Outcome of treatment of MDR-TB or drug-resistant patients treated with bedaquiline and delamanid: Results from a large global cohort

(1)

University of Groningen

Outcome of treatment of MDR-TB or drug-resistant patients treated with bedaquiline and

delamanid

GTN; Koirala, S; Borisov, S; Danila, E; Mariandyshev, A; Shrestha, B; Lukhele, N; Dalcolmo,

M; Shakya, S R; Miliauskas, S

Published in:

Pulmonology

DOI:

10.1016/j.pulmoe.2021.02.006

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from

it. Please check the document version below.

Document Version

Version created as part of publication process; publisher's layout; not normally made publicly available

Publication date:

2021

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):

GTN, Koirala, S., Borisov, S., Danila, E., Mariandyshev, A., Shrestha, B., Lukhele, N., Dalcolmo, M.,

Shakya, S. R., Miliauskas, S., Kuksa, L., Manga, S., Aleksa, A., Denholm, J. T., Khadka, H. B., Skrahina,

A., Diktanas, S., Ferrarese, M., Bruchfeld, J., ... Migliori, G. B. (2021). Outcome of treatment of MDR-TB or

drug-resistant patients treated with bedaquiline and delamanid: Results from a large global cohort.

Pulmonology. https://doi.org/10.1016/j.pulmoe.2021.02.006

Copyright

Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policy

If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.

(2)

www.journalpulmonology.org

ORIGINAL

ARTICLE

Outcome

of

treatment

of

MDR-TB

or

drug-resistant

patients

treated

with

bedaquiline

and

delamanid:

Results

from

a

large

global

cohort

S. Koirala

a,*

_,

_S.

_Borisov

b,*

_,

_E.

_Danila

c,*

_,

_A.

_Mariandyshev

d

_,

_B.

_Shrestha

e

_,

_N.

_Lukhele

f

_,

M. Dalcolmo

g

,

S.R.

Shakya

h

,

S. Miliauskas

i

,

L. Kuksa

j

,

S. Manga

k

,

A. Aleksa

l

,

J.T.

Denholm

m

_,

_H.B.

_Khadka

n

_,

_A.

_Skrahina

o

_,

_S.

_Diktanas

p

_,

_M.

_Ferrarese

q

_,

J. Bruchfeld

r

_,

_A.

_Koleva

s

_,

_A.

_Piubello

t

_,

_G.S.

_Koirala

u

_,

_Z.F.

_Udwadia

v

_,

_D.J.

_Palmero

w

_,

M. Munoz-Torrico

x

_,

_R.

_GC

y

_,

_G.

_Gualano

z

_,

_V.I.

_Grecu

A

_,

_I.

_Motta

B

_,

_A.

_{Papavasileiou}

C

_,

Y. Li

D

_,

_W.

_Hoefsloot

E

_,

_H.

_Kunst

F

_,

_J.

_{Mazza-Stalder}

G

_,

_M.-C.

_Payen

H

_,

_O.W.

_Akkerman

I,J

_,

E. Bernal

K

_,

_V.

_Manfrin

L

_,

_A.

_Matteelli

M

_,

_H.

_Mustafa

_Hamdan

N

_,

_M.

_Nieto

_Marcos

O

_,

J. Cadi˜

nanos

Loidi

P

_,

_J.J.

_Cebrian

_Gallardo

Q

_,

_R.

_Duarte

R

_,

_N.

_Escobar

_Salinas

S

_,

R. Gomez

Rosso

T

_,

_R.

_{Laniado-Laborín}

U,V

_,

_E.

_Martínez

_Robles

W

_,

_S.

_Quirós

_Fernandez

X

_,

A. Rendon

Y

_,

_I.

_Solovic

Z

_,

_M.

_Tadolini

aa,bb

_,

_P.

_Viggiani

cc

_,

_E.

_Belilovski

b

_,

_M.J.

_Boeree

E

_,

Q. Cai

dd

_,

_E.

_Davidaviˇ

_cien˙

_e

ee,ff

_,

_L.D.

_Forsman

r

_,

_J.

_De

_Los

_Rios

gg

_,

_J.

_Drakˇ

_sien˙

_e

p

_,

A. Duga

hh,ii

_,

_S.E.

_Elamin

N

_,

_A.

_Filippov

b

_,

_A.

_Garcia

w

_,

_I.

_Gaudiesiute

i

_,

_B.

_Gavazova

jj

_,

R. Gayoso

g

_,

_V.

_Gruslys

c

_,

_J.

_Jonsson

kk

_,

_E.

_Khimova

d

_,

_G.

_Madonsela

ll

_,

_C.

_{Magis-Escurra}

E

_,

V. Marchese

M

_,

_M.

_Matei

mm,nn

_,

_C.

_Moschos

C

_,

_B.

_Nakˇ

_cerien˙

_e

ee,ff

_,

_L.

_Nicod

G

_,

_F.

_Palmieri

z

_,

A. Pontarelli

oo

_,

_{A. ˇ}

_Smite

j

_,

_M.B.

_Souleymane

t

_,

_M.

_Vescovo

w

_,

_R.

_Zablockis

c

_,

D. Zhurkin

o

_,

_J.-W.

_Alffenaar

pp,qq,rr

_,

_J.A.

_Caminero

ss,tt

_,

_L.R.

_Codecasa

q

_,

J.-M.

García-García

uu

_,

_S.

_Esposito

vv

_,

_L.

_Saderi

ww

_,

_A.

_Spanevello

xx,yy

_,

_D.

_Visca

xx,yy

_,

S. Tiberi

F,zz

_,

_E.

_Pontali

AA

_,

_R.

_Centis

BB

_,

_L.

_D’Ambrosio

CC

_,

_M.

_van

_den

_Boom

DD

_,

_G.

_Sotgiu

ww

_,

G.B.

Migliori

BB,∗

a_Damien_Foundation_Nepal,_Kathmandu,_Nepal

b_Moscow_Research_and_Clinical_Center_for_TB_Control,_Moscow_{Government’s}_Health_Department,_Moscow,_Russian_Federation c_Clinic_of_Chest_Diseases,_Immunology_and_Allergology,_Vilnius_University_Medical_Faculty,_Centre_of_Pulmonology_and

Allergology,VilniusUniversityHospitalSantarosKlinikos,Vilnius,Lithuania

d_Northern_State_Medical_University,_Northern_(Arctic)_Federal_University,_Arkhangelsk,_Russian_Federation e_Kalimati_Chest_{Hospital/GENETUP/Nepal}_Anti_Tuberculosis_Association,_Kathmandu,_Nepal

f_TB/HIV,_Hepatitis,_&_PMTCT_Department,_World_Health_{Organization,}_Eswatini_WHO_Country_Ofﬁce,_Mbabane,_Eswatini g_Reference_Center_Hélio_Fraga,_Fundac_¸ão_Oswaldo_Cruz_{(Fiocruz)/Ministry}_of_Health,_Rio_de_Janeiro,_Brazil

h_Lumbini_Provincial_Hospital,_Butwal,_Nepal

∗_{Corresponding} _author _at: _Servizio_di_{Epidemiologia} _Clinica _delle_Malattie_{Respiratorie,} _Istituti_Clinici _Scientiﬁci_Maugeri_IRCCS,_Via

Roncaccio16,Tradate,Varese,21049,Italy.

E-mailaddress:giovannibattista.migliori@icsmaugeri.it(G.B.Migliori).

