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Update of drug-resistant tuberculosis treatment guidelines: A turning

point

E. Vanino , B. Granozzi , OW. Akkerman , M. Munoz-Torrico ,

F. Palmieri , B. Seaworth , S. Tiberi , M. Tadolini

PII: S1201-9712(23)00089-9
DOI: https://doi.org/10.1016/j.ijid.2023.03.013
Reference: IJID 6658

To appear in: International Journal of Infectious Diseases

Received date: 31 January 2023

Revised date: 5 March 2023
Accepted date: 6 March 2023

Please cite this article as: E. Vanino , B. Granozzi , OW. Akkerman , M. Munoz-Torrico ,
F. Palmieri , B. Seaworth , S. Tiberi , M. Tadolini , Update of drug-resistant tuberculosis treat-
ment guidelines: A turning point, International Journal of Infectious Diseases (2023), doi:
https://doi.org/10.1016/j.ijid.2023.03.013

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Highlights

 A guideline update regarding DR-TB treatment has been recently published by WHO

 6-month BPaLM is recommended rather than 9-month or longer regimens in MDR/RR-TB

 9-month regimen is suggested rather than longer regimens in FQ-susceptible MDR/RR-TB

 18-month regimens remain a valid option if shorter regimens cannot be implemented

 Further studies to clarify the use of BPaL/BPaLM in special situations are needed

1
Update of drug-resistant tuberculosis treatment guidelines: a turning point

Vanino E1*, Granozzi B2*, Akkerman OW3, Munoz-Torrico M4, Palmieri F5, Seaworth B6, Tiberi S7, Tadolini
M2,8
1
Infectious Diseases Unit, Santa Maria delle Croci Hospital, AUSL Romagna, Ravenna, Italy (viale Randi, 48128,
Ravenna, Italy)
2
Infectious Diseases Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy (Via Albertoni 9,
40136, Bologna, Italy)
3
University of Groningen, University Medical Centre Groningen, Department of Pulmonary Diseases and TB
Center Beatrixoord, Groningen, The Netherlands (Hanzeplein 1, 9713 GZ, Groningen, the Netherlands)
4
Clínicaen Tuberculosis y Enfermedades Pleurales, Instituto Nacional de Enfermedades Respiratorias - INER -
Ciudad de México, México (Calzada de Tlalpan 4502, CP 14080 Mexico City, Mexico)
5
Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases Lazzaro Spallanzani Scientific
Institute for Research, Hospitalization and Healthcare, Rome, Italy (Via Portuense 292 – 00149, Rome, Italy)
6
Heartland National TB Center, University of Texas Health Science Center at Tyler, Tyler, TX,USA (2303 SE Military
Drive, San Antonio TX 78218 USA)
7
Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London,
London, UK (4 Newark St London E1 2AT, UK)
8
Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy(Via
Albertoni 9, 40136, Bologna, Italy)

*Equally contributed

Corresponding author:

Marina Tadolini

Infectious Diseases Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy

Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy

Via Albertoni 9

40136 Bologna

Italy

[email protected]

[email protected]

2
Abstract

In December 2022 World Health Organization (WHO) released a new treatment of multidrug-

resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) guideline.

The main novelty of this update are two new recommendations: 1) a 6-month treatment regimen

composed of bedaquiline, pretomanid, linezolid (600 mg) and moxifloxacin (BPaLM) is

recommended in place of the 9-month or longer (18-month) regimens in MDR/RR-TB patients,

now including extensive pulmonary TB and extrapulmonary TB (except TB involving CNS, miliary TB

and osteoarticular TB); 2) the use of the 9-month all-oral regimen rather than longer (18-months)

regimen is suggested in patients with MDR/RR-TB and in whom resistance to fluoroquinolones has

been excluded.

Longer (18-month) treatments remain a valid option in all cases in which shorter regimens cannot

be implemented due to intolerance, drug-drug interactions, XDR-TB, extensive forms of

extrapulmonary TB or previous failure.

The new guidelines represent a milestone in MDR/RR-TB treatment landscape, setting the basis

for a shorter, all oral, more acceptable, equitable, and patient-centred model for MDR/RR-TB

management. However, some challenges remain to be addressed to allow full implementation of

the new recommendations.

