10.2 Treatment regimens in programmatic conditions

10.2.1 Short treatment regimens

A. 6-month BPaLM regimen

Eligibility

(adapted from WHO [1] Citation 1. World Health Organization. WHO operational handbook on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment, 2022 update.
https://www.who.int/publications/i/item/9789240065116 )

 

BPaLM is the preferred treatment regimen for all MDR/RR-TB patients meeting the following criteria:
1 - Bedaquiline, pretomanid, linezolid and moxifloxacin are likely effective.

2 - Age ≥ 14 years.

3 - No miliary TB, osteoarticular TB or TB of the central nervous system (CNS), i.e. brain, spinal cord or meninges.

Regimen composition

Box 10.1 – 6-month BPaLM regimen

 

6Bdq-Pa-Lzd-Mfx

 

In the BPaLM regimen, the starting dose of linezolid (600 mg once daily) is reduced after 16 weeks to 300 mg once daily.

 

Note:

In the event of resistance to fluoroquinolones (FQs), i.e. pre-XDR-TB, this guide recommends a short four-drug regimen under operational research conditions where possible (Section 10.3). An LTR or BPaL (6-9Bdq-Pa-Lzd with linezolid given at 600 mg for 6 months) can be used in settings where an STR under operational research conditions is not feasible. Note that linezolid causes frequent toxicity. Management of linezolid adverse effects include temporary or early permanent interruption of the drug. If interruptions are recurrent or linezolid is stopped permanently early in the treatment, patients on BPaL would receive a two-drug regimen for a significant period of time, which is not optimal [1] Citation 1. World Health Organization. WHO operational handbook on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment, 2022 update.
https://www.who.int/publications/i/item/9789240065116 .

B. 9-month bedaquiline-containing regimens [1] Citation 1. World Health Organization. WHO operational handbook on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment, 2022 update.
https://www.who.int/publications/i/item/9789240065116

Eligibility

If pretomanid is not available or for patients not eligible for the BPaLM regimen, a 9-month STR should be used in MDR/RR-TB patients meeting the following criteria [2] Citation 2. World Health Organization. WHO operational handbook on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment. Geneva 2020.
​​​​​​​https://www.who.int/publications/i/item/9789240006997 :
1 - Susceptibility to FQs is confirmed by a rapid molecular test (RMT).
2 - Other drugs used in the regimen, except isoniazid, are likely effective (Section 10.1.2). High treatment failure rates and amplification of FQ resistance have been observed in some countries [3] Citation 3. du Cros P, Khamraev A, Tigay Z, et al. Outcomes with a shorter multidrugresistant tuberculosis regimen from Karakalpakstan, Uzbekistan. ERJ Open Res 2021; 7: 00537-2020.
https://doi.org/10.1183/23120541.00537-2020 in patients with strains presenting resistance to other drugs in the STR.

3 - No extensive pulmonary TB (PTB):

• no bilateral lung cavities or extensive lung damage,        
• no cavities or bilateral disease in patients < 15 years.

4 - No severe extrapulmonary TB (EPTB):

• no miliary TB, osteoarticular TB, TB of the CNS, or pericardial TB,
• no EPTB other than lymph node TB (peripheral nodes or isolated mediastinal mass without compression) in patients < 15 years.

5 - No pregnancy or breastfeeding for the ethionamide-containing regimen.

Regimen composition

Box 10.2 – 9-month bedaquiline-containing regimens

 

4 to 6Bdq<6>-Lfx-Cfz-Z-E-Hh-Lzd<2>/5Lfx-Cfz-Z-E or 4 to 6Bdq<6>-Lfx-Cfz-Z-E-Hh-Eto/5Lfx-Cfz-Z-E

 

This guide recommends the regimen that includes linezolid (a drug from Group A), rather than the regimen that includes ethionamide.

 

Regimen 4 to 6Bdq_<6>-Lfx-Cfz-Z-E-H^h-Lzd_<2>/5Lfx-Cfz-Z-E

 

• Bdq_<6> means that bedaquiline is administered for 6 months (not for 4 months). However, it should be extended to 9 months if the sputum microscopy is positive at Month 4.
• Lzd_<2> means that linezolid is administered for 2 months (not for 4 months).
• H^h is administered for 4 months or extended to 6 months if the sputum microscopy is positive at Month 4.
• Lfx-Cfz-Z-E is administered for 9 months or extended to 11 months if the sputum microscopy is positive at Month 4.
• Moxifloxacin (Mfx) at standard dose can be used instead of levofloxacin.

