Host-Directed Therapiesfor TB. Update.

Dr. Cris Vilaplana, UTEhttps://unitatdetuberculosiexperimental.wordpress.com/

Mortality rate from TB 1855-1955 UK

“Half of the Western Europe has more or less faulty lungs.”

(Kafka to Milena, 1922)

http://sphweb.bumc.bu.edu/otlt/mph-modules/ep/ep713_descriptiveepi/EP713_DescriptiveEpi6.html

>50’: Targeting the mycobacteria

Fast acquisition of DR to newly approveddrugsDelamanid and Bedaquiline!

WHAT IF WE FOCUS ON THE HOST RATHER THAN

ON THE BACTERIA?

HOST-DIRECTED THERAPIES

HDT

Interfere with Host mechanismsrequired for Mtb

Replication/Persistence

Modulatesdisbalanced host R

at site pathology

⬇ Inflammation

⬆ Immune R

IFN$g

AUTOPHAGY......

MacrophagesManLAMESX1Eis$gene$related virulence factors

-+

Interfere with Host mechanisms required for

MtbReplication/Persistence

!

MYCOBACTERIA.DESTRUCTION

⬆ROS

+

METFORMIN HOW?⬆ROS

⬆AUTOPHAGY

WHAT?Anti-DM2

CT?NO (but Case-Control)

Exp Groups:Case: DM+TB, 152Control: DM, 299

Main outcome: n patients w Metformin in the Case group

Results: 1-poor glyc control is related to TB2-Metformin is protective (3.9 foldreduction in TB risk)NOT A CT!WHAT IS PROTECTIVE, METFORMIN BY ITSELF OR BY REDUCING GLYC?

VITAMINSHOW?⬆ROS

⬆AUTOPHAGYANTIMICROBIAL (VIT A)

WHAT?DIETARY

SUPPLEMENTS

CT?YES

RESULTS: UNCONCLUSIVE.

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

CT: VIT D: 12 completed CTVIT A: 9 completed CT

Main outcome: weight and TB score

Main outcome: PET-CT 8-w FU

Main outcome: Immune R & Serum [25(OH)D]

Main outcome: Safety

Main outcome: LTBI- active TB incidence

IMPACT ON IMMUNE R

IFN-gTNF-aIL-1

TISSUE DAMAGE

X

IFN-g HOW?⬆ANTIMICROBIAL

ACTIVITY OF MACS

WHAT?IFN-g

CT?YES

Exp Groups:TBTB+ rIFN-g1b nebulized (4M)TB+ rIFN-g1b sc (4M)

Results: 1-IFN-g groups: higher immune R2-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

IL-2 HOW?MODULATING IMMUNE R

WHAT?rhIL-2

CT?YES

(2003)Exp Groups:DS-TB in TTDS-TB in TT + rIL-2 (1M)

ONGOING (China) NCT03069534: MDR-TB, 1ary outcome: CURE RATE

1ary OUTCOME: sputumculture conversion

Results: daily rIL-2 (1M) betterMtb clearance, better clinicsymptoms and Rx

(1997) Exp Groups (n=24):MDR-TB, TTMDR-TB, TT + rIL-2 (1M)MDR-TB, TT + rIL-2 (pulse)

Results: No effect detected

N=47. CT WITHDRAWN FOR TOXICITY…13% deaths in theThalidomide groupROOM FOR ANALOGUES?

THALIDOMIDE HOW?MODULATES TNF-A

SIGNALING

WHAT?MODULATOR

TNF-a

CT?YES

Exp Groups:TB+/-HIV, TT+placeboTB+/-HIV, TT+Thalidomide

Results: ⬆weight gain and ⬇TNF-a production in vivo and exvivo

ETANERCEPT HOW?BLOCKS TNF-A

WHAT?SOLUBLE TNF RECEPTOR

CT?YES

Exp Groups:TB+/-HIV, TT+ ETANERCEPT sc 2/w(compared with historicalcontrols)

Results: 1- safe2- positive trends in weight, clinical evolution & time to sputum culture conversion

mAbs against TNF –infliximab/adalimumab –might be beneficial forlife-threatening TB (1 case) BUT can reactivate LTBI

NR®HOW?