∗ _These_authors_equally_contributed

https://doi.org/10.1016/j.pulmoe.2021.02.006

Please cite this article in press as: S. Koirala, S. Borisov, E. Danila et al., Pulmonology, https://doi.org/10.1016/j.pulmoe.2021.02.006

(3)

i_Department_of_Pulmonology,_Lithuanian_University_of_Health_Sciences,_Kaunas,_Lithuania j_MDR-TB_Department,_Riga_East_University_Hospital_for_TB_and_Lung_Disease_Centre,_Riga,_Latvia k_Department_of_Infectious_Diseases,_University_National_San_Antonio_Abad_Cusco,_Cusco,_Peru l_Department_of_Phthisiology_and_Pulmonology,_Grodno_State_Medical_University,_Grodno,_Belarus

m_Victorian_Tuberculosis_Program,_Melbourne_Health,_Department_of_Infectious_Diseases,_University_of_Melbourne,_Melbourne,

Australia

n_Nepalgjunj_TB_Referral_Center,_TB_Nepal,_Nepalgunj,_Nepal

o_Republican_Research_and_Practical_Centre_for_Pulmonology_and_{Tuberculosis,}_Minsk,_Belarus p_Tuberculosis_Department,_3rd_Tuberculosis_Unit,_Republican_Klaip˙_eda_Hospital,_Klaip˙_eda,_Lithuania q_TB_Reference_Centre,_Villa_Marelli_Institute,_Niguarda_Hospital,_Milan,_Italy

r_Division_of_Infectious_Diseases,_Department_of_Medicine,_Solna,_Karolinska_Institute,_Department_of_Infectious_Diseases,

KarolinskaUniversityHospital,Stockholm,Sweden

s_Pulmonology_and_{Physiotherapy}_Department,_Gabrovo_Lung_Diseases_Hospital,_Gabrovo,_Bulgaria t_Damien_Foundation,_Niamey,_Niger

u_Nepal_Anti_Tuberculosis_Association,_Morang_Branch,_TB_Clinic,_Biratnagar,_Province_1,_Nepal v_Department_of_Respiratory_Medicine,_P.D._Hinduja_National_Hospital_and_MRC,_Mumbai,_India w_Pulmonology_Division,_Municipal_Hospital_F._J._Mu˜_niz,_Buenos_Aires,_Argentina

x_Clínica_de_{Tuberculosis,}_Instituto_Nacional_De_Enfermedades_{Respiratorias}_Ismael_Cosio_Villegas,_Ciudad_De_Mexico,_Mexico y_Damien_Foundation,_Midpoint_District_Community_Memorial_Hospital,_Danda,_Nawalparasi,_Nepal

z_Respiratory_Infectious_Diseases_Unit,_National_Institute_for_Infectious_Diseases_‘L._{Spallanzani’,}_IRCCS,_Rome,_Italy A_National_Programme_for_Prevention,_Surveillance_and_Control_of_{Tuberculosis,}_Dolj_Province,_Romania

B_Department_of_Medical_Science,_Unit_of_Infectious_Diseases,_University_of_Torino,_Italy C_Department_of_{Tuberculosis,}_Sotiria_Athens_Hospital_of_Chest_Diseases,_Athens,_Greece D_Department_of_Infectious_Diseases,_Huashan_Hospital,_Fudan_University,_Shanghai,_China E_Radboud_University_Medical_Center,_Center_Dekkerswald,_Nijmegen,_The_Netherlands

F_Blizard_Institute,_Barts_and_The_London_School_of_Medicine_and_Dentistry,_Queen_Mary_University_of_London,_London,_United

Kingdom

G_Division_of_Pulmonary_Medicine,_University_Hospital_of_Lausanne_CHUV,_Lausanne,_Switzerland

H_Division_of_Infectious_Diseases,_CHU_{Saint-Pierre,}_Université_Libre_de_Bruxelles_(ULB),_Brussels,_Belgium

I_University_of_Groningen,_University_Medical_Center_Groningen,_Department_of_Pulmonary_Diseases_and_{Tuberculosis,}_Groningen,

TheNetherlands

J_University_of_Groningen,_University_Medical_Center_Groningen,_TB_Center_Beatrixoord,_Haren,_The_Netherlands K_Unidad_de_Enfermedades_Infecciosas,_Hospital_General_{Universitario}_Reina_Soﬁa,_Murcia,_Spain

L_Infectious_and_Tropical_Diseases_Operating_Unit,_S._Bortolo_Hospital,_Vicenza,_Italy

M_Clinic_of_Infectious_and_Tropical_Diseases,_WHO_{Collaborating}_Centre_for_TB_Elimination_and_TB/HIV_{Co-infection,}_University_of

Brescia,Brescia,Italy

N_MDR-TB_Department,_Abu_Anga_Teaching_Hospital,_Khartoum,_Sudan O_Internal_Medicine_Department,_Hospital_Doctor_Moliner,_Valencia,_Spain

P_Internal_Medicine_Department,_Hospital_General_de_Villalba,_Collado_Villalba,_Spain Q_Unidad_de_Neumología,_Agencia_Sanitaria_Costa_del_Sol,_Marbella,_Spain

R_National_Reference_Centre_for_MDR-TB,_Hospital_Centre_Vila_Nova_de_Gaia,_Department_of_Pneumology,_Public_Health_Science

andMedicalEducationDepartment,FacultyofMedicine,UniversityofPorto,Porto,Portugal

S_Division_of_Disease_Prevention_and_Control,_Department_of_Communicable_Diseases,_National_Tuberculosis_Control_and

EliminationProgramme,MinistryofHealth,Santiago,Chile

T_National_Institute_of_Respiratory_and_{Environmental}_{Diseases ¨}_Prof._Dr._Juan_Max_Boettner¨_Asunción,_Paraguay U_Universidad_Autónoma_de_Baja_California,_Baja_California,_Mexico

V_Clínica_de_Tuberculosis_del_Hospital_General_de_Tijuana,_Tijuana,_Baja_California,_Mexico

W_Internal_Medicine_Department,_Hospital_de_Cantoblanco-_Hospital_General_{Universitario}_La_Paz,_Madrid,_Spain

X_Pneumology_Department,_Tuberculosis_Unit,_Hospital_de_Cantoblanco-_Hospital_General_{Universitario}_La_Paz,_Madrid,_Spain Y_Centro_de_{Investigación,}_Prevención_y_Tratamiento_de_Infecciones_{Respiratorias}_CIPTIR,_University_Hospital_of_Monterrey_UANL

(UniversidadAutonomadeNuevoLeon),Monterrey,Mexico

Z_National_Institute_for_TB,_Lung_Diseases_and_Thoracic_Surgery,_Vysne_Hagy,_Catholic_University_Ruzomberok,_Slovakia aa_Infectious_Diseases_Unit,_IRCCS_Azienda_{Ospedaliero-Universitaria}_di_Bologna,_Policlinico_di_{Sant’Orsola,}_Bologna,_Italy bb_Department_of_Medical_and_Surgical_Sciences_Alma_Mater_Studiorum_University_of_Bologna,_Bologna,_Italy

cc_Reference_Center_for_MDR-TB_and_HIV-TB,_Eugenio_Morelli_Hospital,_Sondalo,_Italy dd_Zhejiang_Integrated_Traditional_and_Western_Medicine_Hospital,_Hangzhou,_China ee_National_TB_Registry,_Public_Health_Department,_Ministry_of_Health,_Vilnius,_Lithuania ff_Vilnius_University_Hospital_Santaros_Klinikos,_Vilnius,_Lithuania

gg_Centro_de_Excelencia_de_TBMDR,_Hospital_Nacional_Maria_Auxiliadora,_Lima,_Peru hh_Baylor_College_of_Medicine,_Children’s_Foundation,_Mbabane,_Eswatini

ii_National_{Pharmacovigilance}_Center,_Eswatini_Ministry_of_Health,_Matsapha,_Eswatini jj_Improve_the_{Sustainability}_of_the_National_TB_Programme,_Soﬁa,_Bulgaria

(4)

