New developments in the treatment of drug-resistant tuberculosis: clinical utility of bedaquiline and delamanid

Figures & data

Table 1 Results of trial 204 for delamanid in MDR-TB patients

Drug + dose	Number of patients in mITT group	2-month sputum conversion (on liquid culture)	P-value	Prolonged QTa
Del 100 mg (2 times/day) + OBR	141	45.40%	0.008	9.9%
Del 200 mg (2 times/day) + OBR	136	41.90%	0.04	13.1%
Placebo + OBR	125	29.60%		3.8%

Notes:

a No cases of prolonged QTc interval resulted in syncope or arrhythmia and no patient stopped delamanid due to QTc prolongation. Data devised from Gler et al.¹¹

Abbreviations: Del, delamanid, MDR-TB, multidrug-resistant tuberculosis; mITT, modified intention to treat; OBR, optimized background treatment regimen.

Table 2 Results of trial C208 for bedaquiline

Drug + dose	Number of patients in mITT group	6-month sputum conversion	P-value	Median time to culture conversion
Bedaquilinea + 5 drug regimen	66	78.80%	0.009	12 weeks
Placebo + 5 drug regimen	66	57.60%		18 weeks

Notes:

a Given at 400 mg daily for the first 2 weeks, followed by 200 mg three times per week for the remaining 22 weeks. Data devised from Diacon et al.¹⁶

Abbreviation: mITT, modified intention to treat.

Table 3 Ongoing and planned clinical trials of new drugs in new regimens for treating MDR-TBa

Study name	Study summary	Description	Status	Study investigator (organization)
STREAM I trial	Evaluation of a Standardized treatment regimen of anti-TB drugs for patients with MDR-TB	Comparison of standard WHO MDR-TB regimen with 9-month modified Bangladesh regimen	Open to recruitment	Andrew Nunn, Sarah Meredith (The Union)
STAND trial: PA-824/Mfx/Z (GATB NC-006)	Treatment shortening trial of PA-824/Mfx/Z for 4 or 6 months compared to HRZE for 6 months	Study of PA-824/Mfx/Z for DS-TB; one arm enrolling patients with MDR-TB whose isolates are susceptible to FQ and Z	Expected to begin enrolling Q2 2015	Dan Everitt (TB Alliance)
Bdq/PA-824/Z (GATB NC-005)	8-week SSCC study of Bdq + PA-824 + Z	Study of Bdq/PA-824/Z for DS-TB. One MDR-TB arm adds moxifloxacin to Bdq-PA-824-Z	Now enrolling	TB Alliance
NiX-TB	PA-824, Lzd, and Bdq; single arm for 6 or 9 months duration depending on rate of sputum culture conversion	Salvage regimen for patients with XDR-TB	Enrolling patients in South Africa	Dan Everitt (TB Alliance)
STREAM II trial	STREAM stage II: multicountry clinical trial evaluating the shortened MDR-TB regimen	Comparison of 6- vs 9-month Bdq-containing regimens to WHO and Bangladesh regimens	Expected to being enrolling Q4 2015	Andrew Nunn and Sarah Meredith (The Union)
PRACTECAL	Novel short course, 6-month regimens without injectables; uses new and repurposed drugs	3 regimens with Bdq + PA-824 + Lzd	Protocol finalized Expected start Q3 2015	Dr Bern-Thomas Nyang’wa (MSF)
End TB	9 month: novel short course regimens without injectables; uses new and repurposed drugs	Novel, no injectibles, regimens with 4–5 drugs including Bdq and/or Dlm	Protocol near finalized	Franics Varaine, Carole Mitnik (MSF/PIH/HMS)
NExT Trial	Evaluating new treatment regimen for patients with MDR-TB – a randomized controlled Phase III trial	Open label RCT of a 6–9 month injection-free regimen with Bdq, Lzd, Lfx, ethionamide/high dose H, and Z	Waiting for MCC approval, expected enrollment at five sites in South Africa	Keertan Dheda, Akther Goolam-Mohamed

Notes: Copyright 2015. RESIST-TB. All rights reserved. This material has not been reviewed by Research Excellence to Stop TB Resistance prior to release; therefore RESIST-TB may not be responsible for any errors, omissions or inaccuracies, or for any consequences arising there from, in the content. Reproduced with permission of RESIST-TB.

a Adapted from the RESIST DR-TB-Clinical Trial Progress Report,⁶³ excluding those which are adding new drugs to the standard WHO recommended regimen.

Abbreviations: Bdq, bedaquiline; Dlm, delamanid; DS, drug senstive; FQ, fluoroquinolone; H, isoniazid; HMS, Harvard Medical School; HRZE, isoniazid, rifampicin, pyrazinamide, ethambutol; Lfx, levofloxacin; Lzd, linezolid; Mfx, moxifloxacin; MDR-TB, multidrug-resistant tuberculosis; MMC, Medicines Control Council; MSF, Médecins Sans Frontières; PIH, Partners in Health; Q2, second quarter of; Q3, third quarter of; SSCC, serial sputum colony counting; TB, tuberculosis; WHO, World Health Organization; Z, pyrazinamide.

