WHO consolidated WHO recommendations on DR-TB

management

Global TB Programme, Geneva, SwitzerlandMay 2019

5 priority actions

The global TB situation

Consolidation of WHO guidelines and advice on MDR-TB management

ConsolidatedDR-TB treatment

Guidelines

GROUP MEDICINES

Group A Levofloxacin OR Moxifloxacin Lfx / MfxBedaquiline BdqLinezolid Lzd

Group B Clofazimine CfzCycloserine OR Terizidone Cs/ Trd

Group C Ethambutol EDelamanid DlmPyrazinamide ZImipenem-cilastatin OR Meropenem Ipm-Cln / MpmAmikacin (OR Streptomycin) Am (S)Ethionamide OR Prothionamide Eto / Ptop-aminosalicylic acid PAS

Longer MDR-TB regimensRevised classification of component medicines

Longer MDR-TB regimensComposition

• All three most effective medicines from Group A ( Lfx or Mfx; Bdq, Lzd) are strongly recommended for all patients

Relative risk for (i) treatment failure or relapse and (ii) death (versus treatment success), 2018 IPD-MA for longer MDR-TB regimens

Group A Treatment failure or relapse vs. treatment

success

Death vs. treatment success

Number treated

Adjusted OR

(95% CI)

Number treated

Adjusted OR

(95% CI)

Levofloxacin ORmoxifloxacin

3,143 0.3 (0.1-0.5) 3,551 0.2 (0.1-0.3)

Bedaquiline* 1,391 0.3 (0.2-0.4) 1,480 0.2 (0.2-0.3)

Linezolid 1,216 0.3 (0.2-0.5) 1,286 0.3 (0.2-0.3)

- Bdq for patients > 18 yrs (Strong recommendation) - Bdq may also be included in for patients aged 6-17 yrs

Longer MDR-TB regimensComposition

• Add one or both medicines from Group B

Relative risk for (i) treatment failure or relapse and (ii) death (versus treatment success), 2018 IPD-MA for longer MDR-TB regimens

Group B Treatment failure or relapse vs. treatment success

Death vs. treatment success

Number treated

Adjusted OR

(95% CI)

Number treated

Adjusted OR

(95% CI)

Clofazimine 991 0.3 (0.2-0.5) 1,096 0.4 (0.3-0.6)Cycloserine ORterizidone

5,483 0.6 (0.4-0.9) 6,160 0.6 (0.5-0.8)

Longer MDR-TB regimens

Relative risk for (i) treatment failure or relapse and (ii) death (versus treatment success), 2018 IPD-MA for longer MDR-TB regimens and delamanid Trial 213 (intent-to-treat population)Group C Treatment failure or

relapse vs. treatment success

Death vs. treatment success

Number treated

Adjusted OR

(95% CI)

Number treated

Adjusted OR

(95% CI)

Ethambutol 1,163 0.4 (0.1-1.0) 1,245 0.5 (0.1-1.7)Delamanid 289 1.1 (0.4-2.8)* 290 1.2 (0.5-3.0)*

Pyrazinamide 1,248 2.7 (0.7-10.9) 1,272 1.2 (0.1-15.7)Imp-cln OR meropenem 206 0.4 (0.2-0.7) 204 0.2 (0.1-0.5)Amikacin 635 0.3 (0.1-0.8) 727 0.7 (0.4-1.2)Streptomycin 226 0.5 (0.1-2.1) 238 0.1 (0.0-0.4)Ethionamide ORprothionamide

2,582 1.6 (0.5-5.5) 2,750 2.0 (0.8-5.3)

p-aminosalicylic acid 1,564 3.1 (1.1-8.9) 1,609 1.0 (0.6-1.6)

* unadjusted risk ratios as defined by the study investigators of Trial 213 by month 24

