Bedaquiline-containing regimens and multidrug-resistant tuberculosis: a systematic review and meta-analysis

Hatami, Hossein; Sotgiu, Giovanni; Bostanghadiri, Narjess; Abadi, Sahel Shafiee Dolat; Mesgarpour, Bita; Goudarzi, Hossein; Migliori, Giovanni Battista; Nasiri, Mohammad Javad

doi:10.36416/1806-3756/e20210384

Hossein Hatami

. Department of Public Health, School of Public Health and Safety; Environmental and Occupational Hazards Control Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

http://orcid.org/0000-0002-1448-3598

Giovanni Sotgiu

. Unità di Epidemiologia Clinica e Statistica Medica, Dipartimento di Scienze Mediche Chirurgiche e Sperimentali, Università degli Studi di Sassari, Sassari, Italia.

http://orcid.org/0000-0002-1600-4474

Narjess Bostanghadiri

. Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.

http://orcid.org/0000-0002-7343-5289

Sahel Shafiee Dolat Abadi

. Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

http://orcid.org/0000-0003-4231-844X

Bita Mesgarpour

. Department of Public and International Affairs, National Institute for Medical Research Development - NIMAD - Tehran, Iran.

http://orcid.org/0000-0002-4004-8493

Hossein Goudarzi

. Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

http://orcid.org/0000-0001-8965-8690

Giovanni Battista Migliori

. Istituti Clinici Scientifici Maugeri - IRCCS - Tradate, Italia.

http://orcid.org/0000-0002-2597-574X

Mohammad Javad Nasiri

. Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

http://orcid.org/0000-0002-3279-0671

Correspondence to:
Mohammad Javad Nasiri. Shahid Beheshti University of Medical Sciences, Arabi Avenue, Daneshjoo Blvd, Velenjak, 19839-63113, Tehran, Iran. Tel.: 98 21 22 43 25 56. E-mail: mj.nasiri@hotmail.com or Giovanni Battista Migliori. Istituti Clinici Scientifici Maugeri - IRCCS, Via Roncaccio 16, 21049, Tradate, Italia. Tel.: 39 0331 829404. E-mail: gbmigliori@fsm.it

AUTHOR CONTRIBUTIONS

All authors participated in the drafting and revision of the manuscript, as well as in the approval of the final version.

CONFLICTS OF INTEREST

None declared.

