François-Xavier BLANC, MD, PhD Nantes University France Tuberculosis in Europe: The impact of migration New methods and drugs for tuberculosis diagnosis and treatment: an update François-Xavier BLANC, MD, PhD Nantes University France xavier.blanc@chu-nantes.fr WEWS0105 26 JULY 2017

Conflict of interest Other conflicts I have no conflicts of interest to declare. Other conflicts I had no time to read all the existing litterature  subjective choices, mainly covering the 2015-2017 period. Please, be indulgent!

In what kind of world do we actually live? Medical density Territory size shows the proportion of all physicians (doctors) that work in that territory (map #219, worldmapper.org)

In what kind of world do we actually live? Tuberculosis cases Territory size shows the proportion of worldwide tuberculosis cases found there (map #228, worldmapper.org)

In what kind of world do we actually live? Tuberculosis deaths! Territories are sized in proportion to the absolute number of people who died from TB in one year (map #373, worldmapper.org)

In what kind of world do we actually live? HIV/AIDS deaths!!! Territories are sized in proportion to the absolute number of people who died from HIV/AIDS in one year (map #374, worldmapper.org)

TB diagnosis: ‘new’ tools Xpert MTB/RIF Ultra Urine LAM: recent data Blood markers Electronic nose Imaging

TB diagnosis: ‘new’ tools Xpert MTB/RIF Ultra Urine LAM: recent data Blood markers Electronic nose Imaging

Xpert MTB/RIF Ultra 2 different multi-copy amplification targets (IS6110 and IS1081) a larger DNA reaction chamber than Xpert MTB/RIF (50 μl PCR reaction in Ultra vs. 25 μl in Xpert MTB/RIF) fully nested nucleic acid amplification more rapid thermal cycling improved fluidics and enzymes limit of detection of 16 bacterial colony forming units (CFU) per ml (compared to 114 CFU per ml for Xpert MTB/RIF) melting temperature-based analysis instead of real-time PCR 4 probes identify rifampicin resistance mutations in the rifampicin resistance determining region of the rpoB gene by shifting the melting temperature away from the wild type reference value.

Xpert MTB/RIF Ultra The Technical Expert Group found that the Ultra assay is non-inferior to the Xpert MTB/RIF assay for the detection of M. tuberculosis (MTB) and for the detection of rifampicin resistance. This means that the new Ultra cartridge is at least as good for the detection of MTB and rifampicin resistance as Xpert MTB/RIF. In certain populations, the Ultra performs better for MTB detection especially for individuals whose specimens are frequently paucibacillary. The current WHO recommendations for the use of Xpert MTB/RIF now also apply to the use of Ultra as the initial diagnostic test for all adults and children with signs and symptoms of TB and in the testing of selected extrapulmonary specimens (CSF, lymph nodes and tissue specimens).

TB diagnosis: ‘new’ tools Xpert MTB/RIF Ultra Urine LAM: recent data Blood markers Electronic nose Imaging

Urine LAM Determine® TB-LAM Ag: dipstick (like a pregnancy test). Result available in 25-30 minutes. Lipoarabinomannan (LAM) : lipopolysaccharide of the cell wall of Mycobacterium tuberculosis 12

TB diagnosis: recent data on urine LAM

LAM in comparison with microscopy for the diagnosis of active TB in adults living with HIV CD4 treshold # of studies (participants, % with TB) Pooled sensitivity (95%CI) Pooled specificity (95%CI) CD4 > 200/µL 5 (925, 24%TB) 15% (8-27) 96% (89-99) CD4 ≤ 200/µL 5 (1344, 45%TB) 49% (34-66) 90% (78-95) CD4 > 100/µL 5 (1410, 30%TB) 26% (16-46) 92% (78-97) CD4 ≤ 100/µL 5 (859, 47%TB) 56% (41-70) 90% (81-95) The pooled sensitivity of LAM was 37% (95% CI, 32-42%) compared with 47% (95% CI, 35-59%) for sputum microscopy (using a microbiological reference standard). The pooled specificity of LAM was 95% (95% CI, 93-97%) versus 98% (95% CI, 93-100%) for sputum microscopy.

