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
Scope Focused on treatment of MDR TB (resistant to rifampicin & INH) Limited to drugs in at least phase 2 trials Clinical studies in adults
WHO global report 2015
WHO global report 2015
SA has political will Progressive health minister, TB prioritised Progressive director of drug-resistant TB, Dr Norbert Ndjeka
SA MDR TB treatment gap 16000 14000 12000 10000 8000 6000 4000 45% 49% 46% 72% 56% 46% 2000 0 2007 2008 2009 2010 2011 2012 Diagnosed Started Rx Dr. Norbert Ndjeka http://www.health-e.org.za/wp-content/uploads/2014/03/strategic_overview_of_mdr_tb_rsa.pdf
SA MDR-TB Treatment Outcomes (24 months) 60 Rx Success rate Defaulter rate Death Rate Failure Rate 50 40 30 20 10 0 2007 2008 2009 2010 Dr. Norbert Ndjeka http://www.health-e.org.za/wp-content/uploads/2014/03/strategic_overview_of_mdr_tb_rsa.pdf
Global MDR TB treatment outcomes WHO global report 2015
Factors associated with treatment success: Quinolones aor 2.5 [95% CI 1.1 6.0] 4 effective drugs in the intensive phase aor 2.3 [1.3 3.9] 3 effective drugs in the continuation phase aor 2.7 [1.7 4.1]) Ethionamide or prothionamide aor 1.7 [1.3 2.3] PLoS Med 9(8): e1001300
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;8:778-84 Chest. 2000;117:744-51 PLoS ONE. 2007; 2(11): e1126.
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
Evidence base for current MDR Rx: the bar is low WHO 2011
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
2015 SA standardised MDR regimen: 21-24 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
Need for new DR-TB regimens More effective Shorter duration of therapy Better tolerated RCTs for strong evidence
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
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
Optimised background regimen (OBR) + investigational drug phase 2 studies
Bedaquiline/placebo + OBR for MDR P<0.001 10 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
Delamanid/placebo + OBR for MDR HR 0.44 95%CI 0.29, 0.64 HR 0.54 95%CI 0.36, 0.81 NEJM 2012;366:2151
Clofazimine vs control + OBR for MDR (poor response to therapy for 6 months) P=0.042 Clin Infect Dis 2015;60(9):1361 7
Linezolid for XDR (failing OBR) NEJM 2012;367:1508
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):603-15. Song EBioMedicine 2015 Maartens EBioMedicine 2015 Antimicrob Agents Chemother 2015;59(1):178-85.
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
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)
Conclusions Current MDR regimens long, toxic, & have poor efficacy 9 month Bangladesh regimen likely at least as effective as standard 21-24 months, but toxic & hyperpigmentation from clofazimine a major issue locally Likely will have 6-9 month regimen without injectable within 5 years