Drug-resistant TB therapy: the future is now

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1 Drug-resistant TB therapy: the future is now Gary Maartens Thanks to Francesca Conradie for sharing slides Division of Clinical Pharmacology UNIVERSITY OF CAPE TOWN IYUNIVESITHI YASEKAPA UNIVERSITEIT VAN KAAPSTAD

2 Scope Focused on treatment of MDR TB (resistant to rifampicin & INH) Limited to drugs in at least phase 2 trials Clinical studies in adults

3 WHO global report 2015

4 WHO global report 2015

5 SA has political will Progressive health minister, TB prioritised Progressive director of drug-resistant TB, Dr Norbert Ndjeka

6 SA MDR TB treatment gap % 49% 46% 72% 56% 46% Diagnosed Started Rx Dr. Norbert Ndjeka

7 SA MDR-TB Treatment Outcomes (24 months) 60 Rx Success rate Defaulter rate Death Rate Failure Rate Dr. Norbert Ndjeka

8 Global MDR TB treatment outcomes WHO global report 2015

9 Factors associated with treatment success: Quinolones aor 2.5 [95% CI ] 4 effective drugs in the intensive phase aor 2.3 [ ] 3 effective drugs in the continuation phase aor 2.7 [ ]) Ethionamide or prothionamide aor 1.7 [ ] PLoS Med 9(8): e

10 MDR Adverse Drug Reactions India Argentina Hong Kong Urzbekistan 21% stopped/changed drugs 41% severe toxicity 19% stopped/changed drugs 77% severe adverse event Indian J Chest Dis Allied Sci. 2006;48:183-6 Int J Tuberc Lung Dis. 2004;8: Chest. 2000;117: PLoS ONE. 2007; 2(11): e1126.

11 Discontinuing MDR drugs for toxicity Aminoglycosides 8-25% Ethionamide 17-23% Cycloserine 11-14% Quinolones 0-2% PLoS ONE. 2007; 2(11): e1126 Am J Respir Crit Care Med 2004;169:1103

12 Evidence base for current MDR Rx: the bar is low WHO 2011

13 High dose INH One of the 2 mutations conferring INH resistance, inha, confers low level resistance Small (n=123) Indian RCT: INH dose normal, high (16-18 mg/kg), or placebo added to standard MDR therapy (inha not reported) Relative hazard of sputum culture conversion 2.38 (95%CI 1.45, 3.91) in high dose INH arm Relative risk of neuropathy 9.64 in high dose INH arm EBA study ACTG5312 of INH 5 vs 10 vs 15 mg/kg in patients with inha underway Int J Tuberc Lung Dis 2008;12(2):139 45

14 2015 SA standardised MDR regimen: months Moxifloxacin PZA Terizidone Ethionamide/hdINH Kanamycin Replaced ofloxacin (more active) About 50% resistance Medline n=41, cycloserine n=290 Depends on katg & inha* Switch to bedaquiline if toxicity/ contraindicated *inha 70% E Cape; 48 % W Cape IJTLD 2011;15:344

15 Need for new DR-TB regimens More effective Shorter duration of therapy Better tolerated RCTs for strong evidence

16 At last we have some new toys for TB New drugs developed for TB: Inhibit ATP synthase: bedaquiline. High genetic barrier to resistance. Terminal half-life ±6 months Inhibit mycolic acid synthesis: delamanid & pretomanid. Lower genetic barrier to resistance Repurposed drugs: Linezolid and Clofazimine

17 Bangladesh MDR regimen study Sequential allocation to 6 consecutive regimens all with clofazimine & quinolone Most regimens 15 months Best regimen was 9 months: Kanamycin, prothionamide, ±hdinh, (4 months intensive), clofazimine, gatifloxacin, ethambutol, pyrazinamide 9 month regimen being evaluated in RCT Am J Respir Crit Care Med 2010;182:684 92

18 Optimised background regimen (OBR) + investigational drug phase 2 studies

19 Bedaquiline/placebo + OBR for MDR P< of 79 patients (13%) in the BDQ group and 2 of 81 patients (2%) in the placebo group died (P = 0.02). 9 of 10 died after stopping BDQ (drug still present in patient) NEJM 2014;371:723-32

20 Delamanid/placebo + OBR for MDR HR %CI 0.29, 0.64 HR %CI 0.36, 0.81 NEJM 2012;366:2151

21 Clofazimine vs control + OBR for MDR (poor response to therapy for 6 months) P=0.042 Clin Infect Dis 2015;60(9):1361 7

22 Linezolid for XDR (failing OBR) NEJM 2012;367:1508

23 Linezolid toxicity in DR TB Inhibits mitochondrial protein synthesis Causes myelosuppression & neuropathy 35% interrupt/stop for toxicity Related to cumulative dose/concentration Toxicity threshold very close to the efficacy threshold for tuberculosis Tedizolid has less mitochondrial toxicity, not yet tested in TB J Thorac Dis 2015;7(4): Song EBioMedicine 2015 Maartens EBioMedicine 2015 Antimicrob Agents Chemother 2015;59(1):

24 Phase 2 studies to inform new MDR regimens Bedaquiline, pretomanid, PZA, moxifloxacin (DS or MDR TB) OBR + bedaquiline or delamanid or both Primary aim to determine cardiac safety (QT) ACTG A5343 to start 2016 Linezolid 300 mg vs 600 mg vs 900 mg + delamanid Injection-free regimen ACTG, in development Phase 2/3 adaptive trial planned by MSF

25 Phase 3 MDR studies underway Delamanid/placebo plus OBR will report soon Pretomanid, moxifloxacin, pyrazinamide for 4-6 months in DS & MDR-TB temporary hold following hepatotoxicity Bedaquiline, linezolid, levofloxacin, pyrazinamide and ethionamide/high dose isoniazid for 6-9 months vs SA standard regimen home grown (PI Keertan Dheda)

26 Conclusions Current MDR regimens long, toxic, & have poor efficacy 9 month Bangladesh regimen likely at least as effective as standard months, but toxic & hyperpigmentation from clofazimine a major issue locally Likely will have 6-9 month regimen without injectable within 5 years