Sensitivity and specificity of LAM in adults living with HIV

Sensitivity and specificity of LAM in adults living with HIV

TB diagnosis: recent data on urine LAM Pragmatic, parallel-group, open-label, multicentre, randomised trial 10 urban or periurban hospitals in Africa (4 in South Africa, 2 in Tanzania, 2 in Zambia, 2 in Zimbabwe) Inpatients only; all HIV+ve 2 arms: LAM + routine TB diagnostic tests vs. routine TB diagnostic tests (no LAM)

TB diagnosis: recent data on urine LAM

TB diagnosis: recent data on urine LAM

TB diagnosis: ‘new’ tools Xpert MTB/RIF Ultra Urine LAM: recent data Blood markers Electronic nose Imaging

TB diagnosis: blood markers

TB diagnosis: blood markers Sensitivity and specificity compared with commercially available standard esat6 and 38 kDa antigens. Bacteriologically confirmed TB patients, non-TB disease controls and healthy individuals were included. AUC of the selected antigens were 0.98 (0.98-0.99) for rSS1, 0.88 (0.84-0.92) for rSS2, 0.88 (0.84-0.92) for rSS3, 0.95 (0.93-0.98)for rSS4 and 0.99 (0.98-1.0) for rSS5.

BATF2: basic leucine zipper transcription factor 2

MDR-TB

TB diagnosis: ‘new’ tools Xpert MTB/RIF Ultra Urine LAM: recent data Blood markers Electronic nose Imaging

TB diagnosis: electronic nose

TB diagnosis: electronic nose

TB diagnosis: electronic nose

TB diagnosis: ‘new’ tools Xpert MTB/RIF Ultra Urine LAM: recent data Blood markers Electronic nose Imaging

TB diagnosis: imaging F-fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) Inability to distinguish tubercular from malignant lesions Two distinct patterns of pulmonary TB: the lung pattern, related to a restricted and slight hypermetabolic infection, with 18F-FDG uptake in areas of lung consolidation ± cavitation surrounded by micronodules and mild uptake within lymph nodes, the lymphatic pattern, related to a systemic and intense infection, with more enlarged and 18F-FDG-avid hilar and mediastinal lymph nodes. Skoura E, et al. Imaging in tuberculosis (review). Int J Infect Dis 2015; 32: 87-93

F-18 FDG PET/CT Skoura E, et al. Imaging in tuberculosis (review). Int J Infect Dis 2015; 32: 87-93 18F-FDG PET is able to differentiate active PTB from old or inactive disease: active tuberculoma has significantly higher SUVmax values compared with inactive tuberculoma1. When a SUVmax of 1.05 (at 60 min) was used as the cut-off, the sensitivity and specificity were 100% and 100%, respectively1. A recent study concluded that 18F-FDG PET/CT has the potential to become a tool for monitoring the treatment response in selected cases of extra-pulmonary TB or multidrug resistance2. An interesting study of patients with radiographic lesions suggestive of old healed TB aimed to gather information on the metabolic status of TB lesions using 18F-FDG PET/CT imaging. The authors showed that patients with old healed TB lesions with a higher SUVmax may be at higher risk of active TB3. 1. Kim IJ, et al. Eur J Nucl Med Mol Imaging 2008;35:808-14 2. Heysell SK, et al. BMC Pulm Med 2013;13:14 3. Jeong YJ, et al. J Korean Med Sci 2014;29:386-91

F-18 FDG PET/CT Vorster M, et al. Advances in imaging of tuberculosis: the role of 18F-FDG PET and PET/CT. Curr Opin Pulm Med 2014; 20: 287-93 In extrapulmonary TB, 18F-FDG PET detects more tuberculous lesions than CT, is of value in assessing response to tuberculostatic treatment, and helps in diagnosing spinal infection and identifying TB-related spondylitis However, differentiation of malignant versus TB lymph node involvement is problematic. 18F-FDG PET can also be considered a marker of disease status in patients with HIV and TB co-infection. Overall, evaluation of treatment response is potentially the most important clinical application of 18F-FDG PET in TB, owing to its ability to distinguish active from inactive disease. 18F-FDG PET and PET/CT may assist early diagnosis and facilitate differentiation between malignancies and TB, identification of extra-pulmonary TB, staging of TB, and assessment of treatment response.

TB treatment Existing molecules at higher dose (RIF) Modification of existing molecules (new formulations, better delivery, suitable for children) New molecules New regimen to shorten duration of TB treatment and improve outcomes in MDR/XDR-TB

TB treatment

TB treatment: new molecules Everything you need to know is @: http://www.newtbdrugs.org/pipeline/clinical

http://www.newtbdrugs.org/pipeline/clinical

Conclusion TB diagnosis: we have to make it earlier and better, especially in HIV+ve individuals (extrapulmonary TB, disseminate TB, children) Lots of research done in the past 5 years ‘New’ tools like Xpert MTB/RIF & urine LAM More POC tools urgently needed TB treatment will change dramatically within the next 10 years Ultimate goal: decreasing +++ mortality

Thanks for your attention ! xavier.blanc@chu-nantes.fr