Table 4 Criteria for introduction of new TB drugs

Category	Specific criteria
Proper patient inclusion	Special caution required in people ≥65 years old; in adults living with HIV. Use in children and in pregnant or breast-feeding women not advised.
Effective treatment and monitoring	Treatment must be closely monitored for effectiveness and safety, using sound treatment and management protocols approved by relevant national authorities.
Treatment regimen must adhere to WHO recommendations	Use of new drugs must follow all principles underlying WHO-recommended MDR-TB treatment regimens, particularly inclusion of four effective second-line drugs plus pyrazinamide. New drugs should not be introduced singly into regimens that do not show effectiveness.
Informed consent	Patients must be fully aware of new drug’s potential benefits and harms; must give informed consent before starting treatment.
Pharmacovigilance and management of adverse events	Active pharmacovigilance measures must be in place to ensure early detection and proper management of adverse drug reactions and potential drug–drug interactions.

Abbreviations: TB, tuberculosis; WHO, World Health Organization; MDR-TB, multidrug-resistant TB.

Table 5 Characteristics of clofazimine, linezolid, and imipenem

Drug	Class	Route of administration	Main side effects	Indication for TB treatment
Clofazimine	Riminophenazine	Oral with loading schedule	Skin discoloration; GI effects; QT prolongation potential; long half-life	No
Linezolid	Oxazolidinone	Oral	Peripheral neuropathy; hematological effects, particularly thrombocytopenia	No
Imipenem/cilastatin	Carbapenem	Intravenous	Generally well tolerated. Reactions around injection site	No

Abbreviations: GI, gastrointestinal; TB, tuberculosis.

Table 6 Description of three cohorts of patients started on bedaquiline-containing treatment regimens

Period reported	France^Citation36	South Africa^Citation37	Armenia^Citation38
	January 2010–July 2013	March 2013–July 2014	March 2013–January 2015
Number of patients	35a	91	53
XDR-TB	54.3%	37.4%	45%
Pre-XDR-TB (FQ)	28.6%	45.1%	49%
Pre-XDR-TB (Inj)	11.4%	17.6%	6%
Median age (years)	39	35	42.5
Sex, male	80%	60.4%	87%
HIV positive	0	59.3%	4%
Lzdb	94.3%	70.3%	100%
Impb	65.7%	0%	75%
Cfzb	14.3%	74.7%	74%

Notes: Pre-XDR-TB (FQ): MDR with additional resistance to fluoroquinolones, pre-XDR-TB (Inj): MDR with additional resistance to second-line injectable drugs;

a from March 2011 to June 2014, 53 patients started bedaquiline treatment but descriptive results have been published for 35 patients;

b data shown are percentage of patients whose regimen included the indicated drug.

Abbreviations: Cfz, clofazamine; FQ, fluoroquinolone; Imp, imipenem; Inj, injectable; Lzd, linezolid; MDR-TB, multidrug-resistant TB; TB, tuberculosis; XDR-TB, extensively drug-resistant TB.

Table 7 Summary of available culture conversion and safety data from three cohorts of patients given bedaquiline-containing regimens

	France^Citation36	South Africa^Citation37	Armenia^Citation38
Culture conversion at 6 months among patients culture positive at baseline	28/29 (97%)	33/43 (77%)	22/26 (84%)
Early mortality (<24 weeks bedaquiline)a	1/35 (3%)	1/63 (1.6%)	4/53 (7.5%)
Increase in QTcB/F (ms)	1.96b	8c	Not reported
QTcB/F increase	7/35 (20%) >60 ms	24/91 (26.3%) >50 ms	Not reported
QTcB/F >500 ms	3/35 (9%)	3/91 (3.2%)	Not reported
Discontinuation of bedaquiline	2/35d (6%)	1/91e (1%)	Not reported
Patients with serious adverse events reported (unrelated to bedaquiline)	1/35 (3%)	9/91 (9.9%)	4/53 (8%)

Notes: Data shown as n/N (%).

a One death in France due to malignancy, three deaths in total in South Africa reported as unrelated to Bedaquiline, four deaths in Armenia also reported as unrelated to bedaquiline (J Faqirzai, Médecins Sans Frontières, Armenia, personal communication, June, 2015);

b increase in median QTcB;

c increase in median QTcF;

d related to increase in QTcB;

e atrial fibrillation, unclear if related to bedaquiline.

GlerMTSkripconokaVSanchez-GaravitoEDelamanid for multidrug-resistant pulmonary tuberculosisN Engl J Med2012366232151216010.1056/NEJMoa111243322670901

 PubMed Web of Science ®Google Scholar

DiaconAHPymAGrobuschMPMultidrug-resistant tuberculosis and culture conversion with bedaquiline for the TMC207-C208 study group*N Engl J Med201483712172373210.1056/NEJMoa131386525140958

 PubMed Web of Science ®Google Scholar

RESIST-TB DR-TB Clinical Trial Progress Report Updated May 2015. Available from: http://www.resisttb.org/?page_id=1602Accessed July 11, 2015

 Google Scholar

GuglielmettiLLe DûDJachymMCompassionate use of bedaquiline for the treatment of multidrug-resistant and extensively drug-resistant tuberculosis: interim analysis of a French cohortClin Infect Dis201560218819410.1093/cid/ciu78625320286

 PubMed Web of Science ®Google Scholar

NdjekaNConradieFSchnippelKTreatment of drug-resistant tuberculosis with bedaquiline in a high HIV prevalence setting: an interim cohort analysisInt J Tuberc Lung Dis201519897998526162365

 PubMed Web of Science ®Google Scholar

YeghiazaryanLArmenian experience on treatment of XDR and pre-XDR patients with new drugs under compassionate use programPresented at: Tuberculosis Symposium – Eastern Europe and Central AsiaFebruary 17–18, 2015 Available at: http://www.tb-symposium.org/documents/en/presentations/Lusine_Yeghiazaryan_BDQ_practical_use_eng.pdfAccessed July 11, 2015

 Google Scholar