Composition• Add to complete the regimens and when medicines

from group A or B cannot be used

Longer MDR-TB regimens

Relative risk for (i) treatment failure or relapse and (ii) death (versus treatment success), 2018 IPD-MA for longer MDR-TB regimens

Other medicines Treatment failure or relapse vs. treatment

success

Death vs. treatment success

Number treated

Adjusted OR

(95% CI)

Number treated

Adjusted OR

(95% CI)

Kanamycin 2,946 1.9 (1.0-3.4) 3,269 1.1 (0.5-2.1)Capreomycin 777 2.0 (1.1-3.5) 826 1.4 (0.7-2.8)Amoxicillin-clavulanic acid 492 1.7 (1.0-3.0) 534 2.2 (1.3-3.6)

• Kanamycin and Capreomycin linked to pooreroutcomes in IPD meta-analysis and no longerrecommended

Composition

Longer MDR-TB regimensRegimen composition

Choice of medicines depends upon the • expected balance of effectiveness and harms• preference for oral over injectable agents• the results of drug-susceptibility testing (DST)• reliability of DST methods• population drug resistance levels• history of previous use of medicine in a patient• drug tolerability• potential drug-drug interactions

Longer MDR-TB regimensSerious adverse events (SAEs) in patients on longer MDR-TB regimens

Medicine Absolute risk of AEMedian % 95% credible

intervalBedaquiline 2.4% [0.7, 7.6]Moxifloxacin 2.9% [1.4, 5.6]Amoxycillin-Clavulanic acid 3.0% [1.5, 5.8]Clofazimine 3.6% [1.3, 8.6]Ethambutol 4.0% [2.4, 6.8]Levofloxacin 4.1% [1.9, 8.8]Streptomycin 4.5% [2.3, 8.8]Cycloserine / terizidone 7.8% [5.8, 10.9]Capreomycin 8.4% [5.7, 12.2]Pyrazinamide 8.8% [5.6, 13.2]Ethionamide / prothionamide 9.5% [6.5, 14.5]Amikacin 10.3% [6.6, 17.0]Kanamycin 10.8% [7.2, 16.1]p-aminosalicylic acid 14.3% [10.1, 20.7]Thioacetazone 14.6% [4.9, 37.6]Linezolid 17.2% [10.1, 27.0]

Longer MDR-TB regimensNumber of agents

• All three Group A agents and at least one Group B agent should be included to

ensure that treatment starts with:

➢ at least four TB agents likely to be effective and

➢ at least three agents are included for the rest of treatment

Number of likely effective agents*

Treatment failure or relapse vs. treatment

success

Death vs. treatment success

Adjusted OR (95% CI) Adjusted OR (95% CI)

IP

4 vs 5 1.0 (0.7-1.3) 1.1 (0.9-1.5)6 vs 5 1.0 (0.6-1.7) 0.9 (0.6-1.3)2 vs 1 highly effective agent* 0.9 (0.5-1.6) 0.6 (0.3-0.96)>2 vs 1 highly effective agent* 0.6 (0.2-1.8) 0.4 (0.2-1.01)

CP

2 vs 3 1.3 (0.8-2.1) 1.3 (0.8-2.0)4 vs 3 1.2 (0.9-1.5) 1.0 (0.8-1.3)>1 vs 1 highly effective agent* 0.5 (0.1-1.7) 0.8 (0.2-2.5)

* Highly effective agent = Lfx, Mfx, Gfx (if DST=susceptible) and Lzd, Bdq, Imp-Cln, Mpm (unless resistance documented)

• The optimal duration of Bdq, Dlm and Lzd is not known. Use of Bdq & Dlm beyond 6 months still considered “off label”

• Amx-Clv to be used only with Imp-Cln or Mpm and do not count as a separate effective agent

• Eto/Pto and PAS only proposed for regimens which do not contain Bdq, Lzd, Cfz or Dlm (or very last resort)

• Delamanid may be included in the treatment of MDR/RR-TB patients aged 3 years or more