Author	Year	Country	Type of study	Mean/ median age	HIV+, n (%)	Previously treated for TB	TB disease	No. of patients receiving BDQ	Other drugs included in the regimen	Duration of treatment (months)	Outcomes
Author	Year	Country	Type of study	Mean/ median age	HIV+, n (%)	Previously treated for TB	TB disease	No. of patients receiving BDQ	Other drugs included in the regimen	Duration of treatment (months)	Treatment success	Treatment failure	Death
Koirala et al.¹¹11 Koirala S, Borisov S, Danila E, Mariandyshev A, Shrestha B, Lukhele N, et al. Outcome of treatment of MDR-TB or drug-resistant patients treated with bedaquiline and delamanid: Results from a large global cohort. Pulmonology. 2021;27(5):403-412. https://doi.org/10.1016/j.pulmoe.2021.02.006 https://doi.org/10.1016/j.pulmoe.2021.02...	2021	Multicenter	PC	39	27 (5.7)	329	MDR/XDR	383	WHO-recommended regimen	6	284	11	25
Kwon et al.¹⁶16 Kwon YS, Jeon D, Kang H, Yim JJ, Shim TS. Concurrent use of bedaquiline and delamanid for the treatment of fluoroquinolone-resistant multidrug-resistant tuberculosis: a nationwide cohort study in South Korea. Eur Respir J. 2021;57(3):2003026. https://doi.org/10.1183/13993003.03026-2020 https://doi.org/10.1183/13993003.03026-2...	2021	South Korea	RC	49	0	19	Pre-XDR/XDR	28	DLM+LZD+CFZ+MEM/CLV+CYC	6	23	2	1
Shi et al.¹⁷17 Shi L, Gao J, Gao M, Deng P, Chen S, He M, et al. Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study. Infect Dis Ther. 2021;10(1):457-470. https://doi.org/10.1007/s40121-021-00396-9 https://doi.org/10.1007/s40121-021-00396...	2021	China	RC	49.8	N/R	186	MDR	72	FLQs+LZD+CFZ+CYC	6	197	4	0
							pre-XDR	78
							XDR	64
Gao et al.¹⁸18 Gao M, Gao J, Xie L, Wu G, Chen W, Chen Y, et al. Early outcome and safety of bedaquiline-containing regimens for treatment of MDR- and XDR-TB in China: a multicentre study. Clin Microbiol Infect. 2021;27(4):597-602. https://doi.org/10.1016/j.cmi.2020.06.004 https://doi.org/10.1016/j.cmi.2020.06.00...	2021	China	RC	40	1 (0.6)	168	MDR	39	FLQs+LZD+CFZ+CYC	6	151	23	3
							pre-XDR	56
							XDR	82
Barvaliya et al.¹⁹19 Barvaliya SV, Desai MK, Panchal JR, Solanki RN. Early treatment outcome of bedaquiline plus optimised background regimen in drug resistant tuberculosis patients. Indian J Tuberc. 2020;67(2):222-230. https://doi.org/10.1016/j.ijtb.2020.03.002 https://doi.org/10.1016/j.ijtb.2020.03.0...	2020	India	PC	31	N/R	110	Pre-XDR	87	FLQs+LZD+CFZ	5.5	102	10	14
	2020	India	PC	31	N/R	110	XDR	40	FLQs+LZD+CFZ	5.5	102	10	14
Kashongwe et al.²⁰20 Kashongwe IM, Mawete F, Mbulula L, Nsuela DJ, Losenga L, Anshambi N, et al. Outcomes and adverse events of pre- and extensively drug-resistant tuberculosis patients in Kinshasa, Democratique Republic of the Congo: A retrospective cohort study. PLoS One. 2020;15(8):e0236264. https://doi.org/10.1371/journal.pone.0236264 https://doi.org/10.1371/journal.pone.023...	2020	Congo	RC	32.4	3 (9.4)	23	Pre-XDR	29	FLQs+LZD+CFZ+CYC	20	17	0	15
	2020	Congo	RC	32.4	3 (9.4)	23	XDR	3	FLQs+LZD+CFZ+CYC	20	17	0	15
Das et al.²¹21 Das M, Mamnoon F, Mansoor H, Meneguim AC, Singh P, Shah I, et al. New TB drugs for the treatment of children and adolescents with rifampicin-resistant TB in Mumbai, India. Int J Tuberc Lung Dis. 2020;24(12):1265-1271. https://doi.org/10.5588/ijtld.20.0165 https://doi.org/10.5588/ijtld.20.0165...	2020	India	RC	Children/adolescents	0	N/R	Pre-XDR/XDR	13	DLM+ LZD+CFZ	22	12 or 13	N/R	N/R
Lee et al.²²22 Lee HH, Jo KW, Yim JJ, Jeon D, Kang H, Shim TS. Interim treatment outcomes in multidrug-resistant tuberculosis patients treated sequentially with bedaquiline and delamanid. Int J Infect Dis. 2020;98:478-485. https://doi.org/10.1016/j.ijid.2020.07.001 https://doi.org/10.1016/j.ijid.2020.07.0...	2020	South Korea	RC	49.8	1 (1.4)	49	MDR	13	DLM+FLQs+ LZD+CFZ+CYC	5.5	42	1	4
							Pre-XDR	41
							XDR	20
Kim et al.²³23 Kim JH, Kwon OJ, Kim YS, Park MS, Hwang S, Shim TS. Bedaquiline in multidrug-resistant tuberculosis treatment: Safety and efficacy in a Korean subpopulation. Respir Investig. 2020;58(1):45-51. https://doi.org/10.1016/j.resinv.2019.08.004 https://doi.org/10.1016/j.resinv.2019.08...	2020	South Korea	RC	33	9 (3.5)	254	MDR	159	AMGs+FLQs+LZD+CYC	6	139/225	35/225	15/225
							Pre-XDR	51
							XDR	44
