Host-Directed Therapies for TB. Update. Dr. Cris Vilaplana, UTE

Transcription

1 Host-Directed Therapies for TB. Update. Dr. Cris Vilaplana, UTE

2 Half of the Western Europe has more or less faulty lungs. (Kafka to Milena, 1922) Mortality rate from TB UK >50 : Targeting the mycobacteria

3 Fast acquisition of DR to newly approved drugs Delamanid and Bedaquiline!

4 WHAT IF WE FOCUS ON THE HOST RATHER THAN ON THE BACTERIA? HOST-DIRECTED THERAPIES

5 Interfere with Host mechanisms required for Mtb Replication/Persistence Immune R HDT Modulates disbalanced host R at site pathology Inflammation

6 Interfere with Host mechanisms required for Mtb Replication/Persistence Macrophages ROS + MYCOBACTERIA. DESTRUCTION + ManLAM ESX1 Eis$gene$related virulence factors - AUTOPHAGY...! IFN$g

7 METFORMIN Exp Groups: Case: DM+TB, 152 Control: DM, 299 Anti-DM2 ROS AUTOPHAGY NO (but Case-Control) Main outcome: n patients w Metformin in the Case group Results: 1-poor glyc control is related to TB 2-Metformin is protective (3.9 fold reduction in TB risk) NOT A CT! WHAT IS PROTECTIVE, METFORMIN BY ITSELF OR BY REDUCING GLYC?

8 VITAMINS DIETARY SUPPLEMENTS CT: VIT D: 12 completed CT VIT A: 9 completed CT RESULTS: UNCONCLUSIVE. ROS AUTOPHAGY ANTIMICROBIAL (VIT A) In general, multivitamins might be associated to weight gain, less mortality? High doses Vit D might be associated to: better non$microbiological outcomes and reduction in.the time of.negativization of.the sputum culture if genotype Taql vitamin D.receptor.polimorphism

9 Main outcome: weight and TB score Main outcome: PET-CT 8-w FU Main outcome: Immune R & Serum [25(OH)D] Main outcome: LTBI- active TB incidence Main outcome: Safety

10 IMPACT ON IMMUNE R IFN-g TNF-a IL-1 X TISSUE DAMAGE

11 IFN-g IFN-g ANTIMICROBIAL ACTIVITY OF MACS Exp Groups: TB TB+ rifn-g1b nebulized (4M) TB+ rifn-g1b sc (4M) Results: 1-IFN-g groups: higher immune R 2-IFN-g nebulized: increased Mtb clearance (sputum) + less clinical symptoms at w4 Another! rifn-g SC, in MDR-patients (8): pilot in Cuba---! better outcomes than usual

12 IL-2 rhil-2 MODULATING IMMUNE R (1997) Exp Groups (n=24): MDR-TB, TT MDR-TB, TT + ril-2 (1M) MDR-TB, TT + ril-2 (pulse) (2003)Exp Groups: DS-TB in TT DS-TB in TT + ril-2 (1M) 1ary OUTCOME: sputum culture conversion Results: daily ril-2 (1M) better Mtb clearance, better clinic symptoms and Rx Results: No effect detected ONGOING (China) NCT : MDR-TB, 1ary outcome: CURE RATE

13 THALIDOMIDE Exp Groups: TB+/-HIV, TT+placebo TB+/-HIV, TT+Thalidomide MODULATOR TNF-a Results: weight gain and TNF-a production in vivo and exvivo MODULATES TNF-A SIGNALING N=47. CT WITHDRAWN FOR TOXICITY 13% deaths in the Thalidomide group ROOM FOR ANALOGUES?

14 ETANERCEPT SOLUBLE TNF RECEPTOR BLOCKS TNF-A Exp Groups: TB+/-HIV, TT+ ETANERCEPT sc 2/w (compared with historical controls) Results: 1- safe 2- positive trends in weight, clinical evolution & time to sputum culture conversion mabs against TNF infliximab/adalimumab might be beneficial for life-threatening TB (1 case) BUT can reactivate LTBI

15 NR hk M.manresensis (M.fortuitum complex) Exp Groups ADULTS LTBI+/- (n=47): PLACEBO NR 10 4 NR 10 5 CHILDREN LTBI+/- (ONGOING): PLACEBO NR ary OUTCOME: tolerability & immunogenicity MODULATING IMMUNE R Results (adults): safe & specific mem Treg NCT ONGOING (Georgia): EFFICACY TRIAL! N=3300 TB CONTACTS 1ary outcome: INCIDENCE OF ACTIVE TB

16 MSC AUTOLOGOUS MESENCHIMAL STROMAL CELLS INDUCE REGULATORY PHENOTYPES IN DC & T CELLS- MODULATE IMMUNE R Exp Groups MDR/XDR (n=30, Belarus) TT TT+ MSC (1 infusion 1st M) 1ary OUTCOME: Safety Results (adults): Safe.

17 ANTIBIOTICS DOXYCICLIN, AZITHROMYCIN INHIBIT MATRIX METALLOPROTEINASES (MMS) TISSUE DAMAGE IN INFLAMMATORY CONDITIONS AZITHROMYCIN AS HDT: NCT ONGOING- GRONINGEN, n=24 EXP GROUPS: TT TT+ AZYTHROMYCIN DAILY 1M 1ary OUTCOME: systemic inflammation (blood cell counts and serum infl markers)

18 ANTI- INFLAMMATORIES NSAIDS COX-INHIBITORS RESULTS (n=146): Better outcomes in High Dose group (100mg) BUT one death Exp Groups (ZA) HIV+TB (n=150) TT TT+ MELOXICAM 2M 1ary OUTCOME: Incidence in TB IRIS Exp Groups (GEORGIA) PRE-XDR/XDR (n=24) TT TT+ IBUPROFEN 400mg 2M 1ary OUTCOME: Sputum conversion, TB Outcomes, Changes Xray Exp Groups (NORWAY) PRE-XDR/XDR (n=40) TT TT+ ETORICOXIB 140d TT+ H56:IC31 vaccine TT+ ETORICOXIB + H56:IC31 1ary OUTCOME: Safety+ Immunogenicity

19 GLUCOCORTICOIDS CORTICOSTEROIDS MODULATES THE IMMUNE R: PRO-INFL MEDIATORS (TNF!) 41 CT pulmonary TB; 20 prior modern RIF-TT 18 pulomary TB prior modern RIF-TT STEROIDS EFFECTIVE REDUCING MORTALITY IN ALL FORMS TB DEMONSTRATED TO BE USEFUL IN TB FORMS WITH HIGH INFLAMMATION: MENINGITIS, IRIS, PERICARDITIS

20 GLUCOCORTICOIDS CORTICOSTEROIDS 8 CT registered in clinicaltrials.gov: 2 withdrawn (1 no funding, 1 flood in Thailand) MODULATES THE IMMUNE R: PRO-INFL MEDIATORS (TNF!) NCT TB MENINGITIS (n=520) (Vietnam&Indonesia) TT TT+ DEXAMETHASONE 8W 1ary OUTCOME: Survival at 12 M after randomisation ONGOING NCT (ZA) HIV+TB (n=240) TT TT+ PREDNISONE 2W 40MG+2 W 20MG 1ary OUTCOME: Development of IRIS COMPLETED NCT TB PERICARDITIS (AFRICA) HIV+TB (n=1400) TT TT+ PREDNISOLONE 6W TT+ IMMUVAC 5 DOSES 1ary OUTCOME: Combined end-point Death+clinica cardíaca asociada a pericarditis COMPLETED

21 Hk-fragmented M.tuberculosis IMMUNE R ALSO AGAINST LATENT BACILLI AGs Results (adults): 1-safe in healthy and LTBI (HIV- and HIV+) 2-immunogenic NCT MDR-TB (n=27) TT TT+ RUTI (ONE SHOT) 1ary OUTCOME: Safety RECRUITING

22 GRÀCIES!