Frank CobelensTBVI SymposiumLes Diablerets, 29 January 2019
NEW TB REGIMENS AND PROSPECTS FOR THERAPEUTIC VACCINES AND HOST-DIRECTED THERAPY
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Content
New drugs and trials
Host-directed therapies & therapeutic vaccination
Cavities
Needs in TB treatment
Improve outcomes in drug-resistant TB
Shorten TB treatment
Reduce long-term residual lung impairment
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Nix-TB Trial
Conradie et al. Union Conference, 2018
Phase III ZeNIX trial
MDR/XDR-TBNix regimen for 26 weeks4 dosing/duration schedules LinezolidFollow-up 78 weeks post-completionN = 180
ClinicalTrials.gov
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NC-005 Trial: Bedaquiline – Pretomanid –Pyrazinamide (BPaZ) w/o Moxifloxacin (BPaMZ)
Dawson et al. CROI 2017
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Revised recommendationfor use of 2nd line drugs in treating MDR/XDR-TB
WHO. Rapid communication, 2018
Potential for host-directed therapy
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Strategies for treatment shortening
Drug-susceptible TB or drug-resistant TB
1. New drug combinations
2. Personalized, biomarker-based
◦ Identify those patients who need standard duration/prolonged Tx to achieve relapse-free cure
◦ Treat remaining patients for 2-3 months
3. Combine 1 and/or 2 with host-directed therapeuticsss
Only 2-3 months of standard HREZ treatment results in 70-80% relapse-free cure
Thus far treatment shortening <=4 monthshas proven difficult to achieve
Treatment shortening to >= 4 monthsunlikely to have major public health impact
Agents that can augment host defense mechanisms, modulate excessive inflammation or both, by manipulating the hosts response to a pathogen rather than targeting the pathogen itself
Stek et al. Front Microbiol 2018
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Residual lung damage post-TB treatment
0 20 40 60 80 100
Cavitation
Fibrosis
Bonchiectasis
Pleural thickening
Based on X-ray0 20 40 60 80 100
Cavitation
Fibrosis
Bonchiectasis
Pleural thickening
Nodules
Based on CT scan
Systematic review of 37 radiography studies, minimum/maximum prevalence
Meghji et al. PLoS One 2016
34% – 94% of successfully treated TB patients have residual impaired lung function(obstructive and/or restrictive)
Stek et al. Front Microbiol 2018
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Factors affecting lung damage during TB disease
Stek et al. Front Microbiol 2018
MMPs = Matrix metalloproteinases
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Host-directed therapies for TB: repurposed drugs and vitamins
Drug/class Mechanism Evidence
Glucocorticoids ↓ INFg, ↓ TNFα, ↓IL-1b Improved outcomes in human TB meningitis, pericarditis, pleurisy; IRIS (HIV)
NSAIDs ↑ LXA4, ↓ COX Improved survival in mice
Selective COX2 inhibitors ↓ COX2, ↑ PGE2 Improved survival in mice, trial ongoing
Statins ↓HMG-CoA reductase Reduce pathology and relapse in mice
Phosphodiesterase inhibitors ↑ Cyclic AMP/ GMP Reduce lung inflammation and promote lung repair in mice
Tyrosine kinase inhibitors ↑ autophagy Reduce pathology and bacterial load in mice
Metformin ↑ autophagy↑ reactive oxygen species
Reduces bacterial burden and lung pathology in miceand humans (but no effect in diabetic TB patients)
Rapamycine, everolimus ↑ autophagy Everolimus being tested in human TB trial
Vitamin D3 (colecalciferol) ↑ autophagy↓ IFN-g, IL-6, IL-10, TNFα↓ MMP-7 and -9
Tiberi et al, Lancer Infect Dis 2018; Palucci & Delogu. Chemotherapy 2018; Stek et al. Front Microbiol 2018
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Vitamin D3 supplementation
Meta-analysis of 8 trials of vit D3 supplementation (1787 patients)
No effect on bacteriological treatment outcomesLimited effect in MDR-TB patientsLimited effect on CXR resolution
Wu et al. BMC Pulm Med 2018
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Host-directed therapies for TB: immunomodulators and therapeutic vaccines
vaccine Composition Trials*
M. vaccae Heat-killed, intradermal Meta-analysis of 13 RCTs (DR/DS-TB): faster culture conversion, no difference in end-of-treatment outcomes.