 

In practice the patient receives:

 

A 9-month regimen if microscopy negative at Month 4:

TB drugs	Intensive phase				Continuation phase
Months	M1	M2	M3	M4	M5	M6	M7	M8	M9
Bdq
Lfx-Cfz-Z-E
Hh
Lzd

 

An 11-month regimen if microscopy positive at Month 4:

TB drugs	Intensive phase						Continuation phase
Months	M1	M2	M3	M4	M5	M6	M7	M8	M9	M10	M11
Bdq
Lfx-Cfz-Z-E
Hh
Lzd

 

Regimen 4 to 6Bdq_<6>-Lfx-Cfz-Z-E-H^h-Eto/5Lfx-Cfz-Z-E

 

• Bdq_<6> means that bedaquiline is administered for 6 months (not for 4 months). However, it should be extended to 9 months if the sputum microscopy is positive at Month 4.
• H^h-Eto are administered for 4 months or extended to 6 months if the sputum microscopy is positive at Month 4.
• Lfx-Cfz-Z-E are administered for 9 months or extended to 11 months if the sputum microscopy is positive at Month 4.
• Mfx at standard dose can be used instead of Lfx.

 

In practice the patient receives:

 

A 9-month regimen if microscopy negative at Month 4:

TB drugs	Intensive phase				Continuation phase
Months	M1	M2	M3	M4	M5	M6	M7	M8	M9
Bdq
Lfx-Cfz-Z-E
Hh-Eto

 

An 11-month regimen if microscopy positive at Month 4:

TB drugs	Intensive phase						Continuation phase
Months	M1	M2	M3	M4	M5	M6	M7	M8	M9	M10	M11
Bdq
Lfx-Cfz-Z-E
Hh-Eto

 

10.2.2 Long treatment regimens

Eligibility

All MDR/RR-TB patients not eligible for STRs (programmatically or under operational research).

Regimen composition

The regimen should include a minimum number of likely effective drugs.

 

Box 10.3 – Number of likely effective drugs required in LTRs

At least 4 likely effective TB drugs, including: 3 from Group A 1 from Group B   If this optimal combination is not feasible: At least 5 likely effective TB drugs, prioritizing Group A and B drugs and adding Group C drug(s) to bring the total to at least 5 TB drugs.

 

LTRs may contain more than 5 TB drugs if there is uncertainty of effectiveness in some of the drugs used.

 

While waiting for full DST results, patients can be treated with:

• An individualized LTR, or
• An empirical a Citation a. An empirical regimen is a regimen designed to treat most patients in a region whilst waiting the full DST results.  LTR according to the known resistance profile.

It may be necessary to switch from an empirical LTR to an individualized LTR, based on the latest DST results and/or clinical evolution during treatment course (e.g. drug intolerance, persistence of a positive culture).

Individualized long regimens

To build an individualized LTR, a stepwise process is recommended.

 

Table 10.3 – Steps to build an LTR

 