Pulmonologyxxx(xxxx)xxx---xxx

kk_Department_of_Public_Health_Analysis_and_Data_Management,_Public_Health_Agency_of_Sweden,_Solna,_Sweden ll_Eswatini_National_Aids_Programme,_Mbabane,_Eswatini

mm_Hospital_of_{Pneumophtisiology}_Leamna,_Dolj_Province,_Romania nn_University_of_Medicine_and_Pharmacy,_Craiova,_Romania

oo_Respiratory_Infectious_Diseases_Unit,_Cotugno_Hospital,_A.O.R.N._dei_Colli,_Naples,_Italy pp_University_of_Sydney,_Faculty_of_Medicine_and_Health,_School_of_Pharmacy,_Sydney,_Australia qq_Westmead_Hospital,_Sydney,_Australia

rr_Marie_Bashir_Institute_of_Infectious_Diseases_and_Biosecurity,_University_of_Sydney,_Sydney,_Australia

ss_Pneumology_Department,_Hospital_General_de_Gran_Canaria_‘‘Dr._{Negrin’’,}_Las_Palmas_de_Gran_Canaria,_Spain tt_Vital_Strategies,_New_York,_USA

uu_Tuberculosis_Research_Programme_(PII-TB),_SEPAR,_Barcelona,_Spain

vv_Pediatric_Clinic,_Pietro_Barilla_Children’s_Hospital,_University_of_Parma,_Parma,_Italy

ww_Clinical_Epidemiology_and_Medical_Statistics_Unit,_Department_of_z,_University_of_Sassari,_Sassari,_Italy xx_Division_of_Pulmonary_{Rehabilitation,}_Istituti_Clinici_Scientiﬁci_Maugeri,_IRCCS,_Tradate,_Italy

yy_Department_of_Medicine_and_Surgery,_Respiratory_Diseases,_University_of_Insubria,_Tradate,_Varese-Como,_Italy zz_Department_of_Infection,_Royal_London_and_Newham_Hospitals,_Barts_Health_NHS_Trust,_London,_United_Kingdom AA_Department_of_Infectious_Diseases,_Galliera_Hospital,_Genova,_Italy

BB_Servizio_di_{Epidemiologia}_Clinica_delle_Malattie_{Respiratorie,}_Istituti_Clinici_Scientiﬁci_Maugeri_IRCCS,_Tradate,_Italy CC_Public_Health_Consulting_Group,_Lugano,_Switzerland

DD_World_Health_Organization_Regional_ofﬁce_for_Europe,_Copenhagen,_Denmark

Received15February2021;accepted15February2021

KEYWORDS Tuberculosis; MDR-TB; Delamanid; Bedaquiline; Treatmentoutcomes; PreventionofTB sequelae

Abstract TheWorldHealthOrganization(WHO)recommendscountriesintroducenewanti-TB drugsinthetreatmentofmultidrug-resistanttuberculosis.

Theaimofthestudyistoprospectivelyevaluatetheeffectiveness ofbedaquiline(and/or delamanid)-containingregimensinalargecohortofconsecutiveTBpatientstreatedglobally. This observational, prospectivestudy isbased on data collected andprovided by Global TuberculosisNetwork(GTN)centresandanalysedtwiceayear.

All consecutivepatients (including children/adolescents)treatedwith bedaquilineand/or delamanidwereenrolled,andmanagedaccordingtoWHOandnationalguidelines.

Overall, 52centresfrom29countries/regionsinallcontinentsreported883patientsasof January31st2021,24/29countries/regionsprovidingdataon100%oftheirconsecutivepatients (10---80%intheremaining5countries).

Thedrug-resistancepatternofthepatientswassevere(>30%withextensivelydrug-resistant -TB;mediannumberofresistantdrugs5(3−7)intheoverallcohortand6(4−8)amongpatients withaﬁnaloutcome).

Forthepatientswithafinaloutcome(477/883,54.0%)themedian(IQR)numberofmonthsof anti-TBtreatmentwas18(13₋₂₃₎(indays553(385---678)).Theproportionofpatientsachieving sputumsmearandcultureconversionrangedfrom93.4%and92.8%respectively(wholecohort) to89.3%and88.8%respectively(patientswithafinaloutcome),amedian(IQR)timetosputum smearandcultureconversionof58 (30−90)daysforthe wholecohortand60 (30−100)for patientswithafinaloutcomeand,respectively,of55(30−90)and60(30−90)daysforculture conversion.

Of383patientstreatedwithbedaquilinebutnotdelamanid,284(74.2%)achievedtreatment success,while25(6.5%)died,11(2.9%)failedand63(16.5%)werelosttofollow-up.

Introduction

The World Health Organization (WHO) estimated that about halfmillionpeoplesufferfrommultidrug-(MDR-) or rifampicin-resistant(RR-)tuberculosis(TB)in2019,ofwhom

38%accessed treatment and,amongthem,57% were suc-cessfullytreated.1,2

Effective treatment, coupled with rapid and accurate diagnosis,ofbothdrug-susceptibleand-resistant(MDR-and extensively drug-resistant, XDR-) TB cases is an essential

(5)

ARTICLE IN PRESS

+Model

PULMOE-1605; No.ofPages10

S.Koirala,S.Borisov,E.Danilaetal. intervention tocurbtheTB epidemic andpreventfurther

development and transmission of drug-resistant Mycobac-teriumtuberculosisstrains.3,4

Newdrugs(i.e.,delamanidandbedaquiline)have been recently licensed to manage MDR- and XDR-TB2_; _they were included into a new WHO drug classiﬁcation where bedaquiline belongs to Group A and delamanid to Group C.5---18

Although more evidence is becoming available from experimentalandobservationalstudiesontheefﬁcacyand effectivenessofnewdrugs,19---23 _programmatic_information ontheireffectivenessisstillincompleteworldwide.1

TheGlobalTuberculosisNetwork(GTN)project,24 _which recentlyreportedonthesafetyofthesedrugs,allowedto shedfurtherlightontheeffectivenessofthesedrugs ina largecohortofpatients(Table1,Fig.1).24---26

The aim of the study is to prospectively evaluate the effectivenessofbedaquilineand/ordelamanid-containing regimensinacohortofconsecutiveTBpatientstreated glob-ally.

Methods

Studydesign

The study is observational, prospective and based onthe collectiontwiceayearandanalysisofdataprovidedbyGTN centres.

Followingapilotstudyimplementedin2015topre-test theproject’sfeasibility,theresultsoftheproject (manage-mentofadverseevents)waspublishedelsewhere.25,26

ThestudywasapprovedbytheEthicsCommitteeofthe coordinatingcentre,andtheparticipatingcentresobtained ethical clearancebased onlocal regulationsand signed a data-sharingagreement.25,26

Allconsecutivepatients(includingchildren and adoles-cents) treated with bedaquiline and/or delamanid were enrolledeitherfromthebeginningofthestudyorfromthe timethedrugsunderstudywereintroducedinthe respec-tivecountrycentre(e.g.inMexico,Nepal,Paraguay,Spain, SlovakiaandSudan).25,26

Inallparticipatingcountries,thepatientsweremanaged according toWHO andNational guidelines,under supervi-sionofacoordinatingteamsupervisingthepatients’clinical management and validation of data.27 _{Investigators} _were contacted by the coordinating centre toensure accuracy after recoding and validation of the dataset before ﬁnal analysis was conducted. Discrepancies were resolved by consensus.

WHO case and treatment outcome deﬁnitions were used.1,5,6,28,29

Thepresentmanuscriptreportstheresultsoftheinterim analysis conducted on the data collected up to the 31st January2021.

Variables

collected

Thedatawerecollectedviaanadhocdevelopedcollection forminelectronicformat.25,26

Theinformationcollected(fromtheclinicalﬁlesofthe participatingcentres)included,amongothers,anonymized

Table1 Participating countries,estimatedcoverage and numberofcasesenrolled.

