Shorter Bedaquiline Regimen for DR-TB

(National Guidelines for Management of DR-TB, India – March 2025)

1. Overview and Context

1. Introducing BPaLM regimen under programmatic conditions
2. Introducing Bdq and Delamanid (Dlm) in all age groups
3. Adopting the 9-11 month shorter oral MDR-TB regimen with Lzd replacing Eto

2. BPaLM Regimen (6-Month Shorter Regimen)

A. Definition

• Duration: 26 weeks (extendable to 39 weeks under specific criteria)
• First choice for all eligible MDR/RR-TB patients aged 14 years and above, regardless of FQ resistance status or HIV status

B. Evidence Base

C. Eligibility Criteria

• Age 14 years and above with new microbiologically confirmed MDR/RR-TB or probable MDR-TB who failed H mono/poly DR-TB treatment
• Drug exposure: < 1 month prior exposure to Bdq, Lzd, and/or Pa; OR >1 month but documented sensitivity; OR no prior failure on Bdq/Lzd regimen with documented sensitivity
• QTcF on ECG: ≤450 ms in males and ≤470 ms in females (or correctable with electrolyte correction)
• Non-lactating or non-breastfeeding women; non-pregnant women; or pregnant women <20 or <24 weeks gestation willing for MTP

• Age below 14 years
• Documented resistance to Bdq, Lzd, and/or Pa
• Significant liver dysfunction: AST/ALT >3.0 × ULN AND Total Bilirubin >2.0 × ULN
• Severe forms of extrapulmonary MDR-TB: CNS-TB, spinal/skeletal TB, disseminated/miliary TB
• Significant cardiac conduction abnormalities (structural heart disease, long QT syndrome, AV blocks, arrhythmia)
• Baseline QTcF >450 ms (males) or >470 ms (females) with normal electrolytes

D. Regimen, Dosage, and Administration

• Magnesium supplements/antacids should be avoided 2 hours before and after the regimen (binds FQs)
• All doses administered under direct observation (minimum 6 days/week)

E. Moxifloxacin in BPaLM

• In TB PRACTECAL, 23% of BPaLM arm had FQ resistance, yet Mfx was continued throughout
• BPaLM had better outcomes than BPaL: 89% vs 77% treatment success
• BPaLM reduced recurrence (1% vs 4% BPaL), protected against Bdq resistance amplification
• No recurrences observed at week 48 in BPaLM group; sustained 94% success at 108 weeks

F. Dose Reduction of Linezolid

• All efforts must be made to maintain Lzd 600 mg throughout
• If grade 3/4 toxicity within first 9 weeks: declare treatment failed (do NOT reduce dose before 9 weeks)
• Dose reduction to 300 mg only considered after 9 weeks for grade 3/4 toxicity
• If Lzd dose is reduced to 300 mg, the regimen is extended to 39 weeks
• For optic neuritis (any grade): permanent discontinuation of Lzd
• For peripheral neuropathy grade 2: reduce to 300 mg + 1-2 week drug holiday
• For myelosuppression grade 3/4: often reversible with 1-2 week drug holiday then reduce to 300 mg

G. Extension Criteria (BPaLM extended to 39 weeks)

• Lzd dose reduced to 300 mg after 9 weeks due to grade 3/4 toxicity
• Grade 3/4 intolerance to Mfx: drop Mfx, complete as BPaL for 39 weeks
• Extension must be accompanied by strict clinical evaluation and monthly smear/culture monitoring

H. Follow-up Monitoring (BPaLM)

I. Treatment Failure Criteria for BPaLM

• Culture positive at month 4 or later
• Amplification of resistance to Bdq, Pa, or Lzd
• No clinical response
• Discontinuation of Bdq, Pa, or Lzd due to intolerance/toxicity at any time
• Treatment cannot be completed within 30 weeks (26-week course) or 43 weeks (39-week course) after interruption

3. 9-11 Month Shorter Oral MDR/RR-TB Regimen

A. Key Change

B. Regimen Structure

(2) Lzd + (4-6) Lfx + Cfz + Z + E + Hh → (6-9) Bdq + (5) Lfx + Cfz + Z + E

C. Eligibility Criteria

• Rifampicin resistance detected
• MDR/RR-TB with FQ resistance NOT detected
• No prior exposure >1 month to 2nd-line drugs in the regimen
• No extensive TB disease
• No severe forms of extra-pulmonary MDR-TB (CNS-TB, spinal/skeletal, miliary)
• Can be given to pregnant women irrespective of gestational age (since Eto replaced by Lzd)
• Both KatG and InhA mutations present: use Lzd-containing regimen (NOT Eto regimen)

D. Regimen Modification

• Bdq usually for 6 months but can be extended to 11 months if IP extended due to positive sputum at month 4
• Lzd given for only 2 months; if discontinued early due to intolerance, replace with Eto for (4 months minus period of Lzd consumed)
• If Z or E cannot be tolerated: drop one (only one); if two or more drugs stopped, declare treatment failed

4. Comparison: BPaLM vs. 9-11 Month Regimen

5. Special Situations

• HIV patients: BPaLM can be given regardless of HIV status/CD4 count; avoid Efavirenz (induces Bdq metabolism); Ritonavir requires close monitoring
• Children <14 years: BPaLM not established; use 9-11 month regimen or longer regimen
• Elderly (≥65 years): Careful assessment needed; closer monitoring required
• Renal insufficiency: Bdq, Lzd, and Mfx generally safe; monitor for anaemia and electrolyte imbalance
• Diabetes: Higher risk of peripheral neuropathy with Lzd; close monitoring required; avoid high-dose metformin + Lzd (lactic acidosis risk)

6. Key Points for Exam

1. BPaLM = 6-month (26-week) all-oral regimen for MDR/RR-TB aged ≥14 years
2. Bdq loading dose: 400 mg daily × 2 weeks, then 200 mg thrice weekly
3. Lzd 600 mg throughout; reduce to 300 mg only after 9 weeks of grade 3/4 toxicity; dose reduction → extend to 39 weeks
4. Mfx continued throughout regardless of FQ resistance status
5. Direct observation mandatory (minimum 6 days/week)
6. ECG mandatory before start; QTcF ≤450 ms (male) and ≤470 ms (female)
7. 9-11 month regimen: Eto replaced by Lzd for 2 months in IP phase
8. Both regimens are completely oral (injection-free)
9. BPaLM is cost-effective and reduces workload compared to longer regimens
10. Pyridoxine (vitamin B6) co-administered throughout to prevent neuropathy