Longer MDR-TB regimens

Longer MDR-TB regimensDuration & bacteriological monitoring

Regimen duration (conditional upon response)

• Total length = 18-20 months

• Time after conversion = 15-17 months

• Injectable phase (if applicable) = 6-7 months

Monitoring patient response

In MDR/RR-TB patients on longer regimens:

✓ Sputum culture in addition to sputum smearmicroscopy is recommended to monitor treatmentresponse (Strong recommendation)

✓ It is desirable for sputum culture to be repeated atmonthly intervals

▪ Other important markers of treatment response:- patients general condition- weight gain over time- results of other texts and etc

Duration & bacteriological monitoring

Shorter MDR-TB regimen

Stud

y resu

lts

STREAM Stage 1 trial: In patients eligible for STR, the likelihood of tr. success was close to 80% in both arms

Observational studies: A comparable likelihood of tr. success with longer regimens overall

Higher risk of failure or relapse in the STR, especially when resistance was present or when Group A agents were included in longer regimens.

The shorter regimen had a lower risk of treatment interruption

• Preference by the clinician and patient for a longer MDR-TB regimen• Confirmed resistance or suspected ineffectiveness to a medicine in the shorter MDR-TB regimen (except isoniazid resistance)• Exposure to one or more 2nd line medicines in the shorter MDR-TB regimen for >1 month (unless susceptibility to these 2nd line medicines is confirmed)• Intolerance to medicines in the shorter MDR-TB regimen or risk of toxicity (e.g. drug-drug interactions)• Pregnancy• Disseminated, meningeal or central nervous system TB• Any extrapulmonary disease in PLHIV• One or more medicines in the shorter MDR-TB regimen not available

YESFAILING SHORTER REGIMEN or NON-RESPONSE,

DRUG INTOLERANCE, EMERGENCE OF ANY OTHER EXCLUSION CRITERION

Standardized, shorter MDR-TB regimen

may be offered(conditional recommendation)

NO

New, individualized longer MDR-TB

regimens

Shorter MDR-TB regimenTighter criteria, different landscape

• Programmes already implementing the shorter MDR-TB regimen with good results and capacity to monitor for ototoxicity • switch from Km to Am• while Km is used close follow-up for non-response to

treatment or early relapse• lower the threshold to switch non responders to a new

longer regimen

• Programmes planning to offer the shorter regimen to newly-diagnosed patients to continue only if they have DST capacity to exclude at least FQ and SLI resistance

• Programmes considering modified shorter regimens (e.g. replacing injectable with BDQ) can do so as operational research

Shorter MDR-TB regimen (2)Implications for future use

Longer MDR-TB regimensImplementation considerations

❑ Fully oral regimen is possible and should become preferred option for most patients

❑ Access to rapid diagnostic tests, and DST remains crucial for the better choice of treatment regimen

❑ All recommended agents are available via the GDF❑ Kanamycin and capreomycin are no longer recommended

to use❑ Amikacin and streptomycin lower down in priority

ranking (if audiometry possible)

Modified Shorter MDR-TB regimenImplementing under operational research

• The following steps recommended:– Develop appropriate protocol:

• Specifying the eligibility criteria, regimen composition, monitoring schedules etc.

– Approval by a national ethics review committee:

• Protocol should be approved ahead of any patient enrolment.

– Treatment delivery under WHO-recommended standards:

• informed consent; adherence to principles of good clinical practice; aDSM; and regular patient monitoring to assess regimen effectiveness.

– May solicit WHO advice prior to initiating operational research for modified shorter regimens.

,,Systematically

assessing and

addressing the

needs and

expectations of

patients who should

be provided with

emotional,

educational and

economic support

based on their

needs’’

END TB Strategy Pillar 1 : integrated, patient-centered care and prevention

80% treatment success is reachable

when a properly designed MDR-TB

regimen is delivered with a patient-

centred care approach

Health education and counselling on thedisease and treatment adherence should beprovided to patients on TB treatment

(Strong recommendation, moderatecertainty of evidence)

Recommendation 1

Information and education

A package of treatment adherence interventions may be offered for patients on TB treatment in conjunction with the selection of a suitable treatment administration optionRemarks:

• Treatment adherence interventions include social support, communication with patient, medication monitor, and staff education.

• Treatment administration options include DOT, VOT, non-daily DOT (e.g. not every dose supervised treatment, weekly or a few times per week supervision), or unsupervised treatment).

• The interventions should be selected on the basis of the assessment of individual patient's needs, provider's resources and conditions for implementation.

Recommendation 2

Treatment adherence package

One or more of the following treatment adherence interventions may be offered to patients on TB treatment or to health-care providers:• material support to patient (e.g. meals, food baskets, food supplements, food vouchers,

transport subsidies, living allowance, housing incentives, or financial bonus)

• psychological support to patient (e.g. counselling sessions or peer-group support)

• tracers (e.g. telephone calls, SMS or home visit) or digital medication monitor

• staff education (adherence education, chart or visual reminder, educational tools and desktop

aids for decision-making and reminder)

Recommendation 3

Treatment adherence interventions

The following treatment administration optionsmay be offered to patients on TB treatment:

Recommendation 4Treatment administration options

TREATMENT ADMINISTRATION OPTIONS

Community- or home-based directly observed treatment (DOT) is

recommended over health facility-based DOT or unsupervised

treatment

DOT administered by trained lay providers or health-care workers is

recommended over DOT administered by family members or

unsupervised treatment .

Video supported treatment (VOT) may replace DOT when the

technology and internet provision are available and can be operated

by health-care providers and patients

Treatment principles (1)

• Ahead of enrolment on MDR-TB treatment, all patients should receive appropriate counselling to enable informed and participatory decision-making.

• Patient information material needs to reflect the new changes so that patients are appropriately informed about their treatment options.

See Companion handbook for more details on patient-centred carehttps://apps.who.int/iris/bitstream/handle/10665/130918/9789241548809_eng.pdf

Treatment principles (2)• Social support to enable

adherence to treatment is very important to ensure a patient-centred approach to the delivery of care.

• Active TB drug safety monitoring and management (aDSM) is essential for all patients enrolled on MDR-TB treatment.

Overall, the following principles can be

followed for patient-centred care and support:

1. Develop a treatment partnership with your patient and ensure that he or she is aware of rights and responsibilities

regarding TB treatment and care.

2. Focus on your patient’s concerns and priorities.

3. Use the 5 A’s: Assess, Advise, Agree, Assist and Arrange

4. Link the patient with a DOT provider for MDR-TB regimens (also called a drug-resistant TB treatment supporter).

5. Support patient self-management, as it relates to personal care and needs.

6. Organize proactive follow-up care.

7. Involve expert patients, peer educators and support staff in your health facility.

8. Link the patient to community-based resources and support and to the government social protection scheme for

which the patient is eligible according to local law.

9. Use written information – registers, treatment plans, treatment cards and written information for patients – for

documenting, monitoring and reminding.

10. Work as a team with the patient.

11. Assure continuity of care.

▪ Patient-centered care

is the heart of the

management of TB

▪ Patient support guidelines

are an essential

component of MDR TB

management

WHO recommends countries to rapidly adjust theirnational treatment policies, drug procurement plansand monitoring systems to quickly switch MDR-TBpatients to the new priority medicines and expresses astrong desirability to have a fully oral treatment.

Regimens that deviate significantly from thoserecommended may be investigated under operationalresearch conditions, making sure that the patient’s bestinterest are served, collecting data of use for futurepolicy updates.

Key messages for country implementation

Acknowledgements (non exhaustive)Guideline Development Group (GDG 2018): Holger Schünemann (Chair), Geraint (Rhys) Davies (Co-chair), Eden Abadiano Mariano, Susan Abdel Rahman, Sarabjit S Chadha, Daniela Cirillo, Fernanda Dockhorn Costa Johansen, Bernard Fourie, Edwin Herrera-Flores, Ayuko Hirai, Alexander Kay, Rafael Laniado-laborin, Lawrence Mbuagbaw, Payam Nahid, Austin Arinze Obiefuna, Cristina Popa, Wipa Reechaipichitkul, Maria Rodriguez, Adman Skirry Shabangu, Sabira Tahseen, Carrie Tudor, Zarir Udwadia, Andrew Vernon.

Evidence reviewers: McGill University (Canada) - Richard (Dick) Menzies, Zhiyi Lan, Jonathon Campbell, Faiz Ahmad Khan, Syed Abidi

External Review Group (ERG): Essam Elmoghazi, Mildred Fernando-Pancho, Anna Marie Celina Garfin, Barend (Ben) Marais, Andrei Maryandyshev, Alberto Matteelli, Giovanni Battista Migliori, Thato Mosidi, Nguyen Viet Nhung, Rohit Sarin, Welile Sikhondze, Ivan SOLOVIC, Pedro Suarez, Carlos Torres

WHO Guideline Steering Group: Nicola Cocco, Dennis Falzon, Giuliano Gargioni, Chris Gilpin, LicéGonzalez-Angulo, Malgorzata Grzemska, Ernesto Jaramillo, Alexei Korobitsyn, Corinne Merle, Lorenzo Moja, Fuad Mirzayev, Piero Luigi Olliaro, Andreas Alois Reis, Satvinder Singh, Karin Weyer, Matteo Zignol

WHO rapporteur: Kerri Viney

WHO Guideline Review Committee (GRC): Nathan Ford, Susan Norris

Acknowledgements (non exhaustive)Observers: Charles Daley, Kelly Dooley, Gregory Kearns, Anneke Hesseling, Gary Maartens, Norbert Ndjeka, Michael Rich, H Simon Schaaf, Valérie Schwoebel, Shenjie Tang, Ye Tun, Kitty Van Weezenbeek, Francis Varaine, Irina Vasilyeva, Draurio Barreira Cravo Neto, Edward M Cox, Jennifer Furin, Brian Kaiser, Lindsay McKenna, Yadiul Mukadi, Eric Pelfrene, Anna Scardigli

Trial / study data: Challenge TB (Gunta Draviciene, Mavluda Makhmudova, Yulia Aleshkina); EndTBProject (Carole Mitnick, Michael Rich, Francis Varaine); Johnson & Johnson Services, Inc. (Tine De Marez, Chrispin Kambili); Otsuka (Marc Destito, Lawrence Geiter, Rajesh Gupta, Jeffery Hafkin, Keiso Yamasaki); STREAM Trial (Sarah Meredith, Andrew Nunn, Patrick Phillips, Ira D. Rusen); UNION (Antonio Piubello, Valérie Schwoebel, Arnaud Trébucq)

Observational data (surname of first authors for IPD 2018): Ahmad, Ahuja, Anderson, Bang, Barkane, Barry, Bonnet, Brode, Brust, Cegielski, Chan, Dheda, Fox, Gegia, Guglielmetti, Hughes, Isaakidis, Kempker, Koenig, Koh, Kvasnovsky, Lange, Laniado-Laborin, Leung, Marks, Migliori, Milanov, Ndjeka, O’Donnell, Palmero, Podewils, Riekstina, Rodrigues, Seo, Seung, Shim, Singla, Skrahina, Smith, Udwadia, van der Werf, Vasilyeva, Viiklepp, Yim

Funding: Russian Govt; USAID; support of ATS/CDC/IDSA and the European Respiratory Society and the Canadian Institutes of Health Research for compilation of earlier studies of the IPD 2018

WHO Regional and country offices

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