Keywords: MDR/RR-TB, DR-TB treatment guidelines, shorter regimen, longer regimens

3
Introduction

Drug-resistant tuberculosis (DR-TB) remains a major global health threat, with an estimated

burden of 450,000 (95% UI: 399,000–501,000) new cases of rifampicin-resistant TB (RR-TB) in 2021

[1-2]. Globally DR-TB treatment success rates have increased from 50% in 2012 to 60% in 2019

with 15% of MDR/RR-TB patients still dying from the disease [3].

In December 2022, WHO released “The WHO Consolidated Guidelines on Tuberculosis (TB),

Module 4: Treatment - Drug-Resistant Tuberculosis Treatment 2022 update” [3], which builds on

the previous “Rapid communication” published in 2022 [4] and replaces the 2020 “WHO

consolidated guidelines on drug-resistant tuberculosis treatment” [5].

The 2022 WHO DR-TB treatment update includes seven main sections on treatment regimens for

MDR/RR-TB and isoniazid-resistant TB (Hr-TB), monitoring patient response to treatment, timing

of antiretroviral therapy start in MDR/RR-TB patients living with HIV and use of surgery for

patients on MDR/RR-TB treatment [2].

The 2022 update contains two new recommendations (based on a review of new evidence)

regarding treatment regimens for MDR/RR-TB: 1) the use of the 6-month treatment regimen

composed of bedaquiline, pretomanid, linezolid (600 mg) and moxifloxacin (BPaLM) rather than

the 9-month or longer (18-month) regimens in MDR/RR-TB patients 2) the use of the 9-month all-

oral regimen rather than longer (18-months) regimens in patients with MDR/RR-TB and in whom

resistance to fluoroquinolones (FQ) has been excluded. Longer regimens remain a valid option in

some circumstances (unchanged recommendation). Table 1 summarizes the main indications and

contraindications of each treatment regimen.

6-month treatment regimens

4
Based on the evidence generated by the TB-PRACTECAL [6, 7] and ZeNix [8, 9] randomised control

trials, the Guidelines Development Group (GDG) concluded that BPaLM regimen, composed of

bedaquiline, pretomanid, linezolid (600 mg od – 26 weeks) and moxifloxacin, is recommended

over the currently recommended longer regimens in patients with MDR/RR-TB. Drug susceptibility

testing (DST) to fluoroquinolones is strongly encouraged, but it should not delay treatment

initiation; in cases when resistance to fluoroquinolones is documented after the start of BPaLM,

moxifloxacin should be stopped, and the regimen continued as BPaL (without moxifloxacin).

BPaLM regimen is also recommended over the currently recommended 9-month regimen with 4

months ethionamide or with 2 months linezolid, and over 18-month longer regimen in patients

with pulmonary MDR/RR-TB without fluoroquinolone resistance.

Among the 6-month BPaL-based regimens assessed by the TB-PRACTECAL trial (e.g., BPaL, BPaLM,

and BPaLC containing clofazimine), the BPaLM regimen is preferred, as it led to more treatment

success, fewer failures or recurrences and less emerging drug resistance with little difference in

adverse events.

BPaLM regimen is suggested for all people with MDR/RR-TB regardless of HIV status, who have not

had prior exposure to bedaquiline, pretomanid and linezolid (defined >1 month exposure). When

exposure is >1 month, resistance to the specific drugs with such exposure must be excluded. If

resistance to bedaquiline, linezolid or pretomanid is confirmed or suspected, the BPaLM/BPaL

regimen should be stopped, and patients should be referred for a longer individualized regimen

[10].

No efficacy data are available yet to propose the use of BPaLM regimen in patients affected by

central nervous system (CNS), osteoarticular and disseminated (miliary) TB, in those under 14

years of age and in pregnant and breastfeeding women due to limited evidence on pretomanid

safety in this population [10, 11].