MODULATING IMMUNE RWHAT?

hk M.manresensis(M.fortuitum complex)

CT?YES

NCT03069534 ONGOING (Georgia): EFFICACY TRIAL! N=3300 TB CONTACTS 1ary outcome: INCIDENCE OF ACTIVE TB

1ary OUTCOME: tolerability & immunogenicity

Exp GroupsADULTS LTBI+/- (n=47):PLACEBONR 104

NR 105

CHILDREN LTBI+/- (ONGOING):PLACEBONR 105

Results (adults): safe & ⬆specific mem Treg

MSCHOW?

INDUCE REGULATORY PHENOTYPES IN DC & T CELLS-

MODULATE IMMUNE R

WHAT?AUTOLOGOUS

MESENCHIMAL STROMAL CELLS

CT?YES

1ary OUTCOME: Safety

Exp GroupsMDR/XDR (n=30, Belarus)TTTT+ MSC (1 infusion 1st M)

Results (adults):Safe.

ANTIBIOTICS HOW?INHIBIT MATRIX

METALLOPROTEINASES (MMS)�⬇TISSUE DAMAGE IN INFLAMMATORY CONDITIONS

WHAT?DOXYCICLIN,

AZITHROMYCIN

CT?YES

1ary OUTCOME: systemic inflammation(blood cell counts and serum infl markers)

AZITHROMYCIN AS HDT: NCT03160638 –ONGOING-GRONINGEN, n=24EXP GROUPS:TTTT+ AZYTHROMYCIN DAILY 1M

ANTI-INFLAMMATORIES

HOW?COX-INHIBITORS

WHAT?NSAIDS

CT?YES

1ary OUTCOME: Sputum conversion, TB Outcomes, Changes Xray

Exp Groups (GEORGIA) PRE-XDR/XDR (n=24)TTTT+ IBUPROFEN 400mg 2M

1ary OUTCOME: Incidence in TB IRIS

Exp Groups (ZA)HIV+TB (n=150)TTTT+ MELOXICAM 2M

1ary OUTCOME: Safety+ Immunogenicity

Exp Groups (NORWAY)PRE-XDR/XDR (n=40)TTTT+ ETORICOXIB 140dTT+ H56:IC31 vaccineTT+ ETORICOXIB + H56:IC31

RESULTS (n=146): Better outcomes in High Dose group(100mg) BUT one death

GLUCOCORTICOIDS HOW?MODULATES THE

IMMUNE R: ⬇PRO-INFL MEDIATORS (TNF!)

WHAT?CORTICOSTEROIDS

CT?YES

STEROIDS EFFECTIVE REDUCING MORTALITY IN ALL FORMS TB

41 CT ---18 pulmonary TB; 20 prior modern RIF-TT18 pulomary TB -----13 prior modern RIF-TT

DEMONSTRATED TO BE USEFUL IN TB FORMS WITH HIGH INFLAMMATION: MENINGITIS, IRIS, PERICARDITIS

GLUCOCORTICOIDS HOW?MODULATES THE

IMMUNE R: ⬇PRO-INFL MEDIATORS (TNF!)

WHAT?CORTICOSTEROIDS

CT?YES

8 CT registered in clinicaltrials.gov: 2 withdrawn (1 no funding, 1 flood in Thailand)

1ary OUTCOME: Survival at 12 M afterrandomisation

NCT03092817TB MENINGITIS (n=520)(Vietnam&Indonesia)TTTT+ DEXAMETHASONE 8W

ONGOING

1ary OUTCOME: Development of IRIS

NCT01924286 (ZA)HIV+TB (n=240)TTTT+ PREDNISONE 2W 40MG+2 W 20MG

COMPLETED

1ary OUTCOME: Combined end-pointDeath+clinica cardíaca asociada a pericarditis

NCT00810849TB PERICARDITIS (AFRICA)HIV+TB (n=1400)TTTT+ PREDNISOLONE 6WTT+ IMMUVAC 5 DOSES

COMPLETED

HOW?⬆IMMUNE R –ALSO AGAINST

LATENT BACILLI AGs

WHAT?Hk-fragmentedM.tuberculosis

CT?YES

Results (adults): 1-safe in healthy and LTBI (HIV- and HIV+) 2-immunogenic

1ary OUTCOME: Safety

NCT02711735 MDR-TB (n=27)TTTT+ RUTI® (ONE SHOT)

RECRUITING

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GRÀCIES!