The TB diagnostic pipeline a realistic view

Transcription

1 The TB diagnostic pipeline a realistic view Claudia Denkinger, MD PhD MSc Head of TB Programme at FIND 26 th October 2016, Union Meeting, Liverpool

2 Understanding diagnostic needs: Diagnostics gaps in the care cascade All Patients Patients with MDR TB 4.3 million undiagnosed or not reported >80% not diagnosed and treated WHO Global TB report 2016

3 Health care seeking Reference Labs District Labs Understanding diagnostic needs: Where do patients seek and receive care? Diagnosis Treatment for DS-TB Treatment for DR-TB Reference Labs 6 million tests (LPA/Cx) District Labs MDR or pre- XDR or XDR or more 5 million tests (Xpert, smear) Reference District Reference Short course or standard or individualized regimen Microscopy Centers Microscopy Centers Microscopy Centers District Community/ Health Posts 60 million tests TB (smear, or not TB rapid serology) DS or not DS Community/ Health Posts High risk for TB HRZE Community/ Microscopy Health Posts Centers Microscopy Centers

4 Non-sputum based tests for diagnosis or triage Goal: Early identification of patients with TB or at high-risk of TB on easy to access samples ideally at level 0 Note: Blood-based markers in separate talk 31 October

5 Ease of translating onto a point of care platform The biomarker landscape Level of certainty in biomarker VOC (breath) The enose Company Rapid Biosensor Systems Avisa Menssana BreathLink Hill, Dartmouth Antibodies (b) Several Proteins (s, b, u) Dobos Moritz Walt/Ahmed Feldheim Campos-Neto Somalogic Kaufmann Walzl/Chegou Laal Krishna Drain Lawn Li Bradbury Hust Blackburn FIND LAM (u, b, s) FIND/Fujifilm Pinter Brennan/Chatterjee Hamasur/Källenius Global Good/IVT Swanson/Mukundan Cellular, stimulation (b) Geldmacher Pantaleo Modlin Lewinsohn Rengerajan Schaller Walzl Bruchfeld Mycolic acids/ Iipids (s) McNerney Moody Nucleic Acids (u, b) microrna (b, u) LMU Levin (host RNA) Zak (host RNA) Cirillo (srna) Cannas (tr-dna) Joosten/Ottenhoff (hostrna) Sweeney (hostrna) O Garra/Bloom (RNA signatures) Vlaminck (cfdna) Cirillo/Miotto Zhou Xu Goa/Nyrolles Zhang Meyerhans s sputum u urine b whole blood

6 A lot of work for little clinical benefit Science stops at exploratory studies with limited sample size Limited knowledge sharing among researchers Concerns about revealing IP Poste, Nature, 2011 FIND Systematic Review unpublished

7 Accelerating path to success - a TB Biomarker Database Goal: Overcome data and IP sharing barriers Enable comparison of markers and assessment of combinations of markers to identify signatures Drive biomarker research towards usecase focused test development Includes: Published literature from an ongoing systematic search for evidence Unpublished results from the assessment of ongoing R&D efforts using banked patient specimens FIND IJID unpublished

8 Current LAM assay a niche test Absolute reduction in mortality 4% Peter et al. The Lancet , DOI: ( /S (15) ) Peter Lancet 2016

9 Can we do better with LAM? Matrix Advantages Challanges and Disadvantages Urine Potential in EPTB & paediatric TB Serum More direct correlation to MTB load expected Potential in EPTB & paediatric TB LAM might be related to GU TB Immunocompetent concentrations may be low or absent Complex formation with anti-lam Abs in systemic circulation requires sample treatment Graphic confidential Sputum Correlation to Mtb load in lungs (useful in treatment monitoring?) Probably highest LAM concentrations Only useful for PTB Complex sample matrix 31 October

10 Detection on breath Overview of the processes involved in breath testing. Konvalina and Haick 2014 Metal-oxide-based olfactory sensor [Bruins et al. 2013] Cough/aerosol collection combined with immunoassay based antigen detection [McNerney et al. 2010] Portable GC coupled to surface acoustic wave (SAW) detector [Phillips et al. 2013] 13 C-urea is converted to 13 CO 2 in the patients lung if bacteria is present and detected in a spectrometer [Jassal et al. 2010] Proof-of-principle data from feasibility studies available for some technologies (performance thus far not meeting TPP, limited independent study data)

11 Smear replacement tests Goal: ENABLE TEST and TREAT through Accurate, rapid, easy detection Universal DST 31 October

12 What do we need to overcome diagnostic gaps? Health care seeking Reference Labs District Labs Diagnosis Treatment for DS-TB Treatment for DR-TB Reference Labs 6 million tests (LPA/Cx) District Labs Expanded DST 5 million tests (Xpert, smear) Reference Labs District Labs Reference Labs Short course or standard or individualized regimen Microscopy Centers Microscopy Centers Microscopy Centers District Labs Community/ Health Posts 60 million tests TB (smear, or not TB rapid serology) Which DS or regimen not DS Community/ Health Posts HRZE/ new regimens Community/ Microscopy Health Posts Centers Microscopy Centers