5
Several different dosing and duration schemes of linezolid were used in ZeNix trial and data

suggested that a daily linezolid dose of 600 mg for 26 weeks was associated with higher levels of

treatment success, lower levels of failure and recurrence and fewer adverse events compared to

1200 mg/day [12, 13]. The GDG considered the possibility to reduce the daily dose of linezolid to

300 mg/daily if necessary to mitigate toxicity, even though it is preferable to use linezolid at the

dosage of 600 mg/daily throughout the regimen [14, 15]. The GDG acknowledged the slight

differences in the treatment duration of the BPaLM and BPaL regimens as studied in TB-

PRACTECAL and ZeNIX trials and suggested standardizing the treatment duration of BPaLM to

6 months (26 weeks); for BPaL, extension to a total of 9 months (39 weeks) if sputum cultures are

positive between months 4 and 6 can be considered. Missed doses of all three or four drugs in the

regimen should be avoided; therefore, 26 or 39 weeks of prescribed doses should be completed

within an overall period of 7 or 10 months, respectively.

Additional evaluation of bedaquiline, pretomanid, linezolid and clofazimine (BPaLC) regimen was

made although evidence was limited due to smaller sample size compared with BPaL; considering

the increased pill burden, reduced acceptability due to skin discolouration and other potential

adverse effects related to clofazimine use without noticeable benefits, the GDG judged that BPaLC

regimen should not be recommended.

9-month all-oral regimen

Another treatment option for people with MDR/RR-TB and without resistance to fluoroquinolones

who are not eligible for the BPaLM is the 9-month all-oral bedaquiline containing regimen. It

consists of: a) intensive phase: bedaquiline in combination with FQ (levofloxacin or moxifloxacin),

ethionamide (or linezolid at the dosage of 600mg daily), ethambutol, high-dose isoniazid,

pyrazinamide and clofazimine b) continuation phase: fluoroquinolones, clofazimine, ethambutol

and pyrazinamide. The intensive phase is intended as 4-month long (except bedaquiline, which is

6
always 6-month long, and linezolid, which is maximum 2-month long), but it may be extended to

6 months when bacteriological conversion is not seen at the end of the fourth month of

treatment, while the continuation phase remains of 5 months; hence, if extended, the entire

regimen may last 11 months instead of 9. The two regimens are as follows: 4–6 Bdq(6m)-FQ-Cfz-Z-E-

Hh-Eto/5 FQ-Cfz-Z-E (known as ethionamide variation) and 4–6 Bdq(6m)-Lzd(2m)-FQ-Cfz-Z-E-Hh/5 FQ-

Cfz-Z-E, also known as linezolid variation [10]. 9-month regimens represent the preferred

treatment option over the longer regimens for patients without previous exposure to second-line

treatment (including BDQ), except in case of extensive pulmonary disease, severe extrapulmonary,

CNS, miliary and osteoarticular TB where longer treatment is still recommended.

While lack of safety data on pretomanid in children aged below 14 years makes the BPaLM not

recommended in this age group, the 9-month all-oral regimen can be suggested to children of all

ages, in consideration of the recommendation for bedaquiline use in children even below 6 years

of age [14]. Furthermore, considering the contraindication to use of ethionamide in pregnancy and

the consolidated data in using linezolid during pregnancy, the 9-month regimen with linezolid is

recommended instead of ethionamide for pregnant and lactating women. Regarding the choice of

fluoroquinolones, although levofloxacin and moxifloxacin have shown similar efficacy for treating

DR-TB, levofloxacin is often preferred because of moxifloxacin’s higher potential for cardiotoxicity

even if levofloxacin has been associated with musculoskeletal disorders in paediatric populations

[15]. The 9-month regimen can be a preferred option over the longer regimens in newly diagnosed

patients not eligible for the 6-month BPaLM/BPaL; informed decision-making process, including

clinical judgement, DST results and patient preference should be made.