M. indicus pranii Heat-killed, intradermal Phase III (retreatment TB): faster culture conversion, no difference in end-of-treatment outcomes.
RUTI Liposomal detoxified cellularfragments of M tuberculosis
Safe in Phase I, Phase IIa ongoing
Mesenchymal stromal cells Autologous bone marrow-derivedMSCs
Safe in Phase I, no Phase IIa ongoing
V5 immunitor Inactivated pooled blood, oralcapsule
Improved smear conversion in Phase IIa (MDR-TB), no ongoing trials
Cytokines IL-2, intradermal Meta-analysis of 4 trials (2 DS, 2 MDR-TB): marginallyimproved smear and culture conversion
IFN-γ, aerosolized Well tolerated, inconsistent effectiveness
TNFα inhibitors Etanercept oral Phase II: slightly faster culture conversion
Abate & Hoft. Immuno Targets Ther 2016; Zhang et al. PLoS One 2018
*based on published results and trials listed in ClinicalTrials.gov.
Sharma et al. Sci Rep 2017
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Adjunct M. vaccae immunization
Meta-analysis
13 RCTs (N = 22-1337 patients), Drug resistant ranging from 2-98%
Huang & Hsieh. Human Vaccines Immunother 2017
Effect on relapse?
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Cavities: key target for HDT?
Nachiappan et al. Radiography 2017Ndlovu & Malakalala. Front Immunol 2016
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Highly varied drug penetration in caseum
Dartois. Nat Rev Micriobiol 2014Prideaux et al. Nat Med 2015
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Cavities and bacterial load predict who can be treated for 4 months
Individual patient data meta-analysis of 3 treatment shortening trials (OFLOTUB, REMoxTB, RIFAQUIN)
N = 3405 patients with DR-TB
Comparison = 4 months FQ-based vs 6 months standard
Outcome = relapse-free cure
4M non-inferior to 6M
4M inferior to 6M
Imperial et al. Nat Med 2018
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Cavitation may start well before the diagnosis is made
Esmail et al. Nat Med 2016
PET-CT lesions predict onset of TB disease 6 months in advance
Changes in immune parameters canbe observed from 12-15 months
before onset of clinical TB disease
Scriba et al. Plos Pathogens 2017
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Conclusions
There is a potential role for immunomodulating host-directed therapies/therapeutic vaccination to:
◦ Improve treatment outcomes for drug-resistant tuberculosis
◦ Shorten TB treatment
◦ Reduce post-treatment lung damage
Approaches taken thus far have shown limited success
Preventing/reducing cavity formation is probably a key objective for HDT
Early diagnosis would be important to make effective HDT have (public) health impact
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Host-directed therapies: small molecule drugs
Drug/class Host target Mechanism Evidence
Glucocorticoids ↓ INFg, ↓ TNFα, ↓IL-1b Improved outcomes in human TB meningitis, pericarditis, pleurisy; IRIS (HIV)
NSAIDs Eicosanoids ↑ LXA4, ↓ COX Improved survival in mice
Selective COX2 inhibitors Eicosanoids ↓ COX2, ↑ PG-E2 Improved survival in mice, trial ongoing
Statins Cholesterol ↓HMG-CoA reductase Reduce pathology and relapse in mice
Phosphodiesteraseinhibitors
Phosphodiesterase ↑ Cyclic AMP/ GMP Reduce lung inflammation and promotelung repair in mice
tyrosine kinase inhibitors Tyrosine kinase ↑ autophagy Reduce pathology and bacterial load in mice
Metformin AMP-activatedprotein kinase
↑ autophagy↑ reactive oxygen species
reduces bacterial burden and lungpathology in mice and humans (but no effect in diabetic TB patients)
Tiberi et al, Lancer Infect Dis 2018; Palucci & Delogu. Chemotherapy 2018
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