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Innovations in TB treatment : what the future holds

Explore the advances in Tuberculosis treatment, including new drug regimens and shortened treatment durations, to improve cure rates and reduce complications. Stay informed on the latest developments shaping the future of TB therapies.

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Innovations in TB treatment : what the future holds

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  1. Innovations in TB treatment : what the future holds C. Padmapriyadarsini National Institute for Research in Tuberculosis Indian Council of Medical Research, Chennai, India

  2. 1.2 million Incident TB cases in PLHIV Proportion of TB cases co-infected with HIV was highest in countries in African region

  3. HIV And TB : Partners in Crime • WHO Global Report 2015, • Percentage of TB patients with known HIV status highest in African region (79%) • Number of notified HIV+TB patients on ART has grown from 2004 • HIV ass. TB deaths accounted for 25% of all TB deaths

  4. Current Treatment Guidelines for TB • Drug Susceptible TB : 6-months regimen 2EHRZ/4RH, cure rate >90% • Multi-drug resistant TB: At least 20 – 28 months regimen with IP of at least 8 months with minimum 4 II-line drugs /PYZ/and an injectable • Extensively drug-resistant TB : longer to treat than MDR‑TB and requires the use of third-line anti‑TB drugs • Shortening Duration of Treatment for DS & DR-TB • ReMOX, Oflotub, Rifaquin trials • Newer Regimens for DS & DR-TB : Bangladesh regimen / STREAM

  5. Promising TB Drug pipeline Combining these new drugs with existing TB drugs offers hopes for regimens – better tolerated, shorter duration with few drug-interactions

  6. 4-month thrice-weekly regimens of Gatifloxacin or Moxifloxacin with HRZ, were inferior to standard 6-month regimens Jawahar et al.PLoS ONE 2013; 8(7): e67030

  7. Shortening course of treatment : DS-TB Oflotub study 4-mon Gatifloxacin regimen ReMOX study 4-mon Moxifloxacin regimen

  8. High Dose Rifapentine & Moxifloxacin • 2EHRZ/4RH vs 2MEHRZ/4MRif1 (1200mg) vs 2EMRZ/2MRif2 (900mg) • 6-monthly regimen of weekly high-dose rifapentine & Moxifloxacin was as effective as control regimen • It was also safe, well tolerated, reduced number of tablets needed in a course of Rx from 360 to 140, reduced frequency of tablets from every day to once a week. N Eng J Med 2014; 372(17)

  9. Moxifloxacin containing 5-drug regimen showed higher sputum culture conversion in first 2-months than thrice weekly 4-drug regimen Velayudham et al. Clin Infect Dis 2014;59(10):e142

  10. Shorter Standardized Regimen for MDR-TB AJRCCM 2010;182(5):684-92.

  11. STREAM Trial – Stage I • Determine whether a 9-month treatment regimen, that showed cure rates exceeding 80% during a pilot programme in Bangladesh, could achieve similar success in other settings, with successful outcome being as good as that in longer control regimen (G-M) • 421 participants / Recruitment complete / Results in early 2018 ISRCTN78372190

  12. Data from Bedaquiline containing regimens Infect Drug Resist. 2015;8:367-78

  13. STREAM Trail – Stage II • Comparison of a 6 and 9 month bedaquiline-containing regimen against the WHO and Bangladesh regimen • Reg 1: Completely oral/Injectable replaced with Bdq • Reg 2: 6-month regimen, with BDQ Injectable given for only 2 months • Reg 3 : 9-month regimen • Reg 4: WHO Control regimen • Enroll 1155 patients • Results of Stage 2 are expected in 2021 NCT02409290

  14. Oral regimens : 1. NEXT Trial • Phase 3, Prospective Open label RCT to evaluate a 6-9 month injection free regimen containing bedaquiline, linezolid, levofloxacin, ethionamide/high dose isoniazid, and pyrazinamide for Patients With MDR-TB • Outcome : Treatment success, defined as the sum of cured or treatment completed cases, 24 months after initiation of treatment • To enroll 300 pts – currently enrolling in S.Africa - Expected completion Jan 2019 NCT02454205

  15. 2. Nix-TB Trial (BPaL) • All-oral regimen for XDR-TB • To assess Safety, Efficacy, tolerability & PK of 6 months of Bedaquiline + PA-824 (200mg od) + Linezolid (600mg bd) in patients with pulmonary XDR-TB or treatment non responsive MDR TB • Recruiting 14 years & older at three sites in South Africa • Incidence of bacteriologic failure or relapse or clinical failure through follow up until 24 months after the end of treatment • Enrolling - 200 participants - Expected completion 2018 NCT02333799

  16. 3. NC-005 trial (BPaZ) • 2-week study found that Bedaquiline , PA-824 and Pyrazinamide (BPaZ) regimen killed more than 99% of TB bacteria over course of 14 days • Determine the efficacy, safety and tolerability of combinations of Bedaquiline, Moxifloxacin, PA-824 and Pyrazinamide regimens during 8 weeks of treatment in adults with Newly Diagnosed DS or MDR-TB • Plan in 10 sites across Uganda, S.Africa & Tanzania • 240 participants. Expected completion 2018 NCT02193776

  17. STAND TRIAL (PaMZ) • Phase 3 Open-Label Partially Randomized Trial • To assess the efficacy, safety and tolerability of a combination of moxifloxacin, PA-824, and pyrazinamide treatments • After 4 & 6 months of treatment in adults with DS-PTB • After 6 months of treatment in adults with smear positive pulmonary MDR-TB • Outcome : Incidence of combined bacteriologic failure or relapse of clinical failure at 12 months from start of Rx • To enroll 1500 pts • Started Feb 2015; Expected completion May 2018 • Currently suspended participant recruitment NCT02342886

  18. Delamanid for MDR-TB • Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group Trial • Evaluate the Safety & Efficacy of Delamanid 200 mg once daily x 6 months in pulmonary MDR TB • Outcome: Time to Sputum Culture Conversion , Mortality, Rx success & Failure • Ongoing - Estonia, Latvia, Lithuania, Moldova, Peru, South Africa • 511 pts. Exp completion May 2017 NCT01424670

  19. Other DR-TB Clinical Trials

  20. Trials for Pediatric Drug Resistant TB NCT02354014 & NCT01859923

  21. First case of XDR-TB treated with both Delamanid and Bedaquiline • 39 yrs female / Indian / 65-kg / 4- retreatment ERJ Express June 2016

  22. Host directed therapies for TB Rx • An effective host immune system is crucial for the eradication of M. tb infection • To reduce destructive inflammatory responses • pro-inflammatory and anti-inflammatory eicosanoids (imatinib) • Repurposing drugs : efflux pump inhibitors • Immunotherapy

  23. To improve efficiency of new drug evaluation • New Regimens & 14-day EBA studies • New design for Phase II & III trials (MAMS) • Biomarkers for monitoring TB treatment response, cure & relapse • Growing networks for drug development and evaluation

  24. Conclusions • Despite the introduction of cheap and effective treatment, TB is still found in every corner of the globe • Is threatening the gains made in TB control • Great need for shorter, less toxic treatment regimens, new drugs as well as better and shorter ways of evaluating new TB drugs and drug regimens

  25. Perspectives • Recent years, there has been some investment into new TB drug development and evaluation • Urgent need for increased coordination and enhanced collaboration among drug developers, funding agencies & clinical trial networks to bring more new & safe drugs / regimens easily accessible to patients faster and sooner

  26. Thank You

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