Mase et al.²⁴24 Mase S, Chorba T, Parks S, Belanger A, Dworkin F, Seaworth B, et al. Bedaquiline for the Treatment of Multidrug-resistant Tuberculosis in the United States. Clin Infect Dis. 2020;71(4):1010-1016. https://doi.org/10.1093/cid/ciz914 https://doi.org/10.1093/cid/ciz914...	2020	USA	RC	43.5	1 (7)	5	MDR	7	WHO-recommended regimen	5.5	12	N/R	1
							Pre-XDR	4
							XDR	3
Olayanju et al.²⁵25 Olayanju O, Esmail A, Limberis J, Dheda K. A regimen containing bedaquiline and delamanid compared to bedaquiline in patients with drug-resistant tuberculosis. Eur Respir J. 2020;55(1):1901181. https://doi.org/10.1183/13993003.01181-2019 https://doi.org/10.1183/13993003.01181-2... ⁾	2020	South Africa	PC	33	42 (51)	40	MDR	5	AMGs+FLQs+LZD+CFZ+TRD	6	52	N/R	N/R
							Pre-XDR	10
							XDR	67
				34	22 (55)	29	MDR	6	DLM+AMGs+FLQs+LZD+CFZ+TRD	6	27	N/R	N/R
							Pre-XDR	15
							XDR	19
Salhotra et al.²⁶26 Salhotra VS, Sachdeva KS, Kshirsagar N, Parmar M, Ramachandran R, Padmapriyadarsini C, et al. Effectiveness and safety of bedaquiline under conditional access program for treatment of drug-resistant tuberculosis in India: An interim analysis. Indian J Tuberc. 2020;67(1):29-37. https://doi.org/10.1016/j.ijtb.2019.10.002 https://doi.org/10.1016/j.ijtb.2019.10.0...	2020	India	PC	Range: 18-50	8 (1.3)	600	MDR	524	AMGs+FLQs+CFZ	6	513	N/R	73
	2020	India	PC	Range: 18-50	8 (1.3)	600	XDR	96	AMGs+FLQs+CFZ	6	513	N/R	73
Chesov et al.²⁷27 Chesov D, Heyckendorf J, Alexandru S, Donica A, Chesov E, Reimann M, et al. Impact of bedaquiline on treatment outcomes of multidrug-resistant tuberculosis in a high-burden country. Eur Respir J. 2021;57(6):2002544. https://doi.org/10.1183/13993003.02544-2020 https://doi.org/10.1183/13993003.02544-2...	2020	Moldova	RC	37	17 (14.9)	58	MDR	114	AMGs+FLQs+CYC+PZA	6	63	31	10
Kang et al.²⁸28 Kang H, Jo KW, Jeon D, Yim JJ, Shim TS. Interim treatment outcomes in multidrug-resistant tuberculosis using bedaquiline and/or delamanid in South Korea. Respir Med. 2020;167:105956. https://doi.org/10.1016/j.rmed.2020.105956 https://doi.org/10.1016/j.rmed.2020.1059...	2020	South Korea	RC	51.7	0	55	MDR	43	AMGs+FLQs+LZD+CYC	6	86	1	13
							Pre-XDR	47
							XDR	17
				47.7	1 (1.5)	47	MDR	8	DLM+AMGs+FLQs+LZD+CYC	6	58	3	3
							Pre-XDR	37
							XDR	22
Sarin et al.²⁹29 Sarin R, Vohra V, Singla N, Singla R, Puri MM, Munjal SK, et al. Early efficacy and safety of Bedaquiline and Delamanid given together in a "Salvage Regimen" for treatment of drug-resistant tuberculosis. Indian J Tuberc. 2019;66(1):184-188. https://doi.org/10.1016/j.ijtb.2019.02.006 https://doi.org/10.1016/j.ijtb.2019.02.0...	2019	India	PC	Range: 21-33	0	N/R	MDR/Pre-XDR/XDR	42	DLM+ FLQs+LZD+CFZ+IMP	6	25	N/R	10
Kempker et al.³⁰30 Kempker RR, Mikiashvili L, Zhao Y, Benkeser D, Barbakadze K, Bablishvili N, et al. Clinical Outcomes Among Patients With Drug-resistant Tuberculosis Receiving Bedaquiline- or Delamanid-Containing Regimens. Clin Infect Dis. 2020;71(9):2336-2344. https://doi.org/10.1093/cid/ciz1107 https://doi.org/10.1093/cid/ciz1107...	2019	USA	PC	37.3	2 (3)	8	MDR/XDR	64	FLQs+LZD+CFZ+CYC+IMP	5.5	42	1	0
Taune et al.³¹31 Taune M, Ustero P, Hiashiri S, Huang K, Aia P, Morris L, et al. Successful implementation of bedaquiline for multidrug-resistant TB treatment in remote Papua New Guinea. Public Health Action. 2019;9(Suppl 1):S73-S79. https://doi.org/10.5588/pha.18.0071 https://doi.org/10.5588/pha.18.0071...	2019	New Guinea	RC	39	1 (1.3)	33	MDR	55	AMGs+FLQs+LZD+CFZ+CYC+PZA	6	72	N/R	5
							Pre-XDR	10
							XDR	12
Ferlazzo et al.³²32 Ferlazzo G, Mohr E, Laxmeshwar C, Hewison C, Hughes J, Jonckheere S, et al. Early safety and efficacy of the combination of bedaquiline and delamanid for the treatment of patients with drug-resistant tuberculosis in Armenia, India, and South Africa: a retrospective cohort study. Lancet Infect Dis. 2018;18(5):536-544. https://doi.org/10.1016/S1473-3099(18)30100-2 https://doi.org/10.1016/S1473-3099(18)30...	2018	Armenia, India, South Africa	RC	32.5	11 (39)	4	MDR	2	DLM+ FLQs+LZD+CFZ+IMP	6	22	N/R	1
							Pre-XDR	12
							XDR	14
Hewison et al.³³33 Hewison C, Bastard M, Khachatryan N, Kotrikadze T, Hayrapetyan A, Avaliani Z, et al. Is 6 months of bedaquiline enough? Results from the compassionate use of bedaquiline in Armenia and Georgia. Int J Tuberc Lung Dis. 2018;22(7):766-772. https://doi.org/10.5588/ijtld.17.0840 https://doi.org/10.5588/ijtld.17.0840...	2018	Armenia, Georgia	RC	40.5	4 (4.8)	N/R	MDR	6	FLQs+LZD+CFZ+IMP	6	48	6	10