Longer regimens for MDR/RR-TB

The last treatment section of the guidelines is dedicated to longer regimens (18-20 months), based

on the WHO drug grouping A, B, C*. This option, with no changes compared to 2020 WHO

7
guidelines, is still considered when the BPaLM/BPaL or 9-month all-oral regimen cannot be used

(e.g. severe extrapulmonary TB; additional resistance to key medicines of the BPaLM/BPaL

regimen -except moxifloxacin- or the 9-month all-oral regimen; lack of response to shorter

treatment regimens; drug intolerance to the component medicines of the 6-month or 9-month

regimen; pregnant and lactating women or children aged below 14 years). Longer treatment,

preferably all-oral, should be individualized based on DST and treatment history and it must

include an intensive phase with at least four likely to be effective TB agents (three of Group A and

at least one of Group B), and a continuation phase of at least three drugs. If four likely effective

drugs cannot be achieved with agents from Group A and Group B, Group C agents are added to

complete it. When Group C agents are included in the regimen, the number of drugs may exceed

four, to reflect the uncertainty about the efficacy of some of these medicines. Due to the long

duration of therapy and the potential side effects, the GDG agreed that reducing the pill burden to

the minimum effective one is the best strategy to minimize the risk of treatment failure.

Bedaquiline should be included in all age groups, even in pregnancy and in those aged below

6 years; in addition, evidence supports its safe use beyond 6 months in selected patients, under

“off-label” use [16]. Although the GDG did not give recommendation on effectiveness of the co-

administration of bedaquiline and delamanid, due to lack of evidence data, both medicines may be

used in patients who have limited treatment options. Recent data presented from the DELIBERATE

trial highlighted that the QTc effects of co-administration of bedaquiline and delamanid were not

more than additive and they were not associated with grade 3 or 4 QTc prolongation [17].

Balancing desirable and undesirable effects, GDG judged that it would probably be feasible to use

delamanid in children of all ages (using the 25 mg dispersible delamanid formulation in children

below 3 years of age) [18]. Total duration of longer regimens is 18–20 months (15-17 months after

culture conversion) that may be modified according to treatment response.

8
All regimens (BPaLM, BPaL, 9-month and longer treatments) can be safely recommended in people

living with HIV, with careful evaluation of drug-drug interactions and in those with CD4+ cell count

< 100/mmc.

Discussion

The long-awaited new DR-TB treatment guidelines represent a clear push towards the utilization

of all-oral, shorter regimens for most patients with MDR/RR-TB.

Based on available data, the 6-month BPaLM/BPaL regimens can achieve successful outcomes

even in case of extensive pulmonary and extrapulmonary (except CNS, miliary and osteoarticular

TB) MDR/RR-TB, representing the shortest regimens ever proposed for this difficult-to-treat

condition. While the evidence around BPaLM/BPaL regimens is highly promising, some aspects

must be addressed soon to allow their smooth roll-out.

Firstly, access to drug susceptibility tests and second line drugs remains the major issue for

National TB Programs, and only a third of estimated MDR/RR-TB patients have been enrolled on

treatment globally [1]. Once MDR/RR-TB is identified, the limited global access to rapid bedaquiline

and linezolid molecular testing and the lack of pretomanid rapid molecular testing to exclude

baseline resistance are major concerns, especially in consideration of the rise of bedaquiline

resistance [19]. BPaLM regimen, including only four drugs, and even more BPaL, are likely to be

inadequate in case of baseline resistance to one or more drugs included in the regimen, with high

risk of treatment failure. While resistance testing to FQ is available, its global coverage remains

low (being only 50% in 2021) [3], and universal access to rapid fluoroquinolone-DST should also be

pursued, to allow appropriate regimen selection (i.e., BPaL instead of BPaLM) and avoid

unnecessary and potentially toxic drugs administration in case of resistance.

9
In addition, the high cost of bedaquiline, pretomanid and linezolid, together with issues regarding

pretomanid availability in some countries, limit the access to these medicines for many patients,

not only in low resources but also in middle and high-income countries, and should be urgently

addressed.

Beside diagnostic and treatment capacity, there are also some practical aspects that need to be

clarified: 1) BPaLM only considers moxifloxacin use, and not levofloxacin: further studies are

needed to show if levofloxacin can be a safe substituted with same outcomes; 2) the GDG allowed

the reduction of the daily linezolid dose to 300 mg to mitigate linezolid-related side effects (e.g.

anaemia, peripheral neuropathy); it’s our opinion that the reduced dose should be given only if

therapeutic drug monitoring (TDM) and Minimal Inhibitory Capacity (MIC)s are available; 3)

evidence is needed to understand if BPaLM/BPaL can be continued (and how) without linezolid in

case of drug interruption/early discontinuation or, rather, if the entire regimen should be stopped;

4) the 6-month BPaL regimen might be prolonged to 9 months in case of positive sputum cultures

between months 4 and 6. However, when the evidence of culture conversion is not available at 6th

month, we wonder if other elements (i.e. previous failure, smear microscopy results, chest X-ray

picture or Computer Aided Detection (CAD) score) could be considered to predict response to

treatment and, in case of likely poor response, clinicians might decide to prolong the treatment to

9 months.

BPaLM is not supposed to be prolonged beyond 6 months; however, we wonder if the same

elements listed above suggesting poor response to treatment could guide the decision to prolong

it to 9 months as well. Although limited data on BPaLC regimen are available, in case of FQ-

resistance, adding clofazimine to BPaL might be considered to reinforce the regimen and protect

against bedaquiline resistance onset.

10
Last, but not least, future guidance in the following areas would be very useful for national TB

programs in view of BPaLM/BPaL roll-out: BPaLM/BPaL adherence monitoring plan, with details on

adherence methods/digital technologies utilization; BPaL/BPaLM treatment monitoring schedule

(beside culture monitoring); post-treatment follow-up data recording and reporting, to inform

about the sustained treatment success and risk of relapse.

In conclusion, the updated DR-TB treatment guidelines represent a turning point in MDR/RR-TB

treatment evolution, offering multiple all-oral, shorter and more patient-centered options, and

setting the basis for a new, more acceptable, equitable and cost-effective model for MDR/RR-TB

management [20, 21]. Massive efforts in terms of capacity building, strengthening of diagnostic

capacity, actions to ensure new drugs and shorter regimens access and generation of further

evidence around new regimens are urgently needed to expand the MDR/RR-TB treatment

coverage and achieve actual implementation of the new guidelines at a global level.

*Group A = levofloxacin or moxifloxacin, bedaquiline and linezolid; • Group B = clofazimine, and

cycloserine or terizidone; and • Group C = ethambutol, delamanid, pyrazinamide, imipenem–
cilastatin or meropenem, amikacin (or streptomycin), ethionamide or prothionamide, and p-
aminosalicylic acid.

11
Declaration of competing interests

Tiberi S. is an employee of GSK, all opinions are his own and not that of the company. All other authors

declare that they have no known competing financial interests or personal relationships that could have

appeared to influence the work reported in this paper.

Role of the funding source

No funding source required for this paper.

Ethical approval statement

No ethical approval required for this paper.

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Table 1. Indications/contraindications of the shorter and longer MDR/RR-TB treatment regimens,
modified from [11]

Regimen 6-Month 9-Month all-oral Longer individualized

BPaLM/BPaL1 18-month
MDR/RR-TB YES (BPaLM) YES YES when 6-month and 9-
month regimens could not
FQ susceptible
be used

Pre-XDR YES (BPaL only) NO YES when 6-month

regimen could not be used
(FQ resistant)
XDR-TB NO NO YES

Extensive pulmonary TB YES NO YES

Extrapulmonary TB YES YES YES

(except TB involving (except TB meningitis,

CNS, miliary TB and miliary TB, pericardial TB
osteoarticular TB) and osteoarticular TB)

Age < 14 years NO YES YES

PLHIV YES YES YES

Pregnant/breastfeeding NO Ethionamide-sparing YES

regimen is recommended
Exposure to any of the NO° NO° YES
drugs composing the
regimen for  30 days°

History of cardiac disease YES (but must be YES YES

or concomitant drugs that monitored closely)
prolong QTc

14
 BMI < 17 YES (but must be YES YES
monitored closely)

Hb < 8 g/dl or PLT < YES (but prefer other Linezolid-sparing regimen Linezolid-sparing regimen
75.000/mm3 regimes) is suggested is suggested

Pre-existing peripheral YES (but prefer other Linezolid-sparing regimen Linezolid-sparing regimen
neuropathy of Grade 3–4 regimes) is suggested is suggested

1
When the regimen is BPaL from the start or is changed to BPaL, it can be extended to a total of 9 months (39 weeks)
if sputum cultures are positive between months 4 and 6

° When exposure is greater than 1 month, resistance to the specific drugs with such exposure must be ruled out
before considering the regimen

15