Step 1	Use all 3 Group A drugs, unless confirmed resistance or contra-indication.
	1.1 - Levofloxacin (Lfx) or moxifloxacin (Mfx) Use Lfx (rather than Mfx) if the patient takes other QT-prolonging drugs. High dose moxifloxacin (Mfxh) can be used: if low-level resistance to FQs is detected, but not counted as a likely effective drug [1] Citation 1. World Health Organization. WHO operational handbook on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment, 2022 update. https://www.who.int/publications/i/item/9789240065116 . with other QT-prolonging drugs, but only if options are very limited (weigh benefits/risks and discuss with the patient). 1.2 - Bedaquiline (Bdq) 1.3 - Linezolid (Lzd)
Step 2	Add 1 or 2 Group B drug(s), unless confirmed or suspected resistance or contra-indication.
	2.1 - Clofazimine (Cfz) Use Cfz rather than Cs or Trd if possible (better safety profile). 2.2 - Cycloserine (Cs) or terizidone (Trd) Interchangeable and used at the same dose.
Step 3	Add Group C drugs when the combination of 3 Group A drugs and at least 1 Group B drug is not feasible, to bring the regimen to 5 likely effective drugs.
	3.1 - Delamanid (Dlm) First choice (good safety profile and still limited drug resistance). 3.2 - First-line drugs: ethambutol (E), pyrazinamide (Z) 3.3 - Imipenem/cilastatin (Ipm/Cln) or meropenem (Mpm) If no other option (high cost and difficult to administer). Always administered with amoxicillin/clavulanic acid (Amx/Clv). Use Mpm in patients < 15 years or with a history of epilepsy. 3.4 - Amikacin (Am) or streptomycin (S) If no other option and confirmed susceptibility. Use Am rather than S. Use S if Am is unavailable or the strain is resistant to Am. 3.5 - Ethionamide (Eto) or prothionamide (Pto) Interchangeable and used at the same dose. 3.6 - Para-aminosalicylic acid or sodium (PAS) 3.7 - High-dose isoniazid (Hh) Can be used if low-level resistance to H, but not counted as a likely effective drug.

 

Note: isoniazid standard dose can be administered to patients with RR-TB when isoniazid susceptibility is documented. When isoniazid is used in this manner it can be counted as a likely effective drug.

Empirical long regimens

Table 10.4 – Examples of empirical long regimens at treatment initiation

 

Resistance profiles	Examples
Group A and B drugs likely effective	18Lfx-Bdq-Lzd-Cfz If Bdq is contra-indicated: 18Lfx-Lzd-Cfz-Cs-Dlm  If Lzd is contra-indicated: 18Lfx-Bdq-Cfz-Cs-Dlm
FQs not likely effective Other Group A and B drugs likely effective	18Bdq-Lzd-Cfz-Cs-Dlm-[Mfxh] (a) Citation a. Moxifloxacin high dose can be used, but not counted if low-level FQ resistance is suspected or found on DST. If Bdq is contra-indicated: 18Lzd-Cfz-Cs-Dlm-Ipm/Cln

Duration of treatment

At least for 18 months, with at least 15 months after culture conversion (for definition, see Chapter 17). If well tolerated, all drugs should be taken for the full treatment duration [4] Citation 4. endTB. Bedaquiline and delamanid containing regimens achieve excellent interim treatment response without safety concerns: endTB interim analysis. 2018 Jul 13.  
http://www.endtb.org/sites/default/files/2018-07/endTB%20interim%20analysis%20%2813%20July%202018%29.pdf [5] Citation 5. Guglielmetti L, Jaspard M, Le Dû D, et al. French MDR-TB Management Group. Long-term outcome and safety of prolonged bedaquiline treatment for multidrug-resistant tuberculosis. Eur Respir J. 2017 Mar 22;49(3):1601799.
https://doi.org/10.1183/13993003.01799-2016 .

 

Preliminary evidence suggests that stopping bedaquiline at 6 months is associated with high rates of culture reversion (for definition, see Chapter 17) in patients with resistance to several drugs or extensive lung damage [6] Citation 6. Hewison C, 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 Jul 1;22(7):766-772.
https://doi.org/10.5588/ijtld.17.0840 . No safety issues have been reported with bedaquiline treatment longer than 6 months [2] Citation 2. World Health Organization. WHO operational handbook on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment. Geneva 2020.
​​​​​​​https://www.who.int/publications/i/item/9789240006997 [4] Citation 4. endTB. Bedaquiline and delamanid containing regimens achieve excellent interim treatment response without safety concerns: endTB interim analysis. 2018 Jul 13.  
http://www.endtb.org/sites/default/files/2018-07/endTB%20interim%20analysis%20%2813%20July%202018%29.pdf [7] Citation 7. endTB. Bedaquiline- and delamanid-containing regimens achieve excellent interim treatment response without safety concerns: endTB interim analysis. 2018. Boston, MA. .

 

Carbapenems are commonly used for a minimum of 2 months after culture conversion. When the number of likely effective drugs included in the regimen is limited, a carbapenem may be required for the entire duration of treatment.