							Pre-XDR	36
							XDR	40
Ndjeka et al.³⁴34 Ndjeka N, Schnippel K, Master I, Meintjes G, Maartens G, Romero R, et al. High treatment success rate for multidrug-resistant and extensively drug-resistant tuberculosis using a bedaquiline-containing treatment regimen. Eur Respir J. 2018;52(6):1801528. https://doi.org/10.1183/13993003.01528-2018 https://doi.org/10.1183/13993003.01528-2...	2018	South Africa	PC	34	134 (67)	N/R	Pre-XDR	122	FLQs+LZD+CFZ	6	146	9	25
	2018	South Africa	PC	34	134 (67)	N/R	XDR	78	FLQs+LZD+CFZ	6	146	9	25
Zhao et al.³⁵35 Zhao Y, Fox T, Manning K, Stewart A, Tiffin N, Khomo N, et al. Improved Treatment Outcomes With Bedaquiline When Substituted for Second-line Injectable Agents in Multidrug-resistant Tuberculosis: A Retrospective Cohort Study. Clin Infect Dis. 2019;68(9):1522-1529. https://doi.org/10.1093/cid/ciy727 https://doi.org/10.1093/cid/ciy727...	2018	South Africa	RC	Range: 35-49	110 (68)	N/R	MDR	162	FLQs+PZA+ETH+hINH+ETM+TRD	6	111/146	7/119	11/145
Kim et al.³⁶36 Kim CT, Kim TO, Shin HJ, Ko YC, Hun Choe Y, Kim HR, et al. Bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis: a multicentre cohort study in Korea. Eur Respir J. 2018;51(3):1702467. https://doi.org/10.1183/13993003.02467-2017 https://doi.org/10.1183/13993003.02467-2...	2018	South Korea	RC	52	N/R	N/R	MDR/Pre-XDR/XDR	39	FLQs+LZD+CFZ	5.6	24	N/R	N/R
Achar et al.³⁷37 Achar J, Hewison C, Cavalheiro AP, Skrahina A, Cajazeiro J, Nargiza P, et al. Off-Label Use of Bedaquiline in Children and Adolescents with Multidrug-Resistant Tuberculosis. Emerg Infect Dis. 2017;23(10):1711-1713. https://doi.org/10.3201/eid2310.170303 https://doi.org/10.3201/eid2310.170303...	2017	South Africa, Tajikistan, Uzbekistan, Belarus	PC	Children/adolescents	0	N/R	Pre-XDR/XDR	23	FLQs+LZD+CFZ+IMP	6	23	0	0
Guglielmetti et al.³⁸38 Guglielmetti L, Jaspard M, Le Dû D, Lachâtre M, Marigot-Outtandy D, Bernard C, et al. Long-term outcome and safety of prolonged bedaquiline treatment for multidrug-resistant tuberculosis. Eur Respir J. 2017;49(3):1601799. https://doi.org/10.1183/13993003.01799-2016 https://doi.org/10.1183/13993003.01799-2...	2017	France	RC	38	2 (4.4)	34	MDR/Pre-XDR/XDR	45	AMGs+FLQs+LZD+CFZ+CYC+PZA+ETH+ETM	6	36	1	3
Borisov et al.¹⁰10 Borisov SE, Dheda K, Enwerem M, Romero Leyet R, D'Ambrosio L, Centis R, et al. Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study. Eur Respir J. 2017;49(5):1700387. https://doi.org/10.1183/13993003.00387-2017 https://doi.org/10.1183/13993003.00387-2...	2017	Multicenter	RC	35	94 (22.1)	334	MDR	233	AMGs+FLQs+LZD+CFZ+IMP	5.5	176/247	18/247	33/247
	2017	Multicenter	RC	35	94 (22.1)	334	XDR	195	AMGs+FLQs+LZD+CFZ+IMP	5.5	176/247	18/247	33/247
Conradie et al.³⁹39 Conradie F, Diacon AH, Ngubane N, Howell P, Everitt D, Crook AM, et al. Treatment of Highly Drug-Resistant Pulmonary Tuberculosis. N Engl J Med. 2020;382(10):893-902. https://doi.org/10.1056/NEJMoa1901814 https://doi.org/10.1056/NEJMoa1901814...	2020	South Africa	CT	35	56 (51)	N/R	MDR	38	LZD+PMD	6	98	2	7
	2020	South Africa	CT	35	56 (51)	N/R	XDR	71	LZD+PMD	6	98	2	7
Tweed et al.⁴⁰40 Tweed CD, Dawson R, Burger DA, Conradie A, Crook AM, Mendel CM, et al. Bedaquiline, moxifloxacin, pretomanid, and pyrazinamide during the first 8 weeks of treatment of patients with drug-susceptible or drug-resistant pulmonary tuberculosis: a multicentre, open-label, partially randomised, phase 2b trial. Lancet Respir Med. 2019;7(12):1048-1058. https://doi.org/10.1016/S2213-2600(19)30366-2 https://doi.org/10.1016/S2213-2600(19)30...	2019	South Africa, Tanzania, Uganda	CT	34	25 (42)	N/R	RR	60	FLQs+PZA+PMD	6	58	N/R	0
Pym et al.⁴¹41 Pym AS, Diacon AH, Tang SJ, Conradie F, Danilovits M, Chuchottaworn C, et al. Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis. Eur Respir J. 2016;47(2):564-574. https://doi.org/10.1183/13993003.00724-2015 https://doi.org/10.1183/13993003.00724-2...	2016	Multicenter	CT	32	8 (4)	177	MDR	124	AMGs+FLQs+ CYC+PZA+ETH	6	163	N/R	N/R
							Pre-XDR	44
							XDR	37
Diacon et al.⁴²42 Diacon AH, Pym A, Grobusch MP, de los Rios JM, Gotuzzo E, Vasilyeva I, et al. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med. 2014;371(8):723-732. https://doi.org/10.1056/NEJMoa1313865 https://doi.org/10.1056/NEJMoa1313865...	2014	Multicenter	CT	32	5 (8)	N/R	MDR	66	AMGs+FLQs+ CYC+PZA+ETH	6	52	N/R	N/R