Countries Estimated coveragea_% Cases enrolledN Argentina 100 11 Australiac ₁₀₀e ₂₆ Belarusb ₈₀ ₅₃ Belgium 60 3 Brazil 100 39 Bulgaria 100 17 Chile 100 1 Chinac ₁₀₀d ₅ Eswatini 100 41 Greece 100 6 India 100e ₁₅ Italyg ₈₀ ₄₀ Latvia 100 30 Lithuaniah ₁₀₀ ₁₆₀ Mexicoi ₁₀₀ ₁₁ Nepalh ₁₀₀ ₁₂₅ Netherlandsb ₁₀₀ ₆ Niger 100 17 Paraguay 100 1 Peru 80 29 Portugal 100 1 Romaniac ₁₀₀f ₇ RussianFederationb ₁₀₀j ₂₀₂ Slovakia 100 1 Spaing ₁₀₀ ₈ Sudan 100 2 Sweden 100 19 Switzerland 100d ₃ UnitedKingdom 10 4

Total29 Range10%---100% Total883 Legend:

a_Countries’ _estimate _of_the_national_coverage _of_the _aDSM

projectonnewdrugs;

b₂_centres; c ₁_centre;

d_in_the_{Province/Canton}_reporting; e_in_the_State_reporting;

f _in_the_Province_reporting; g₇_centres;

h₅_centres; i₃_centres;

j _in_the₂_Oblasts_reporting.

patient’s demographic data, bacteriological, radiological andclinicalstatusatdiagnosis,anddetailson bacteriologi-calconversionandﬁnaltreatmentoutcomes.

Thestudycoverageandnumberofpatientstreatedper centrearereportedinTable1.

Dataanalysis

Adescriptiveanalysiswasperformedtoevaluatethe char-acteristicsofthecohort.

Qualitativeandquantitativevariablesweresummarised usingabsoluteandrelative(percentage)frequencies, medi-answithinterquartileranges(IQR),andmeanswithstandard 4

(6)

Pulmonologyxxx(xxxx)xxx---xxx

Figure1 Globaldistributionoftheclinicalcentresparticipatinginthestudy.

ThefollowingStates/Regionsarecoveredinthestudy:Australia(StateofVictoria);China(ZhejiangProvince);Romania(Dolj Region);RussianFederation(Arkhangelsk,MoscowOblasts).

deviations (SD). Sputumsmear and culture conversion (as well as the timetosputum and culture conversion) were evaluatedinthewholecohortandinthosecompletingtheir prescribedregimen.

Treatmentoutcomeswereevaluatedonlyinpatientswho completedtheprescribedtreatmentregimen(separatelyfor theentirecohortandinpatientstreatedwithbedaquiline butnotdelamanid)tofavourinternationalcomparisons.

Results

Overall, 52centresfrom29countries/regionsin all conti-nentsreported883patientsasofJanuary31st2021(Fig.1). Argentina,Australia(StateofVictoria),Brazil,Bulgaria, Chile, Eswatini,China (ZhejiangProvince), Greece, India, Latvia, Lithuania, Mexico, Nepal, The Netherlands, Niger, Paraguay, Portugal, Romania, Russian Federation (Moscow and ArkhangelskOblasts), Slovakia,Spain, Sudan,Sweden andSwitzerland(Vaudcounty)reported100%ofthepatients treatedwithnewdrugsinthecountry/region,whileBelarus, Belgium, Italy, Peru and the United Kingdom reported a proportion of national patients ranging from 10% to 80% (Table1).

Demographic, epidemiological, and clinical character-istics of the patients are summarised in Table 2. The bacteriological conversion rates and the time to sputum smearandcultureconversionarereportedinTable3 sepa-ratelyfortheentirecohortandforthepatientscompleting their prescribed treatment regimen. The ﬁnal treatment outcomes of the entire cohort (477/883, 54.0%) are sum-marized inTable4,whileTable5isreportingthepatients treated with bedaquiline only who have a ﬁnal outcome assigned.

Overall, 883 patients were treated with bedaquiline and/or delamanid, 477 of them with a ﬁnal outcome assigned(Table2).

Most patients were male(n=602, 68.2% in the overall cohortandn=333,69.8%withaﬁnaloutcomeassigned)and themedian (IQR)age was38(28---49) yearsfor theentire cohortand(30---50)yearsforthosewithaﬁnaloutcome.

The proportionof foreign born was13.4% in the over-all cohortand 12.8% inthe group of patients withaﬁnal outcome.Themainco-morbiditiesandriskfactorsare sum-marizedinTable2.

PulmonaryTBwasdiagnosedin97%patients,andcavity lesionswerefoundinover60%ofthepatients’radiographs. Overall,therewere575/883(65%)patientswithMDR/RR-TB intheoverallcohort,ofwhom300/477(62.9%)withaﬁnal outcome.AmongthemtheXDR-TBcaseswere,respectively 289/883(32.7%)and169/477(35.4%).Otherresistance pat-ternswerepresentonlyin19/883(2.2%)and8/477(1.7%), respectively.

The median(IQR)numberofdrugsfor whichresistance wasdetectedwas5(3−7)intheoverallcohortand6(4−8) amongpatientswithaﬁnaloutcome.

Bedaquiline was administered to 782/883 patients in the entire cohort (88.6%), of whom416/477 (87.2%) with a ﬁnal outcome. The patients undergoing treatment with delamanidwere,respectively167/883(18.9%)and94/477 (19.7%), some of them having been treated also with bedaquiline.

Themedian(IQR)numberofmonthsofanti-TBtreatment was18(13−23)(indays553(385---678))amongpatientswith aﬁnaloutcome.

Bedaquilinewasprescribedfor180(168−264)daysinthe wholecohortand183(168---364)amongpatientswithaﬁnal outcome.Delamanidwasprescribedfor168(144−184)days

(7)

ARTICLE IN PRESS

+Model

S.Koirala,S.Borisov,E.Danilaetal.

Table2 Characteristicsof883patientsundergoingtreatmentwithbedaquilineanddelamanidinthecohort,including477 whocompletedtheprescribedregimen.

Variable Allpatients(n=883) Patientswithﬁnaloutcome(N=477)

Male,n(%) 602/883(68.2) 333/477(69.8)

Median(IQR)age,years 38(28₋₄₉₎ 39(30₋₅₀₎

Foreignbornn(%) 118/882(13.4) 61/477(12.8)

DiabetesMellitus,n(%) 79/880(9.0) 40/476(8.4)

PeoplelivingwithHIV,n(%) 67/871(7.7) 27/473(5.7)

Thyroiddisease,n(%) 25/795(3.1) 17/399(4.3)

Alcoholmisuse,n(%) 186/879(21.2) 112/475(23.6)

Injectingdrugusern(%) 48/880(5.5) 30/475(6.3)

Methadoneuser,n(%) 10/787(1.3) 4/395(1.0)

Previousanti-TBtreatment,n(%) 544/880(61.8) 329/474(69.4)

Surgicaltherapy,n(%) 90/814(11.1) 59/449(13.1) PulmonaryTB,n(%) 857/883(97.1) 463/477(97.1) Extra-pulmonaryTB,n(%) 72/882(8.2) 39/476(8.2) Cavitarylesions,n(%) 523/831(62.9) 295/448(65.8) MDR/RR-TB,n(%) 575/883(65.1) 300/477(62.9) XDR-TB,n(%) 289/883(32.7) 169/477(35.4)

Otherdrug-resistancepatterns,n*(%) 19/883(2.2) 8/477(1.7) Median(IQR)numberofreporteddrug-resistances 5(3₋₇₎ 6(4₋₈₎

Bdqadministration,n(%) 782/883(88.6) 416/477(87.2)

Dlmadministration,n(%) 167/883(18.9) 94/477(19.7)

Median(IQR)monthsanti-TBtreatmentduration --- 18(13−23) Median(IQR)daysBdqadministration 180(168−264) 183(168−363,5) Median(IQR)daysDlmadministration 168(144₋₁₈₄₎ 168(136₋₁₈₆₎

TB:tuberculosis;IQR:interquartilerange;Bdq: bedaquiline;Dlm:delamanid;MDR/RR-TB:multi-drugresistant/rifampicin-resistant tuberculosis;XDR-TB:extensivelydrug-resistanttuberculosis.

* _Including₃_susceptible_cases_treated_with_second-line_drugs_due_to_AEs_ﬁrst-line_drugs.

Table3 Sputumsmearandcultureconversionandmediantimetobacteriologicalconversionin883patientstreatedwithnew anti-tuberculosisdrugs.

Variable Allpatients(n=883) Patientswithﬁnaloutcome(N=477)

Sputumsmearconversion,n(%) 467/500(93.4) 274/307(89.3) Sputumcultureconversion,n(%) 532/573(92.8) 324/365(88.8) Median(IQR)dayssputumsmearconversion 58(30−90) 60(30−100) Median(IQR)dayssputumcultureconversion 55(30−90) 60(30−90)

IQR:interquartilerange.

intheentirecohortand168(136−186)daystopatientswith aﬁnaloutcome.

The proportion of patients achieving sputum smear conversionwas93.4%inthewholecohortand89.3%among thepatientswithaﬁnaloutcome,withamedian(IQR)time tosputumsmearandcultureconversionof58(30−90)days forthewholecohortand60(30−100)forpatientswithaﬁnal outcome and,respectively, of 55 (30−90)and60(30−90) daysasfarascultureconversionisconcerned(Table3).

The ﬁnal treatment outcomes of the entire cohort (477/883, 54.0%) are summarized in Table 4; 344/477 patients(72.1%)achievedtreatmentsuccess,38died(8%), 20failed(4.2%)and75(15.7%)werelosttofollow-up.

Amongthe383patientstreatedwithbedaquilinebutnot delamanid,284(74.2%)achievedtreatmentsuccess, while 25(6.5%)died,11(2.9%)failedand63(16.5%)werelostto follow-up(Table5).

Discussion

Theaimofthepresentstudywastoprospectivelyevaluate theoutcomeofaglobalcohortofpatientstreatedwithnew anti-TBdrugs.

Although new research results (some summarized in a specialbedaquilineseriesoftheIJTLD)19---23,30---35_have_been recentlypublished,tothebestofourknowledgethisisthe ﬁrstglobal studyprospectivelyreportingdetailed informa-tionontreatmentoutcomes;thereportofthesafetyproﬁle ofthenewdrugswaspublishedelsewhere.25,26

The results of our study show that ∼90% of patients from29countriesinallcontinents,withaseverepatternof drugresistance(>30%withXDR-TB;mediannumberof resis-tances:5---6)achievedsputumsmearandcultureconversion within60daysoftreatmentwithnewanti-TBdrugs.The suc-cessratesachievedwere72.1%inthefullcohort(patients 6

(8)

Pulmonologyxxx(xxxx)xxx---xxx Table 4 Treatment outcomes of the 477 patients who

completed the prescribed regimen including new anti-tuberculosisdrugs.

TreatmentOutcome n/N(%)

Treatmentsuccess(cured+treatment completed) 344/477(72.1) Cured 281/477(58.9) Treatmentcompleted 63/477(13.2) Died 38/477(8.0) Failure 20/477(4.2) Losttofollow-up 75/477(15.7)

Table5 Treatmentoutcomesofthe383patientstreated withbedaquiline(butnodelamanid)whocompletedthe pre-scribedregimen.

Treatmentoutcome n/N(%)

Treatmentsuccess(cured+treatment completed) 284/383(74.2) Cured 226/383(59.0) Treatmentcompleted 58/383(15.1) Died 25/383(6.5) Failure 11/383(2.9) Losttofollow-up 63/383(16.5)

with aﬁnal outcome) and 74.2% amongthe patients (the vast majority) treatedwith bedaquiline. This second out-comeisparticularlyrelevantforinternationalcomparisons. Importantly,inthisspeciﬁcgroupofpatientsthedeathrate was 6.5%, the failurerate 2.9% and the lostto follow-up rate 16.5%; these outcomes need to be read considering that this cohort has been programmatically managed in manydifferentsettings,witharelativelylowprevalenceof HIV infection (5.7%).In aprevious study by theGTN with different patients treated with bedaquiline,9 _the _culture conversion rate was similar(90%) and theoverall success rate76.9%

The study stratified the success rates by geographical area,showingthatinaustralAfrica(wheretheHIV preva-lenceishigher)itwaslower(64.6%)thaninNiger(76.5%) whereHIVprevalenceislow,Europe(76.5%)andelsewhere (77.6%).SpecificallyinXDR-TBpatients,thesuccessratewas 77.6%inAfrica,80.4%inEuropeand77.7%elsewhere;these peculiar results, with treatment outcomes higher among XDR- thanMDR-TBpatients,have beencaused bythefact that the XDR-TB patients had access to better drugs in the regimen (e.g. linezolid, clofazimine) which were not available in all countries(at the timethe study was con-ducted) for MDR-TB patients. The WHO hasfrom January 2021 updated its DR-TB definitions36 _to _include _the _term pre-XDR for patients with an MDR-TB strain resistant to latergenerationfluoroquinoloneandXDR-TBwhichis MDR-TBplusresistancetotwogroupAdrugs(fluoroquinoloneplus bedaquilineorlinezolidresistance).TheMDR-TBdefinition remainsthesame.28,36

Similarly, the death rate was much higher in Africa (23.9%)thaninEurope(3.5%)andelsewhere(6.1%).

Inasub-groupanalysisofthe57severepatients undergo-ingadjuvantsurgery,thecultureconversionratewassimilar (90%)andtheoverallsuccessrate69.1%.37

ASouthAfricanstudyon19,617patientsshoweda3-fold reductionofall-causemortalityamongindividualstreated withbedaquilinewhencomparedwiththosetreatedwithout newdrugs.38

In the large individual patient data meta-analysis on 12,030MDR-TBpatients18_a_small_proportion_of_patients_was treatedwithbedaquiline: 431/491(87.8%)achieved treat-mentsuccess(aOR,95%CI:2.0,1.4---2.9)and59/550(10.7%) died(aOR,95%CI:0.4,0.3−0.5).

The preliminary results of the Challenge-TB Project30 reported, among bedaquiline-treated patients, a culture conversionof71% atmonths6,with58.8%treatment suc-cess,11.8%failure,23.5%died,4.7%losttofollow-upand 1.2%stillontreatmentafter24months(2016cohortdata). Thepatients’drugresistanceprofilewasnotreported.30_The project involved 23 countrieswith 9389 patients enrolled between 2016 and mid-2019. Among the most relevant problems encountered, the Authors identified the limited in-countrycoordinationandtheabsenceofarobustclinical andlaboratorynetworkandthedifficultiesofimplementing effectivemonitoring ofadverseevents relatedtothenew drugs.25,26

AreportfromIndia(interimanalysis)showed83%culture conversionrateamongthepatientstreatedwithbedaquiline withinamediantimeof60days,whiletheﬁnaloutcomes werenotyetavailable.33

InEswatini,between2015and2018,355patientsstarted treatmentwithnewdrugs(bedaquilineand/ordelamanid), ofwhom109weretreatedwithbedaquilineonlyandwith ﬁnaloutcomes.35_Out_of₁₀₉_patients,₈₀_were_treated suc-cessfully(73.4%,aresultconsistentwiththatofourstudy), 18died(16.5%,higherthanourdeathratebuttheHIV preva-lencewashigherinEswatini,72.3%),1failed,1waslostto follow-up (both 0.9%) and 9 were stillin treatment after 24months(8.3%).IntheEswatinicohorttheproportionof males(58−7%),themedian(IQR)age(35(29---44)years)and the proportion of pre-XDR-/XDR-TB patients (26−1%) was consistentwithourstudy.

Although without reporting details on treatment out-comessomestudieshavestartedreportingonthemodiﬁed shorterregimens,whichincludebedaquilineroreplacethe injectabledrugintheformerBangladeshregimen.20,31,34

The projectworked asa ‘register’reportingtreatment outcomes (and aDSM ﬁndings)25,26 _twice _a _year _so _as _to supportcountries in implementingquality monitoring and evaluationoftheprocessofintroducingnewanti-TBdrugs underprogrammaticconditions.

The study has several strengths, including the number ofcountriesparticipating(29)fromallcontinents,alarge sample size(as far we know oneof thelargest studiesof itskind), theprospectivedesign, andtheaccuracy of the informationcollected. Lastbut notleast, themajority of countries/states/regions (24/29) provideddata on all the consecutive patients treated with bedaquiline and dela-manidduringthestudyperiod.

Onelimitation (commontoall thestudiesof thiskind) istheimpossibilityofattributingtheoutcomestoaspeciﬁc drug,astreatmentregimens areinherently polypharmaco-logical.

(9)

ARTICLE IN PRESS

+Model

S.Koirala,S.Borisov,E.Danilaetal. A second limitation is that few paediatric patients

(twenty-sevenindividualsagedlessthan18years)and peo-plelivingwithHIV(n=67;7.7%)wereincludedinthecohort toallowspeciﬁcsub-analyses.

Thestudywillcontinuetoevaluateearlyandﬁnal treat-mentoutcomesasperiodicupdatesoccurandthe‘cohort’ is therefore a ‘living’ one. This cohort allows evaluation ofnovel treatmentsandcombinationsinarelativelyshort time-frame ---particularly important given thesubstantial variation in international practice and guidelines recom-mendingperson-centeredtherapyforMDR-TB.4,5,39---41

This approachwill allow the participating countriesto evaluatethe‘quality’oftheirtreatmentservicesand min-imise the risk of post-treatment sequelae responsible of functionaldamageandimpairedqualityoflife.42---48

Inconclusion,ourGlobalTBNetworkstudyfurther sup-portsthe importanceofaccesstolifesavinganti-TB drugs likebedaquilinetoimproveoutcomeofdrug-resistant(DR) TB patients. Bedaquiline has allowed for an all-oral, less toxicshorterregimenwhichsigniﬁcantlyimprovessurvival, anditisbecomingmorewidelyavailableglobally.49_Future cohortreviewswillshowareductionoftreatmentduration from18monthsto6 months.This globalstudyshows that evenwhenthereisaccesstothesameWHODRTBregimen, outcomescan stilldiffergreatly,highlighting that manag-ingMDR-/DR-TBis notonlyaquestion ofbetterdetection ofDR-TBandstartingtreatment.EventhoughtheWHOhas shortenedtreatmentconsiderablyforthemajorityofDR-TB patients,itisverylikelythatmoreworkandinvestmentare required,especiallyinresourcelimitedsettingsand treat-mentofpeoplelivingwithHIVandtocombatthesmallbut concerningnumberofXDR-TBpatients.

Authors’contribution

The manuscript was conceived, planned, written, edited andapprovedusingacollaborativeapproach,followingthe internal GTN (Global Tuberculosis Network) and interna-tionallyacknowledgedrulesonAuthorship,basedonmajor intellectualcontributiontothestepsmentionedabove.The studyrepresentsaglobaleffortinvolving26countriesinall continents.

Giovanni Sotgiu, Simon Tiberi, Rosella Centis, Lia D’AmbrosioandGiovanniBattistaMiglioriwrotethe proto-col.GiovanniSotgiu,LauraSaderiandRaquelDuarterevised itforthemethodologicalcontent.

Giovanni Sotgiu, Laura Saderi, Rosella Centis and Lia D’Ambrosioperformedtheanalysis.

SimonTiberi,RosellaCentis,LiaD’Ambrosio,Emanuele Pontali,Jan-Willem Alffenaar,Jose A.Caminero, Giovanni SotgiuandGiovanniBattistaMiglioriwrotetheﬁrstdraftof themanuscript.

SushilKoirala,SergeyBorisov,JudithBruchfeld,Alberto Piubello, Onno Akkermann, Justin Denholm, José-María García-García, Rafael Laniado-Laborín, Jesica Mazza-Stalder, Alberto Matteelli, Marcela Munoz-Torrico, Martin vandenBoom,DinaVisca,JoseA.Caminero,GiovanniSotgiu wrotethesectionsofthemanuscript(seconddraft).

Antonio Spanevello, José-María, García-García Zarir Farokh Udwadia, Edvardas Danila, Andrei Maryandyshev,

Susanna Esposito and Margareth Dalcolmo provided com-mentstotheseconddraft(thirddraft).

Bhabana Shrestha, Satya Raj Shakya, Hikmat Bahadur Khadka, Ghan Shyam Koirala, Rajesh GC, Skaidrius Mili-auskas,Liga Kuksa,Selene Manga,AlenaSkrahina,Saulius Diktanas,LuigiRuffoCodecasa,AlenaAleksa,Antoniya Kol-eva, Evgeny Belilovski, Enrique Bernal, Martin J Boeree, JulenCadi˜nanosLoidi,QingshanCai,Jose JoaquínCebrian Gallardo,Moschos Charalampos,Edita Davidaviˇcien˙e, Lina DaviesForsman,JorgeDeLosRios Jefe,AlemayehuDuga, Seifeldin Eltaeb Elamin, Nadia Escobar Salinas, Maurizio Ferrarese, Aleksey Filippov, Blagovesta Gadzheva, Ana Garcia, Ieva Gaudiesiute, Regina Gayoso, Roscio Gomez Rosso, Vygantas Gruslys, Gina Gualano, Wouter Hoefs-loot, Victor Ionel Grecu, Jerker Jonsson, Elena Khimova, HeinkeKunst,YangLi,NomthandazoLukhele,Cecile Magis-Escurra, Gugulethu Madonsela, Vinicio Manfrin, Valentina Marchese,ElenaMartínezRobles,AndreiMaryandyshev, Mar-ius Matei, Ilaria Motta, Hamdan Mustafa Hamdan, Birut˙e Nakˇcerien˙e,LaurenNicod,MagnoliaNietoMarcos,Domingo Juan Palmero, Fabrizio Palmieri, Apostolos Papavasileiou, Marie-Christine Payen, Agostina Pontarelli, Sarai Quirós, Adrian Rendon, LauraSaderi, Agnese ˇSmite, Ivan Solovic, Mahamadou Bassirou Souleymane, Marina Tadolini, Marisa Vescovo,PieroViggiani,RolandasZablockis,DmitryZhurkin andprovidedadditionstothefourthdraft.

Simon Tiberi and Justin Denholm proof read the manuscript.

Allco-Authorsapprovedtheﬁnalmanuscript.

Funding

sources

Thisresearchdidnotreceiveanyspeciﬁcgrantfromfunding agenciesinthepublic,commercial,ornot-for-proﬁtsectors.

Ethical

approval

Ethical approval wasobtained by the coordinating centre andineachcountryaspernationalregulationsinforce.

Conﬂicts

of

interest

Theauthorshavenoconﬂictsofinteresttodeclare.

Acknowledgements

The project is supported by the Global Tuberculosis Net-work(GTN;CommitteesonTBTreatment,Clinicaltrialsand GlobalTB Consilium)andwaspartof theEuropean Respi-ratorySocietyLatinAmericanprojectincollaborationwith ALAT(AsociaciónLatinoAmericanadeTorax-Latino Amer-ican Thoracic Association) and SBPT (Brazilian Society of PulmonologyandTuberculosis).

ThisarticlebelongstothescientiﬁcactivitiesoftheWHO Collaborating Centre for Tuberculosis and Lung Diseases, Tradate,ITA-80,2017-2020-GBM/RC/LDA.

The Authors wish to thank Dr. Algirdas Gauronskis, Dr.Vita Globyt˙e (Clinic of Tuberculosis and Pulmonology, Republican ˇSiauliai county hospital, ˇSiauliai, Lithuania), Dr. Antanas Strazdas (Department of Tuberculosis, Alytus 8

(10)

Pulmonologyxxx(xxxx)xxx---xxx County Tuberculosis Hospital,Alytus,Lithuania), Dr.Paola

Castellotti (Regional TB Reference Centre, Villa Marelli Institute, Niguarda Hospital, Milan, Italy), Ms. Samriddhi Karki(KalimatiChestHospital/ GENETUPNATA,Nepal), Dr Andrea Calcagno, AlbertoGaviraghiandFrancesca Alladio (DepartmentofMedicalScience,UnitofInfectiousDiseases, UniversityofTorino,Italy)fortheircontribution.

References

1.World Health Organization. Global tuberculosis report 2020. Geneva: World Health Organization; 2020. Licence: CC BY-NC-SA 3.0 IGO. Available at: https://apps. who.int/iris/bitstream/handle/10665/336069/9789240013131 -eng.pdfAccessed9December2020.

2.PontaliE,RaviglioneMC,MiglioriGB,Thewritinggroup mem-bersoftheGlobalTBNetworkClinicalTrialsCommittee. Reg-imenstotreatmultidrug-resistanttuberculosis:past,present andfutureperspectives.EurRespirRev.2019;28(152):190035,

http://dx.doi.org/10.1183/16000617.0035-2019.

3.Migliori GB, Nardell E, Yedilbayev A, D’Ambrosio L, Cen-tis R, TadoliniM, et al. Reducing tuberculosis transmission: a consensus document from the World Health Organization RegionalOfﬁcefor Europe.EurRespirJ.2019;53(6):1900391,

http://dx.doi.org/10.1183/13993003.00391-2019.

4.MiglioriGB,TiberiS,ZumlaA,PetersenE,ChakayaJM,WejseC, etal.MDR/XDR-TBmanagementofpatientsandcontacts: Chal-lengesfacingthenewdecade.The2020clinicalupdatebythe GlobalTuberculosisNetwork.IntJInfectDis.2020;92S:S15---25,

http://dx.doi.org/10.1016/j.ijid.2020.01.042.

5.World Health Organization. WHO consolidated guidelines on tuberculosis.Module4:treatment-drug-resistanttuberculosis treatment.Geneva:WorldHealthOrganization;2020.Licence: CCBY-NC-SA3.0IGO.

6.Migliori GB, Global Tuberculosis Network (GTN). Evolu-tion of programmatic deﬁnitions used in tuberculosis pre-vention and care. Clin Infect Dis. 2019;68(10):1787---9,

http://dx.doi.org/10.1093/cid/ciy990.

7.Diacon AH, Pym A, Grobusch MP, de los Rios JM, Gotuzzo E, Vasilyeva I, et al. TMC207-C208 Study Group. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med. 2014;371(8):723---32,

http://dx.doi.org/10.1056/NEJMoa1313865.

8.Pym AS, DiaconAH, Tang SJ, ConradieF,Danilovits M, Chu-chottawornC,et al. TMC207-C209StudyGroup.Bedaquiline inthetreatmentofmultidrug-andextensivelydrug-resistant tuberculosis.EurRespirJ.2016;47(2):564---74.

9.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 multidrug and extensively drug-resistant tuberculosis: a multicentre study. Eur Respir J. 2017;49(5):1700387,

http://dx.doi.org/10.1183/13993003.00387-2017.

10.Pontali E, Sotgiu G, D’Ambrosio L, Centis R, Migliori GB. BedaquilineandMDR-TB:asystematicandcriticalanalysisof theevidence.EurRespirJ.2016;47:394---402.

11.Pontali E, D’Ambrosio L, Centis R, Sotgiu G, Migliori GB. Multidrug-resistance tuberculosis and beyond: an updated analysis of the current evidence on bedaquiline. Eur Respir J. 2017;49(3):1700146,

http://dx.doi.org/10.1183/13993003.00146-2017.

12.Mbuagbaw L, Guglielmetti L, Hewison C, Bakare N, Bas-tard M, Caumes E, et al. Outcomes of Bedaquiline Treatment in Patients with Multidrug-Resistant Tuberculosis. Emerg Infect Dis. 2019;25(5):936---43,

http://dx.doi.org/10.3201/eid2505.181823.

13.Chesov D, Heyckendorf J, Alexandru S, Donica A, Chesov E, Reiman M, et al. Impact of bedaquiline on treatment outcomes of multidrug-resistant tuber-culosis in a high-burden country. Eur Respir J. 2020,

http://dx.doi.org/10.1183/13993003.02544-2020. Dec 17:2002544.

14.Gler MT, Skripconoka V, Sanchez-Garavito E, Xiao H, Cabrera-Rivero JL, Vargas-Vasquez DE, et al. Delamanid for multidrug-resistant pulmonary tuber-culosis. N Engl J Med. 2012;366(23):2151---60,

15.Kim CT, Kim CTO, Shin HJ, Ko YC, Hun Choe Y, Kim HR, et al. Bedaquiline and delamanid for the treat-ment of multidrug-resistant tuberculosis:a multi-center cohort study in Korea. Eur Respir J. 2018;51(3):1702467,

http://dx.doi.org/10.1183/13993003.02467-2017.

16.Kuksa L, Barkane L, Hittel N, Gupta R. Final treatment outcomes of multidrug and extensively drug-resistant tuberculosis patients in Latvia receiving delamanid-containing regimens. Eur Respir J. 2017;50(5):1701105,

http://dx.doi.org/10.1183/13993003.01105-2017.

17.Mohr E, Hughes J, Reuter A, Trivino Duran L, Ferlazzo G, Daniels J, et al. Delamanid for rifampicin-resistant tuberculosis: a retrospective study from South Africa. Eur Respir J. 2018;51(6):1800017,

http://dx.doi.org/10.1183/13993003.00017-2018.

18.Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB treatment---2017, Ahmad N, Ahuja SD, Akkerman OW,Alffenaar JC, Anderson LF, et al. Treat-ment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis. Lancet. 2018;392(10150):821---34,

http://dx.doi.org/10.1016/S0140-6736(18)31644-1.

19.Bernal O, Lopez R, Montoro E, Avedillo P, Westby K, Ghidinelli M. Introduction and scaling up of new drugs for drug-resistant TB: experiences from the Amer-icas. Int J Tuberc Lung Dis. 2020;24(10):1058---62,

http://dx.doi.org/10.5588/ijtld.20.0111.

