Adjunct Host Directed Therapies
Novel host-directed therapies in TB focus on using cutting-edge knowledge concerning biological pathways and functions that can be targeted for improved clinical outcomes. Some of the most important strategies addressed in HDT-NET TB are listed below.
1. CELLULAR THERAPY
Autologous (patient’s own) bone marrow-derived stromal cells (MSCs).
2. RE-PURPOSED DRUGS
Analgesics / Nonsteroidal anti-inflammatory drugs (COX-2 inhibitors eg Ibupofen, indomethacin).
- Cholesterol lowering drugs (HMG-CoA reductase inhibitors eg Simvastatin).
- Asthma drugs (Leukotriene synthesis inhibitors eg Zileuton).
- Diabetes drugs (ROS removal and increased CD8+ T-cell responses (eg Metformin).
- Antibiotics (suppress pathological MMP activity eg doxycycline).
- Anti-convulsants (Inhibition of histone deacylation (eg Valproic acid.)
- Cancer drugs (Dampening regulatory T-cell effect and of overt inflammation eg Alkylating agent -cyclophosphamide).
3. THERAPEUTIC VACCINES
Protein vaccines (eg Granulysin); DNA vaccines; RUTI; Environmental mycobacterial vaccines etc).
4. OTHER HDTs
Micronutrient immunomodulators (eg. Vit D, Zn, Mg, probiotics).
- Anti-microbial peptide inducers (eg 4-phenyl butyrate).
- Checkpoint inhibitors (eg Anti-PD-1 IgG).
- In development: (Cellular: eg T cell chimeric receptor therapy; Cytokines: eg IL-36; Chemokines: eg CCR5 blockers; others).
Note: Many of the repurposed drugs have well established safety profiles and have been used extensively. Since the combination of the numbers of trials for various combination will be large, a large number of trial sites will be required. A list of priority trials will be made. Furthermore the ‘MAMS’ trial designs16 will be used for adjunct therapy trials with the long list of ‘repurposed’ drugs. All trial protocols will be processed through peer and ethics review. Therapeutic vaccines will be evaluated to reduce duration of therapy and to prevent recurrence of disease.
- Microbiological endpoints (time to culture conversion; acquired drug resistance; additional drug resistance; genotype change; change in biomarkers).
- Clinical endpoints (safety, cure, death, relapse, re-infection).
- Duration of chemotherapy.
- Immunological and Imaging endpoints.
- Evaluation of endpoints for HDT.
- Number of trial sites developed to GCP/GLP.
- Number of HDT trials performed (Phase 1, Phase 2, Phase 3, Phase 4 trials).
- Number of trained staff, PhD, MSc, Lab techs, Trial nurses, Followup teams, Counsellors etc.
- Publications, Conferences, symposia, CPD seminars, Expert Reports etc.
- Impact on policy and practice (local, regional, global).
- Implementation of research findings into national programs.
- Reduction in morbidity and mortality.
- Number of trials other than HDT interventions enabled by HDT-NET.
- African networks developed/enhanced enabling joint research, training and data outputs.
- Co-funding acquired and number of grants written and funded.