Author	1	2	3	4	5	6	7	8	9	10	11
Koirala et al.¹¹11 Koirala S, Borisov S, Danila E, Mariandyshev A, Shrestha B, Lukhele N, et al. Outcome of treatment of MDR-TB or drug-resistant patients treated with bedaquiline and delamanid: Results from a large global cohort. Pulmonology. 2021;27(5):403-412. https://doi.org/10.1016/j.pulmoe.2021.02.006 https://doi.org/10.1016/j.pulmoe.2021.02...	N/A	N/A	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Kwon et al.¹⁶16 Kwon YS, Jeon D, Kang H, Yim JJ, Shim TS. Concurrent use of bedaquiline and delamanid for the treatment of fluoroquinolone-resistant multidrug-resistant tuberculosis: a nationwide cohort study in South Korea. Eur Respir J. 2021;57(3):2003026. https://doi.org/10.1183/13993003.03026-2020 https://doi.org/10.1183/13993003.03026-2...	N/A	N/A	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Shi et al.¹⁷17 Shi L, Gao J, Gao M, Deng P, Chen S, He M, et al. Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study. Infect Dis Ther. 2021;10(1):457-470. https://doi.org/10.1007/s40121-021-00396-9 https://doi.org/10.1007/s40121-021-00396...	N/A	N/A	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Gao et al.¹⁸18 Gao M, Gao J, Xie L, Wu G, Chen W, Chen Y, et al. Early outcome and safety of bedaquiline-containing regimens for treatment of MDR- and XDR-TB in China: a multicentre study. Clin Microbiol Infect. 2021;27(4):597-602. https://doi.org/10.1016/j.cmi.2020.06.004 https://doi.org/10.1016/j.cmi.2020.06.00...	N/A	N/A	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Barvaliya et al.¹⁹19 Barvaliya SV, Desai MK, Panchal JR, Solanki RN. Early treatment outcome of bedaquiline plus optimised background regimen in drug resistant tuberculosis patients. Indian J Tuberc. 2020;67(2):222-230. https://doi.org/10.1016/j.ijtb.2020.03.002 https://doi.org/10.1016/j.ijtb.2020.03.0...	N/A	N/A	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Kashongwe et al.²⁰20 Kashongwe IM, Mawete F, Mbulula L, Nsuela DJ, Losenga L, Anshambi N, et al. Outcomes and adverse events of pre- and extensively drug-resistant tuberculosis patients in Kinshasa, Democratique Republic of the Congo: A retrospective cohort study. PLoS One. 2020;15(8):e0236264. https://doi.org/10.1371/journal.pone.0236264 https://doi.org/10.1371/journal.pone.023...	N/A	N/A	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Das et al.²¹21 Das M, Mamnoon F, Mansoor H, Meneguim AC, Singh P, Shah I, et al. New TB drugs for the treatment of children and adolescents with rifampicin-resistant TB in Mumbai, India. Int J Tuberc Lung Dis. 2020;24(12):1265-1271. https://doi.org/10.5588/ijtld.20.0165 https://doi.org/10.5588/ijtld.20.0165...	N/A	N/A	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Lee et al.²²22 Lee HH, Jo KW, Yim JJ, Jeon D, Kang H, Shim TS. Interim treatment outcomes in multidrug-resistant tuberculosis patients treated sequentially with bedaquiline and delamanid. Int J Infect Dis. 2020;98:478-485. https://doi.org/10.1016/j.ijid.2020.07.001 https://doi.org/10.1016/j.ijid.2020.07.0...	N/A	N/A	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Kim et al.²³23 Kim JH, Kwon OJ, Kim YS, Park MS, Hwang S, Shim TS. Bedaquiline in multidrug-resistant tuberculosis treatment: Safety and efficacy in a Korean subpopulation. Respir Investig. 2020;58(1):45-51. https://doi.org/10.1016/j.resinv.2019.08.004 https://doi.org/10.1016/j.resinv.2019.08...	N/A	N/A	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Mase et al.²⁴24 Mase S, Chorba T, Parks S, Belanger A, Dworkin F, Seaworth B, et al. Bedaquiline for the Treatment of Multidrug-resistant Tuberculosis in the United States. Clin Infect Dis. 2020;71(4):1010-1016. https://doi.org/10.1093/cid/ciz914 https://doi.org/10.1093/cid/ciz914...	N/A	N/A	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Olayanju et al.²⁵25 Olayanju O, Esmail A, Limberis J, Dheda K. A regimen containing bedaquiline and delamanid compared to bedaquiline in patients with drug-resistant tuberculosis. Eur Respir J. 2020;55(1):1901181. https://doi.org/10.1183/13993003.01181-2019 https://doi.org/10.1183/13993003.01181-2...	N/A	N/A	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Salhotra et al.²⁶26 Salhotra VS, Sachdeva KS, Kshirsagar N, Parmar M, Ramachandran R, Padmapriyadarsini C, et al. Effectiveness and safety of bedaquiline under conditional access program for treatment of drug-resistant tuberculosis in India: An interim analysis. Indian J Tuberc. 2020;67(1):29-37. https://doi.org/10.1016/j.ijtb.2019.10.002 https://doi.org/10.1016/j.ijtb.2019.10.0...	N/A	N/A	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Chesov et al.²⁷27 Chesov D, Heyckendorf J, Alexandru S, Donica A, Chesov E, Reimann M, et al. Impact of bedaquiline on treatment outcomes of multidrug-resistant tuberculosis in a high-burden country. Eur Respir J. 2021;57(6):2002544. https://doi.org/10.1183/13993003.02544-2020 https://doi.org/10.1183/13993003.02544-2...	Yes	Yes	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Kang et al.²⁸28 Kang H, Jo KW, Jeon D, Yim JJ, Shim TS. Interim treatment outcomes in multidrug-resistant tuberculosis using bedaquiline and/or delamanid in South Korea. Respir Med. 2020;167:105956. https://doi.org/10.1016/j.rmed.2020.105956 https://doi.org/10.1016/j.rmed.2020.1059...	Yes	Yes	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Sarin et al.²⁹29 Sarin R, Vohra V, Singla N, Singla R, Puri MM, Munjal SK, et al. Early efficacy and safety of Bedaquiline and Delamanid given together in a "Salvage Regimen" for treatment of drug-resistant tuberculosis. Indian J Tuberc. 2019;66(1):184-188. https://doi.org/10.1016/j.ijtb.2019.02.006 https://doi.org/10.1016/j.ijtb.2019.02.0...	N/A	N/A	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Kempker et al.³⁰30 Kempker RR, Mikiashvili L, Zhao Y, Benkeser D, Barbakadze K, Bablishvili N, et al. Clinical Outcomes Among Patients With Drug-resistant Tuberculosis Receiving Bedaquiline- or Delamanid-Containing Regimens. Clin Infect Dis. 2020;71(9):2336-2344. https://doi.org/10.1093/cid/ciz1107 https://doi.org/10.1093/cid/ciz1107...	Yes	Yes	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Taune et al.³¹31 Taune M, Ustero P, Hiashiri S, Huang K, Aia P, Morris L, et al. Successful implementation of bedaquiline for multidrug-resistant TB treatment in remote Papua New Guinea. Public Health Action. 2019;9(Suppl 1):S73-S79. https://doi.org/10.5588/pha.18.0071 https://doi.org/10.5588/pha.18.0071...	Yes	Yes	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Ferlazzo et al.³²32 Ferlazzo G, Mohr E, Laxmeshwar C, Hewison C, Hughes J, Jonckheere S, et al. Early safety and efficacy of the combination of bedaquiline and delamanid for the treatment of patients with drug-resistant tuberculosis in Armenia, India, and South Africa: a retrospective cohort study. Lancet Infect Dis. 2018;18(5):536-544. https://doi.org/10.1016/S1473-3099(18)30100-2 https://doi.org/10.1016/S1473-3099(18)30...	N/A	N/A	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Hewison et al.³³33 Hewison C, Bastard M, Khachatryan N, Kotrikadze T, Hayrapetyan A, Avaliani Z, et al. Is 6 months of bedaquiline enough? Results from the compassionate use of bedaquiline in Armenia and Georgia. Int J Tuberc Lung Dis. 2018;22(7):766-772. https://doi.org/10.5588/ijtld.17.0840 https://doi.org/10.5588/ijtld.17.0840...	N/A	N/A	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Ndjeka et al.³⁴34 Ndjeka N, Schnippel K, Master I, Meintjes G, Maartens G, Romero R, et al. High treatment success rate for multidrug-resistant and extensively drug-resistant tuberculosis using a bedaquiline-containing treatment regimen. Eur Respir J. 2018;52(6):1801528. https://doi.org/10.1183/13993003.01528-2018 https://doi.org/10.1183/13993003.01528-2...	N/A	N/A	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Zhao et al.³⁵35 Zhao Y, Fox T, Manning K, Stewart A, Tiffin N, Khomo N, et al. Improved Treatment Outcomes With Bedaquiline When Substituted for Second-line Injectable Agents in Multidrug-resistant Tuberculosis: A Retrospective Cohort Study. Clin Infect Dis. 2019;68(9):1522-1529. https://doi.org/10.1093/cid/ciy727 https://doi.org/10.1093/cid/ciy727...	Yes	Yes	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Kim et al.³⁶36 Kim CT, Kim TO, Shin HJ, Ko YC, Hun Choe Y, Kim HR, et al. Bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis: a multicentre cohort study in Korea. Eur Respir J. 2018;51(3):1702467. https://doi.org/10.1183/13993003.02467-2017 https://doi.org/10.1183/13993003.02467-2...	Yes	Yes	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Achar et al.³⁷37 Achar J, Hewison C, Cavalheiro AP, Skrahina A, Cajazeiro J, Nargiza P, et al. Off-Label Use of Bedaquiline in Children and Adolescents with Multidrug-Resistant Tuberculosis. Emerg Infect Dis. 2017;23(10):1711-1713. https://doi.org/10.3201/eid2310.170303 https://doi.org/10.3201/eid2310.170303...	N/A	N/A	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Guglielmetti et al.³⁸38 Guglielmetti L, Jaspard M, Le Dû D, Lachâtre M, Marigot-Outtandy D, Bernard C, et al. Long-term outcome and safety of prolonged bedaquiline treatment for multidrug-resistant tuberculosis. Eur Respir J. 2017;49(3):1601799. https://doi.org/10.1183/13993003.01799-2016 https://doi.org/10.1183/13993003.01799-2...	N/A	N/A	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Borisov et al.¹⁰10 Borisov SE, Dheda K, Enwerem M, Romero Leyet R, D'Ambrosio L, Centis R, et al. Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study. Eur Respir J. 2017;49(5):1700387. https://doi.org/10.1183/13993003.00387-2017 https://doi.org/10.1183/13993003.00387-2...	N/A	N/A	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes

Author	1	2	3	4	5	6	7	8	9	10	11	12	13
Conradie et al.³⁹39 Conradie F, Diacon AH, Ngubane N, Howell P, Everitt D, Crook AM, et al. Treatment of Highly Drug-Resistant Pulmonary Tuberculosis. N Engl J Med. 2020;382(10):893-902. https://doi.org/10.1056/NEJMoa1901814 https://doi.org/10.1056/NEJMoa1901814...	No	N/A	N/A	No	No	No	No	Yes	Yes	N/A	Yes	Yes	No
Tweed et al.⁴⁰40 Tweed CD, Dawson R, Burger DA, Conradie A, Crook AM, Mendel CM, et al. Bedaquiline, moxifloxacin, pretomanid, and pyrazinamide during the first 8 weeks of treatment of patients with drug-susceptible or drug-resistant pulmonary tuberculosis: a multicentre, open-label, partially randomised, phase 2b trial. Lancet Respir Med. 2019;7(12):1048-1058. https://doi.org/10.1016/S2213-2600(19)30366-2 https://doi.org/10.1016/S2213-2600(19)30...	Yes	No	Yes	No	No	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Pym et al.⁴¹41 Pym AS, Diacon AH, Tang SJ, Conradie F, Danilovits M, Chuchottaworn C, et al. Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis. Eur Respir J. 2016;47(2):564-574. https://doi.org/10.1183/13993003.00724-2015 https://doi.org/10.1183/13993003.00724-2...	No	No	N/A	No	No	No	No	Yes	Yes	N/A	Yes	Yes	No
Diacon et al.⁴²42 Diacon AH, Pym A, Grobusch MP, de los Rios JM, Gotuzzo E, Vasilyeva I, et al. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med. 2014;371(8):723-732. https://doi.org/10.1056/NEJMoa1313865 https://doi.org/10.1056/NEJMoa1313865...	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes

Author	QTc prolongation	Liver disease/ Elevated liver enzyme	Renal failure/ Increased creatinine levels	Optic neuropathy/ Blurred vision	Ototoxicity/Hearing loss	Hematological disorders (anemia, thrombocytopenia, eosinophilia)	Gastrointestinal symptoms (diarrhea, vomiting, nausea, abdominal pain)	Peripheral neuropathy	Electrolyte disturbance	Arthralgia	Psychiatric disorder	Dermatological symptoms
Kwon et al.¹⁶16 Kwon YS, Jeon D, Kang H, Yim JJ, Shim TS. Concurrent use of bedaquiline and delamanid for the treatment of fluoroquinolone-resistant multidrug-resistant tuberculosis: a nationwide cohort study in South Korea. Eur Respir J. 2021;57(3):2003026. https://doi.org/10.1183/13993003.03026-2020 https://doi.org/10.1183/13993003.03026-2...	17	NR	N/R	N/R	N/R	N/R	1	N/R	N/R	N/R	N/R	N/R
Shi et al.¹⁷17 Shi L, Gao J, Gao M, Deng P, Chen S, He M, et al. Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study. Infect Dis Ther. 2021;10(1):457-470. https://doi.org/10.1007/s40121-021-00396-9 https://doi.org/10.1007/s40121-021-00396...	85	59	21	13	10	24	15	16	5	3	9	2
Gao et al.¹⁸18 Gao M, Gao J, Xie L, Wu G, Chen W, Chen Y, et al. Early outcome and safety of bedaquiline-containing regimens for treatment of MDR- and XDR-TB in China: a multicentre study. Clin Microbiol Infect. 2021;27(4):597-602. https://doi.org/10.1016/j.cmi.2020.06.004 https://doi.org/10.1016/j.cmi.2020.06.00...	39	35	9	2	6	15	11	8	11	2	6	N/R
Barvaliya et al.¹⁹19 Barvaliya SV, Desai MK, Panchal JR, Solanki RN. Early treatment outcome of bedaquiline plus optimised background regimen in drug resistant tuberculosis patients. Indian J Tuberc. 2020;67(2):222-230. https://doi.org/10.1016/j.ijtb.2020.03.002 https://doi.org/10.1016/j.ijtb.2020.03.0...	11	6	N/R	5	4	N/R	33	4	N/R	9	4	18
Kashongwe et al.²⁰20 Kashongwe IM, Mawete F, Mbulula L, Nsuela DJ, Losenga L, Anshambi N, et al. Outcomes and adverse events of pre- and extensively drug-resistant tuberculosis patients in Kinshasa, Democratique Republic of the Congo: A retrospective cohort study. PLoS One. 2020;15(8):e0236264. https://doi.org/10.1371/journal.pone.0236264 https://doi.org/10.1371/journal.pone.023...	3	1	N/R	2	5	14	15	15	N/R	N/R	N/R	15
Das et al.²¹21 Das M, Mamnoon F, Mansoor H, Meneguim AC, Singh P, Shah I, et al. New TB drugs for the treatment of children and adolescents with rifampicin-resistant TB in Mumbai, India. Int J Tuberc Lung Dis. 2020;24(12):1265-1271. https://doi.org/10.5588/ijtld.20.0165 https://doi.org/10.5588/ijtld.20.0165...	1	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R
Lee et al.²²22 Lee HH, Jo KW, Yim JJ, Jeon D, Kang H, Shim TS. Interim treatment outcomes in multidrug-resistant tuberculosis patients treated sequentially with bedaquiline and delamanid. Int J Infect Dis. 2020;98:478-485. https://doi.org/10.1016/j.ijid.2020.07.001 https://doi.org/10.1016/j.ijid.2020.07.0...	23	N/R	1	N/R	N/R	N/R	4	N/R	N/R	N/R	N/R	N/R
Kim et al.²³23 Kim JH, Kwon OJ, Kim YS, Park MS, Hwang S, Shim TS. Bedaquiline in multidrug-resistant tuberculosis treatment: Safety and efficacy in a Korean subpopulation. Respir Investig. 2020;58(1):45-51. https://doi.org/10.1016/j.resinv.2019.08.004 https://doi.org/10.1016/j.resinv.2019.08...	7	28	N/R	N/R	N/R	N/R	32	N/R	N/R	34	N/R	8
Mase et al.²⁴24 Mase S, Chorba T, Parks S, Belanger A, Dworkin F, Seaworth B, et al. Bedaquiline for the Treatment of Multidrug-resistant Tuberculosis in the United States. Clin Infect Dis. 2020;71(4):1010-1016. https://doi.org/10.1093/cid/ciz914 https://doi.org/10.1093/cid/ciz914...	6	N/R	N/R	N/R	2	2	4	7	4	N/R	3	3
Olayanju et al.²⁵25 Olayanju O, Esmail A, Limberis J, Dheda K. A regimen containing bedaquiline and delamanid compared to bedaquiline in patients with drug-resistant tuberculosis. Eur Respir J. 2020;55(1):1901181. https://doi.org/10.1183/13993003.01181-2019 https://doi.org/10.1183/13993003.01181-2...	12	36	N/R	8	59	43	30	30	N/R	20	9	N/R
Salhotra et al.²⁶26 Salhotra VS, Sachdeva KS, Kshirsagar N, Parmar M, Ramachandran R, Padmapriyadarsini C, et al. Effectiveness and safety of bedaquiline under conditional access program for treatment of drug-resistant tuberculosis in India: An interim analysis. Indian J Tuberc. 2020;67(1):29-37. https://doi.org/10.1016/j.ijtb.2019.10.002 https://doi.org/10.1016/j.ijtb.2019.10.0...	14	13	4	N/R	8	22	35	26	7	N/R	15	1
Kempker et al.³⁰30 Kempker RR, Mikiashvili L, Zhao Y, Benkeser D, Barbakadze K, Bablishvili N, et al. Clinical Outcomes Among Patients With Drug-resistant Tuberculosis Receiving Bedaquiline- or Delamanid-Containing Regimens. Clin Infect Dis. 2020;71(9):2336-2344. https://doi.org/10.1093/cid/ciz1107 https://doi.org/10.1093/cid/ciz1107...	1	1	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R