13 Greatest progress - NAAT for smear replacement and DST New NAAT platforms Needs to be addressed Decentralization Improving time to diagnosis Improving MTB detection Universal DST Detection of EPTB Higher throughput, broad portfolio Move tests to lower levels or samples to higher levels

14 Improvements on the Cepheid platform Tuberculosis Patient Level 0 Community/POC Level 1 Microscopy centre Level 2 District hospital Level 3 Reference centre Roll-out starts in Q4/2016 Data reporting Omni Established in LMICs > installed modules GeneXpert Omni platform Anticipated for Q Studies planned to assess impact in settings of intended use Xpert cartridges Expanded portfolio: Xpert, Ultra, XDR, other diseases (HIV, HCV, NG/CT, Ebola)

15 31 October Xpert vs Ultra Target Xpert Ultra Benefits Single copy rpob Multi-copy IS6110 & IS rpob Cartridge 25mcl tube 50 mcl tube Increased sensitivity: 20 CFU/ml vs 130 CFU/ml Analysis Rif -Susceptible Real time PCR curves Melt curve analysis Rif-Resistant Improved ability to detect mutations in mixtures. Robust detection of all mutations associated to Rifampin resistance (i.e. rpob 533 C to G mutations). Avoid false + for Rifampin resistance in samples with low bacterial load

16 Results to date & ongoing work Beta-study with 364 patients Ultra: Sensitivity of 92.4% (Smear-: 86.4%); Specificity: 99.2% Xpert: Sensitivity of 85.9% (Smear-: 72.7%); Specificity: 99.0% RIF on Ultra: -4 FP: 3 with disputed mutations or heteroresistance -3 FN: G4 and Ultra are WT, likely mutation outside of rpob Ongoing: 10 sites; 8 country study Reference standard: 4-6 cultures Direct comparison to Xpert Subgroup analysis by smear status, TB history, HIV status Results expected in Q FIND unpublished data 31 October

17 Cepheid Xpert XDR RIFs TB detected/fl regimen TB/RIF RIFr FQ/AG/INH S Short regimen R Individualized Rx/ further testing Graphic confidential Cepheid Xpert XDR promising early results Table confidential D. Alland unpublished data 31 October

18 Expansion of the utility beyond sputum for children & in the diagnosis of EPTB Xpert for MTB detection on stool Xpert vs. Culture Sensitivity Specificity Respiratory 71.4% (29.0%, 96.3%) Swab rectal 42.9% (9.9%, 81.6%) 0.6 g stool 71.4% (29.0%, 96.3%) 98.1% (94.5%, 99.6%) 100.0% (97.7%, 100.0%) 98.7% (95.5%, 99.8%) FIND unpublished; Banada PLOSone

19 Is there a limit to the sensitivity we can achieve with molecular tests? Xpert (G4) specificity in patients with past history of TB (from Theron et al). Graphic confidential Steingart Cochrane 2014; Theron CID 2016; Metcalfe ERJ 2014

20 Expanded drug susceptibility testing Goal: ENABLE individualized therapy

21 What is the drug pipeline telling us about the diagnostic needs? TPP: Drug prioritization: RIF > FQ (incl. Mox)> INH = PZA In use In pipeline PRETOMANID Uncertainties: Success of regimens For DS, MDR, XDR? > defines level of implementation Barrier to resistance; crossresistance Revised prioritization?: RIF > FQ > PZA>BDQ >LZD= PA WHO report 2014; TB Alliance pipeline 31 October

22 Our understanding of the genotypic basis of resistance is improving Contributed Data WGS Unified Pipeline SNP Genotypic data Phenotypi c data Clinical trial data DR study data Surveillanc e data Original WGS SNP reports New SNP reports from Unified Pipeline Expert Panel Review Starks CID 2015, Salamon JID 2015

23 Both integrated platforms & more flexible, comprehensive platforms are necessary Integrated Platform Define number of target resistance mutations Sample to result Changes to targets require revalidation of entire assay Sequencing Modular with extraction, PCR, sequencer Possible directly from sputum Targeted or whole genome Flexible targets Regimen selection at level 1 Individualized care at level 2/3 23

24 Vision for TB diagnostic in 2020 First point of contact Level 0/Level 1 Dedicated unit Level 1/Level 2 Reference level/ Level 3 1.Triage test 1.TB confirmation with rapid integrated DST for critical drugs that drive regimen decisions 2. Latent to active progression 1.Comprehensive DST that covers the extended portfolio of drugs ICT supported solutions; Systems strengthening; Active case finding; Integration across diseases; TB

25 And what we can and should achieve! Undx d TB All cases of TB MDR Minimal undiagnosed or not reported TB No undiagnosed MDR TB WHO Global TB report 2016

26 26 Thank you/ Questions? FIND Tobias Broger David Dolinger Catharina Boehme Samuel Schumacher