded? How many labs? At which level? Which diagnostics will be used? At which level - peripheral, district, regional, central? Planning for infrastructure improvement Planning for procurement of goods (shelf-life) Quantifying and forecasting needs Developing a supply chain (cold) for TB laboratories Is a specimen transport and referral system adapted to this new plan?

19 WHO TB Planning and budgeting tool Ready-made framework for planning/budgeting for each component of TB control Application options to enhance user-friendliness Choosing country via menu system selects correct set of epidemiology/ demographic/financial historical data, projections and default values Menu driven system Summary tables and figures automatically produced Guidance available within tool

20 Example: Pakistan # MDR patients (projections)

21 What diagnostics are needed for previously treated patients? Need estimates of the number of previously treated persons based on case notifications. Need to estimate proportion of rifampicin resistance e.g Pakistan 14,000 previously treated persons 30% Rifampicin resistance among previously treated 3% Rif resistance among new cases 14,000 persons require a rapid DST Xpert MTB/RIF or LPA 4,200 persons (30% of 14,000)(MDR-TB patients) will require culture and DST for secondline drugs Each person will require additional cultures for monitoring response to therapy up to 12 cultures per person or 50,400 cultures Need many more Xpert tests to detect 3% RIF resistance among new cases aim for 20% by 2015

22 What diagnostics are needed for previously treated patients? 14,000 persons require a rapid DST Xpert MTB/RIF or LPA The structure of the laboratory network and referral mechanism will determine which tests to use where. If network is well structured testing can be de-centralised and test previously treated persons using Xpert If only the central level is strong a larger proportion of the tests could be referred to the central level for testing by LPA(where capacity already exists) A combination of specimen referral for LPA and decentralized Xpert testing can be used

23 What diagnostics are needed for person with HIV? Indicator Source Remarks a Annual projected number of HIV positive (adult and children) in care at a clinic, (pre-art and ART) based on a baseline figure (2012) National HIV program (user entry) HIV in care includes HIV treatment, i.e. enrolment in the pre-art register or in the ART register once started on ART. Projections are based on 2012 baseline data. b c Assumption % of HIV positive (adult and children) in care at a clinic are screened Assumption 2. 15% of HIV positive (adult and children) in care at a clinic screened and with presumptive TB User can modify this assumption based on the coverage of TB screening among PLHIV Assumption based on expert group decision for the Spectrum model The TB screening should be done based on national TB/HIV guidelines. This assumption is based on a premise of rule-in TB in order to increase the suspicion of having TB in PLHIV. d Assumption 3. % coverage of Xpert testing for the 15% HIV positive presumed to have TB User entry: based on the capacity to scale up Xpert testing e Estimated number of HIV positive patients tested with Xpert Calculated e= a*b*c*d Default formula appears in costing tool

24 What diagnostics are needed for Annual projected of the number of HIV positive persons in care Assume: 100% screening Assume: 15% with presumptive Consider % coverage of Xpert person with HIV? e.g Africa context 100,000 PLHIV in care Need to test 20-30% have symptoms of TB Up to 30,000 persons will require a rapid diagnostic test Xpert MTB/RIF (depending on Xpert coverage) Assuming 3% MDR-TB among new cases of TB in PLHIV Up to 900 persons (MDR-TB patients) will require culture and DST for secondline drugs Each person will require additional cultures for monitoring response to therapy up to 12 cultures per person or 10,800 cultures

25 Planning for facility maintenance Annual certification of BSC Costs vary depending on setting Centrifuge maintenance GeneXpert module calibration Autoclave Monitoring integrity of ducted exhaust Building maintenance Need to consider approx. 10% of facility cost needed for annual maintenance

26 Technical Assistance Collaboration agreements Quality assurance Appropriate biosafety Diagnostic algorithms Functional networks Rational planning with laboratory experts

27 Acknowledgements Laboratory, Diagnostics and Drug Resistance unit in the WHO Global TB Programme: Karin Weyer, Fuad Mirzayev, Wayne van Gemert, Jean Iragena, Fraser Wares, Ernesto Jaramillo, Dennis Falzon, Vineet Bhatia, Henriikka Huttunen, Lynne Harrop, Diego Zallocco

28 Xpert MTB/RIF What is needed? A Item Cost Comment GeneXpert 4 module with laptop (Ex-Works price) Equipment C UPS $1, $17, >60% price reduction compared to EU/US B Shipment $1, Depends on destination Local purchase, price depends on the market and back up capacity of UPS D Printer $ E Maintenance Annual calibration costs $1, Local purchase, price depends on the market, optional Highest price if done in Cepheid Toulouse, when web-based drops to 450USD F G H I J Consumables Cost per cartridge $ % price reduction compared to EU Number of working days per year Average number of tests per instrument /day Number of tests/1 year/ full load 1 instrument Losses due to error/incorrect use (high estimate 10%) 250 Number can vary depending on local context 12 Number can vary depending on working hours 3000 G*H % of I K HR costs Technician annual salary $5, Country-specific L Training and TA $5, Depends on the needs M N Installation costs Running costs (annual, 1 instrument) $19, A+B+C+D $34, E+F*(I+J) O GRAND TOTAL $64, N+M+L+K