Taune et al.³¹31 Taune M, Ustero P, Hiashiri S, Huang K, Aia P, Morris L, et al. Successful implementation of bedaquiline for multidrug-resistant TB treatment in remote Papua New Guinea. Public Health Action. 2019;9(Suppl 1):S73-S79. https://doi.org/10.5588/pha.18.0071 https://doi.org/10.5588/pha.18.0071...	1	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R
Ferlazzo et al.³²32 Ferlazzo G, Mohr E, Laxmeshwar C, Hewison C, Hughes J, Jonckheere S, et al. Early safety and efficacy of the combination of bedaquiline and delamanid for the treatment of patients with drug-resistant tuberculosis in Armenia, India, and South Africa: a retrospective cohort study. Lancet Infect Dis. 2018;18(5):536-544. https://doi.org/10.1016/S1473-3099(18)30100-2 https://doi.org/10.1016/S1473-3099(18)30...	4	N/R	1	N/R	N/R	N/R	1	1	N/R	N/R	2	N/R
Hewison et al.³³33 Hewison C, Bastard M, Khachatryan N, Kotrikadze T, Hayrapetyan A, Avaliani Z, et al. Is 6 months of bedaquiline enough? Results from the compassionate use of bedaquiline in Armenia and Georgia. Int J Tuberc Lung Dis. 2018;22(7):766-772. https://doi.org/10.5588/ijtld.17.0840 https://doi.org/10.5588/ijtld.17.0840...	12	27	5	1	9	3	34	21	N/R	N/R	N/R	6
Ndjeka et al.³⁴34 Ndjeka N, Schnippel K, Master I, Meintjes G, Maartens G, Romero R, et al. High treatment success rate for multidrug-resistant and extensively drug-resistant tuberculosis using a bedaquiline-containing treatment regimen. Eur Respir J. 2018;52(6):1801528. https://doi.org/10.1183/13993003.01528-2018 https://doi.org/10.1183/13993003.01528-2...	10	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R
Achar et al.³⁷37 Achar J, Hewison C, Cavalheiro AP, Skrahina A, Cajazeiro J, Nargiza P, et al. Off-Label Use of Bedaquiline in Children and Adolescents with Multidrug-Resistant Tuberculosis. Emerg Infect Dis. 2017;23(10):1711-1713. https://doi.org/10.3201/eid2310.170303 https://doi.org/10.3201/eid2310.170303...	0	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R
Guglielmetti et al.³⁸38 Guglielmetti L, Jaspard M, Le Dû D, Lachâtre M, Marigot-Outtandy D, Bernard C, et al. Long-term outcome and safety of prolonged bedaquiline treatment for multidrug-resistant tuberculosis. Eur Respir J. 2017;49(3):1601799. https://doi.org/10.1183/13993003.01799-2016 https://doi.org/10.1183/13993003.01799-2...	13	17	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R
Borisov et al.¹⁰10 Borisov SE, Dheda K, Enwerem M, Romero Leyet R, D'Ambrosio L, Centis R, et al. Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study. Eur Respir J. 2017;49(5):1700387. https://doi.org/10.1183/13993003.00387-2017 https://doi.org/10.1183/13993003.00387-2...	24/248	N/R	47/413	10/413	N/R	86/412	130/413	96/412	N/R	84/412	29/413	63/412
Conradie et al.³⁹39 Conradie F, Diacon AH, Ngubane N, Howell P, Everitt D, Crook AM, et al. Treatment of Highly Drug-Resistant Pulmonary Tuberculosis. N Engl J Med. 2020;382(10):893-902. https://doi.org/10.1056/NEJMoa1901814 https://doi.org/10.1056/NEJMoa1901814...	0	17	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R
Tweed et al.⁴⁰40 Tweed CD, Dawson R, Burger DA, Conradie A, Crook AM, Mendel CM, et al. Bedaquiline, moxifloxacin, pretomanid, and pyrazinamide during the first 8 weeks of treatment of patients with drug-susceptible or drug-resistant pulmonary tuberculosis: a multicentre, open-label, partially randomised, phase 2b trial. Lancet Respir Med. 2019;7(12):1048-1058. https://doi.org/10.1016/S2213-2600(19)30366-2 https://doi.org/10.1016/S2213-2600(19)30...	0	4	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R	N/R
Efeito aleatório combinado	10.4 (6.2-17.0)	11.7 (6.5-20.0)	4.6 (2.3-8.9)	3.8 (2.4-6.1)	7.8 (2.3-23.0)	13.6 (7.1-24.7)	15.3 (7.5-24.1)	13.8 (9.4-24.0)	4.7 (1.3-15.2)	8.1 (4.3-14.6)	5.1 (3.3-7.9)	7.5 (3.3-16.0)
Heterogeneidade, I² (%)	92%	93%	85%	50%	96%	94%	94%	94%	89%	89%	68%	91%
Teste de Begg, p	0.46	0.21	0.13	0.54	0.90	0.71	0.90	0.72	0.65	0.00	0.82	0.22

Subgroup	No. of studies	No. of patients	Treatment success rate (%) (95% CI)	Heterogeneity I² (%)	Begg’s test value of p
Treatment regimen: Regimen containing BDQ Regimen containing BDQ+DLM	22 7	3,287 292	74.5 (67.6-80.3) 73.9 (62.1-83.0)	91 72	0.61 0.03
Type of study: Observational study Experimental study	25 4	3,536 440	74.7 (69.8-79.0) 86.1 (76.8-92)	86 75	0.18 0.08

[1] Correspondence to:
Mohammad Javad Nasiri. Shahid Beheshti University of Medical Sciences, Arabi Avenue, Daneshjoo Blvd, Velenjak, 19839-63113, Tehran, Iran. Tel.: 98 21 22 43 25 56. E-mail: mj.nasiri@hotmail.com or Giovanni Battista Migliori. Istituti Clinici Scientifici Maugeri - IRCCS, Via Roncaccio 16, 21049, Tradate, Italia. Tel.: 39 0331 829404. E-mail: gbmigliori@fsm.it

Brasil

Brasil

Bedaquiline-containing regimens and multidrug-resistant tuberculosis: a systematic review and meta-analysis

ABSTRACT

Objective:

Methods:

Results:

Conclusions: