1. Key Tuberculosis Treatment and Prevention Issues
Prof JG Hakim, Parirenyatwa CRS Leader
Annual Research Day; 8th April 2016

2. TB- A Global Problem

7. TB Transformative Science Group (TB TSG) Agenda
Treatment & prevention of TB with or without HIV co-infection
Anti-TB new drugs & combinations
Develop shorter Rx regimens
Rx for MDR/XDR TB
Optimal Rx of latent TB
Optimal Rx for TB in patients on ART
Evaluation of drug-drug interactions (anti-TB & ART)
Improved TB diagnostic assays & biomarkers to predict & detect disease

8. Recent accomplishments of TB TSG
A5295-Xpert TB/RIF trial in US, RSA, Brazil
A5306-PK/DDI study of Pa824 (Pretomanid), EFV and LPV/r
A5311-High dose rifapentine PK study
A5274-REMEMBER trial, enrolment complete
A5279-Rifapentine-EFV sub-study completed
A5221-STRIDE study, 2Y analysis of CD4 and risk of death

9. TB Treatment Shortening Studies
Study
Description
Status
A5289
Phase 2 trial of Sutezolid for improving sputum conversion at 8 weeks
Protocol in development pending drug availability
A5344/STAND
Phase 3 trial of Pa824/Moxi/PZA to shorten TB therapy to 4 months (with TB Alliance)
Started 2015
PR686/TBTC31
Phase 3 trial of rifpentine + moxi to shorten TB therapy to 4 months (with TBTC)
PR698
Phase 2 trial of clofazamine in drug susceptible TB
Protocol in development

10. MDR TB Sub-studies in Progress or Development
Study
Description
Status
A5312
Early bactericidal activity of high-dose INH in patients with MDR TB and inha mutations
A5343
PK safety study of bedaquiline and delamanid in patients with MDR TB in South Africa (with Janssen and Otsuka)
A5319 (Marvel)
Phase 2 trial of bedaquiline, linezolid (sutezolid) and Pa824 in MDR TB
Deregistered

11. Novel drugs for MDR TB treatment
Class
Agents
Comments
Availability to ACTG
Flouroquinolones
Moxifloxacin
Levofloxacin
QT issues
Available
Nitroimidazoles
Delamanid
Pa824 (Pretominid)
ATP Synthetase
Inhibitor
Bedaquiline
Drug-drug interactions limitations, QT, deaths
Oxazolidinones
Linezolid
Sutezolid
AZD
Tedizolid
Licenced, toxicity
Toxicity/efficacy
Licenced
Phenazine dyes
Clofazamine
Skin toxicity, QT
Access global market

12. TB Preventive Therapy Studies
Study
Description
Status
A5279
Daily Rifapentine/INH for 1 month vs INH for 9 months to prevent TB in HIV+ve patients
Enrolling ~2300/3000
(with IMPAACT)
A5300
Phoenix
Phase 3 trial of levofloxacin vs INH for high-risk contacts M/XDR TB patients

13. Host-Directed Therapies for TB
TB TSG Working Group since March/2013
Collaboration with Bill & Melinda Gates Foundation
Others
Statins to prevent IRIS in TB/HIV
Doxycycline to reduce immunopathology
Imatinib dose selection for TB
Adalibumab for TB
Recombinant IL-7 as adjuvant TB therapy

14. Laboratory and Biomarkers
Laboratory Strengthening in the ACTG
International reference Lab-Stellenbosch
Regional Labs, BARC (Jo’burg, JCRC (Kampala) and TRC (Chennai)
Xpert TB/RIF at all sites
Lab standardization protocol
Biomarker Research
A5302 (with Alliance, TBTC); B-SMART
Four funded discovery Projects
Sputum markers with flow cytometry
Serum markers-proteomic and exosomes
Urine metabolomics fingerprinting
Cellular immune signals

15. Thank You