20.Cox H, Shah NS, Castro KG. Discovering a new drug is only the beginning: progress and challenges in expanding access to BDQfor MDR-TBtreatment.IntJTubercLung Dis. 2020;24(10):985---6,http://dx.doi.org/10.5588/ijtld.20.0562. 21.Rutta E, Kambili C, Mukadi Y. The Bedaquiline donation

program: progress and lessons learned after 4 years of implementation. IntJTubercLungDis.2020;24(10):1039---45,

22.Lachenal N, Hewison C, Mitnick C, Lomtadze N, Coutisson S, Osso E, et al. Setting up pharmacovig-ilance based on available endTB Project data for bedaquiline. Int J Tuberc Lung Dis. 2020;24(10):1087---94,

23.Seung KJ, Khan U, Varaine F, Ahmed S, Bastard M, Cloez S, et al. Introducing new and repurposed TB drugs: the endTBexperience.IntJTubercLungDis.2020;24(10):1081---6,

24.Silva DR, Rendon A, Alffenaar JW, Chakaya JM, Sotgiu G, Esposito S, et al. Global TB Network: working together to eliminate tuberculosis. J Bras Pneumol. 2018;44(5):347---9,

http://dx.doi.org/10.1590/S1806-37562018000000279. 25.Akkerman O, Aleksa A,Alffenaar JW,Al-Marzouqi NH,

Arias-GuillénM,BelilovskiE,etal.MembersoftheInternationalStudy Grouponnewanti-tuberculosisdrugsandadverseevents moni-toring.Surveillanceofadverseeventsinthetreatmentof drug-resistanttuberculosis:aglobalfeasibilitystudy.IntJInfectDis. 2019;83:72---6,http://dx.doi.org/10.1016/j.ijid.2019.03.036. 26.Borisov S, Danila E, Maryandyshev A, Dalcolmo M,

Mil-iauskas S, Kuksa L, et al. Surveillance of adverse events in the treatment of drug-resistant tuberculo-9

(11)

ARTICLE IN PRESS

+Model

S.Koirala,S.Borisov,E.Danilaetal. sis: ﬁrst global report. Eur Respir J. 2019;54(6):1901522,

http://dx.doi.org/10.1183/13993003.01522-2019.

27.Tiberi S, Pontali E, Tadolini M, D’Ambrosio L, Migliori GB. Challenging MDR-TB clinical problems --- the case for a new Global TB Consilium supporting the compassionate use of new anti-TB drugs. Int J Infect Dis. 2019;80S:S68---72,

28.World Health Organization. Deﬁnitions and reporting framework for tuberculosis --- 2013 revision (updated December 2014 and January 2020). Geneva: World Health Organization; 2013. WHO/HTM/TB/2013.2. Available at:

https://www.who.int/tb/publications/deﬁnitions/enAccessed 4February2021.

29.Avaliani Z, Gozalov O, Kuchukhidze G, Skrahina A, Soltan V, van den Boom M, et al. What is behind programmatic treatment outcome deﬁnitions for tuberculosis? Eur Respir J. 2020;56(1):2001751,

http://dx.doi.org/10.1183/13993003.01751-2020.

30.Edwards CG, Wares DF, Dravniece G, Gebhard A, Tiemersma E, van der Grinten E, et al. Introduc-ing bedaquiline: experiences from the Challenge TB Project. Int J Tuberc Lung Dis. 2020;24(10):1046---53,

31.Zabsonre I, Thi SS, Cox V. Overcoming barriers to the access and uptake of newer drugs for multidrug-resistant TB. Int J Tuberc Lung Dis. 2020;24(10):1054---7,

32.Santiago MR, Garﬁn AMC, Balanag VM. Introduction of bedaquiline for the treatment of drug-resistant TB in the Philippines. Int J Tuberc Lung Dis. 2020;24(10):1063---6,

33.Sachdeva KS, Arora N, Solanki R, Singla R, Sarin R, Bhat-nagarA, et al. Strengthened capacityof India’sbedaquiline Conditional Access Programme for introducing new drugs and regimens. Int J Tuberc Lung Dis. 2020;24(10):1067---72,

34.Ndjeka N, Hughes J, Reuter A, Conradie F, Enwerem M, Ferreira H, et al. Implementing novel regimens for drug-resistant TB in South Africa: what can the world learn? Int J Tuberc Lung Dis. 2020;24(10):1073---80,

35.Vambe D, Kay AW, Furin J, Howard AA, Dlamini T, Dlamini N, et al. Bedaquiline and delamanid result in low rates of unfavourable outcomes among TB patients in Eswatini. Int J Tuberc Lung Dis. 2020;24(10):1095---102,

36.WorldHealthOrganization.MeetingreportoftheWHOexpert consultation on the deﬁnition of extensively drug-resistant tuberculosis,27-29October2020.Geneva:WorldHealth Orga-nization;2021.CCBY-NC-SA3.0IGO.

37.Borisov SE, D’Ambrosio L, Centis R, Tiberi S, Dheda K, AlffenaarJW,etal.Outcomesofpatientswith drug-resistant-tuberculosistreatedwithbedaquiline-containingregimensand undergoing adjunctive surgery. J Infect. 2019;78(1):35---9,

http://dx.doi.org/10.1016/j.jinf.2018.08.003.

38.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 treat-ment regimen. Eur Respir J. 2018;52(6):1801528,

http://dx.doi.org/10.1183/13993003.01528-2018.

39.Nunn AJ, Phillips PPJ, Meredith SK, Chiang CY, Con-radie F, Dalai D, et al. STREAM Study Collaborators. A trial of a shorter regimen for rifampin-resistant tuberculosis. N Engl J Med. 2019;380(13):1201---13,

40.Churchyard GJ. A short regimen for rifampin-resistant tuberculosis. N Engl J Med. 2019;380(13):1279---80,

http://dx.doi.org/10.1056/NEJMe1902904.

41.Nahid P, Mase SR, Migliori GB, Sotgiu G, Bothamley GH, Brozek JL, et al. Treatment of drug-resistant tuberculo-sis. An Ofﬁcial ATS/CDC/ERS/IDSA clinical practice guide-line. Am J Respir Crit Care Med. 2019;200(10):e93---142,

http://dx.doi.org/10.1164/rccm.201909-1874ST.

42.Mu˜noz-Torrico M, Rendon A, Centis R, D’Ambrosio L, Fuentes Z, Torres-Duque C, et al. Is there a rationale for pulmonary rehabilitation followingsuccessful chemother-apy for tuberculosis? J Bras Pneumol. 2016;42(5):374---85,

http://dx.doi.org/10.1590/S1806-37562016000000226. 43.Tiberi S, Torrico MM, Rahman A, Krutikov M, Visca D,

Silva DR, et al. Managing severe tuberculosis and its sequelae: from intensive care to surgery and reha-bilitation. J Bras Pneumol. 2019;45(2):e20180324,

http://dx.doi.org/10.1590/1806-3713/e20180324.

44.Visca D, Zampogna E, Sotgiu G, Centis R, Saderi L, D’Ambrosio L, et al. Pulmonary rehabilitation is effective in patients with tuberculosis pul-monary sequelae. Eur Respir J. 2019;53(3):1802184,

http://dx.doi.org/10.1183/13993003.02184-2018.

45.ViscaD,CentisR,Munoz-TorricoM,PontaliE.Post-tuberculosis sequelae:theneedtolookbeyondtreatmentoutcome.IntJ TubercLungDis.2020;24(8):761---2.

46.Visca D, Centis R, D’Ambrosio L, Mu˜noz-Torrico M, Chakaya JM, Tiberi S, et al. The need for pulmonary rehabilita-tion followingtuberculosistreatment.IntJTubercLung Dis. 2020;24(7):720---2.

47.Mu˜noz-Torrico M, Cid-Juárez S, Gochicoa-Rangel L, Torre-Bouscolet L, Salazar-LezamaMA, Villarreal-VelardeH, et al. Functional impact of sequelae in drug-susceptible and multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2020;24(7):700---5.

48.Akkerman OW, Ter Beek L, Centis R, Maeurer M, Visca D, Mu˜noz-Torrico M, et al. Rehabilitation, optimized nutritional care, and boosting host internal milieu to improve long-term treatment outcomes in tuber-culosis patients. Int J Infect Dis. 2020;92S:S10---4,

49.Natarajan S, Singla R, Singla N, Gupta A, Caminero JA, Chakraborty A, et al. Treatment interruption patterns and adverse events among patients on bedaquiline containing regimen underprogrammatic con-ditions in India. Pulmonology. 2020;S2531---0437(20),

http://dx.doi.org/10.1016/j.pulmoe.2020.09.006,30213-0.