1. #AIDS2016 | @AIDS_conference Innovations in TB treatment : what the future holds C. Padmapriyadarsini National Institute for Research in Tuberculosis Indian Council of Medical Research, Chennai, India

2. #AIDS2016 | @AIDS_conference 1.2 million Incident TB cases in PLHIV Proportion of TB cases co-infected with HIV was highest in countries in African region

3. #AIDS2016 | @AIDS_conference 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. #AIDS2016 | @AIDS_conference 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. #AIDS2016 | @AIDS_conference 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. #AIDS2016 | @AIDS_conference 4-month thrice-weekly regimens of Gatifloxacin or Moxifloxacin with HRZ, were inferior to standard 6-month regimens RegimenPts2 month sp. Culture Neg Favorable response Relapse 2 GHRZ 3 2 GHR 3 13683%95%16% 2 MHRZ 3 2 MHR 3 11588%98%10% 2 EHRZ 3 4 HR 3 16578%97%6% Jawahar et al.PLoS ONE 2013; 8(7): e67030

7. #AIDS2016 | @AIDS_conference Shortening course of treatment : DS-TB Oflotub study 4-mon Gatifloxacin regimen ReMOX study 4-mon Moxifloxacin regimen RegimenFav. Outcom Relaps 2 GHRZ / 2 GHR (917) 79%15% 2 EHRZ / 4 HR (919) 83%7%

8. #AIDS2016 | @AIDS_conference 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. #AIDS2016 | @AIDS_conference Moxifloxacin containing 5-drug regimen showed higher sputum culture conversion in first 2- months than thrice weekly 4-drug regimen Intensive phase Continuation phase 3 RHZEM- 2 RHZEM2 RHM 2 RHZEM2 RHM 3 2 RHZEM2 RHEM 3 2 RHZE 3 4 RH 3 Velayudham et al. Clin Infect Dis 2014;59(10):e142

10. #AIDS2016 | @AIDS_conference Shorter Standardized Regimen for MDR-TB AJRCCM 2010;182(5):684-92.

11. #AIDS2016 | @AIDS_conference 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. #AIDS2016 | @AIDS_conference Data from Bedaquiline containing regimens Infect Drug Resist. 2015;8:367-78

13. #AIDS2016 | @AIDS_conference 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. #AIDS2016 | @AIDS_conference 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. #AIDS2016 | @AIDS_conference 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. #AIDS2016 | @AIDS_conference 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. #AIDS2016 | @AIDS_conference 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. #AIDS2016 | @AIDS_conference 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. #AIDS2016 | @AIDS_conference Other DR-TB Clinical Trials

20. #AIDS2016 | @AIDS_conference Trials for Pediatric Drug Resistant TB TrialPopulationOutcomeEnrollment stats /site Exp. End PK, Safety, Tolerability and Anti-mycobac activity of BDQ with OBR 60 HIV uninfected children & adolescents <18 Years with Confirmed or Probable Pulmonary MDR-TB 4-Age based cohorts : 12-17; 5-11, 2-5, <2 yrs No. of Adverse events Max. & Min Plasma conc Time to Max. Plasma conc South Africa (Recruiting) Philippines Russia India Dec 2022 Safety, Efficacy, Tolerability, PK of 6-mon Rx with OBR + Delamanid DLM BD x 6 months 36 Pediatric MDR TB 4-Age based cohorts : 12-17; 5-11, 2-5, <2 yrs Safety, Tolerability, Plasma conc Recruiting Philippines South Africa August 2019 NCT02354014 & NCT01859923

21. #AIDS2016 | @AIDS_conference First case of XDR-TB treated with both Delamanid and Bedaquiline 39 yrs female / Indian / 65-kg / 4- retreatment ERJ Express June 2016

22. #AIDS2016 | @AIDS_conference 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. #AIDS2016 | @AIDS_conference 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. #AIDS2016 | @AIDS_conference 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. #AIDS2016 | @AIDS_conference 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. #AIDS2016 | @AIDS_conference Thank You