National Guidelines 2024 – Drug-Resistant TB Study Notes

Background & Rationale

  • India’s National TB Elimination Programme (NTEP) under the Ministry of Health & Family Welfare (MoHFW) released the “National Guidelines for Management of Drug-Resistant TB” (Nov 2024) to align with latest WHO recommendations and accelerate “TB-Mukt Bharat” by 2025.
  • Key drivers:
    • Rising burden of MDR/RR-TB and Pre-XDR/XDR-TB.
    • Global move to fully-oral, shorter, safer regimens.
    • Evidence from NIX-TB, TB-PRACTECAL, ZeNix and Indian mBPaL trials.
  • 2023 Indian TB stats: 25.52 lakh cases diagnosed; 95.5 % (24.38 lakh) started on treatment; MDR/RR-TB estimated at 2.5 % (new) & 13 % (retreatment); treatment success for MDR-TB grew from 49 % (2017) to 75 % (2021).

Key Definitions & Abbreviations

  • MDR-TB = resistance to H & R.
  • RR-TB = rifampicin-resistant (± other drugs).
  • Pre-XDR-TB = MDR/RR plus FQ resistance.
  • XDR-TB = MDR/RR plus FQ resistance plus resistance to any Group-A drug (Bdq or Lzd).
  • Hr-TB = isoniazid-resistant, rifampicin-susceptible.
  • BPaL/BPaLM = Bdq + Pa + Lzd (± Mfx).
  • Universal DST = rapid DRT for R, and at least FQ DST within 15 days of diagnosis.
  • QTcF prolonged: males > 450\,\text{ms}, females > 470\,\text{ms}.
  • BMI formula \text{BMI}=\dfrac{\text{Weight (kg)}}{\text{Height (m)}^{2}}.

WHO & National Policy Shifts

  • 2022 WHO: 6-month BPaLM may replace 9–11 m or ≥18 m regimens in eligible \ge 14\,\text{yr} MDR/RR-TB.
  • Nine-month all-oral Bdq-containing regimen preferred when BPaLM not possible and no FQ resistance.
  • NTEG (India) endorsed:
    1. Programmatic BPaLM roll-out.
    2. Bdq & Dlm for all paediatric age groups.
    3. Replacing Eto with 2-month Lzd in 9–11 m regimen.
    4. CBNAAT M.tb/XDR cartridge for rapid H, FQ, SLI, Eto detection (Aug 2024).

Case Finding & Diagnosis

  • Up-front NAAT for every presumptive TB case (pulmonary, EP, children, PLHIV, etc.).
  • Integrated algorithm:
    1. NAAT M.tb/Rif.
    2. Reflex NAAT for H & FQ (or FL/SL LPA).
    3. Baseline LC-DST to Bdq, Lzd, Pa, Dlm, Z, Mfx1.0 (where available).
  • Specimen SOPs (Annex-2) detail sterile vs contaminated EP specimens, transport in triple packing at 4–15 °C.

Treatment Regimens – Overview

General Principles

  • Regimen choice by NDR-TBC/DDR-TBC committee after DST, clinical review & PTE.
  • Direct observation ≥6 days/week, preferably with digital adherence (MERM/TB Aarogya Saathi).
  • Avoid Mg-containing antacids ±2 h around FQ dose.
  • Pre-Treatment Evaluation (PTE) includes: history, examination, BMI, CBC, LFT, RFT, RBS, ECG, electrolytes, HIV, pregnancy test, chest X-ray, selective neurology & ophthalmology.

1. Six-Month BPaLM Regimen (26 wks; extendable → 39 wks)

Eligibility

  • Age ≥14 yr.
  • MDR/RR-TB (new or after ≤1 mo exposure to Bdq/Lzd/Pa).
  • QTcF ≤450 ms (M) or ≤470 ms (F) after electrolyte correction.
  • No significant hepatic dysfunction (AST/ALT >3× ULN & T.bil >2× ULN), no severe EP forms (TB meningitis, spine, disseminated), no major cardiac conduction defects.
  • Pregnancy: only if <20/24 wk and willing for MTP (Pa contraindicated in breastfeeding).

Dose (no weight-band)

  • Bdq 400 mg OD wk1-2 → 200 mg thrice-weekly wk3-26/39.
  • Pa 200 mg OD wk1-26/39.
  • Lzd 600 mg OD wk1-26/39 (pyridoxine \ge100\,\text{mg} >30 kg; 50 mg if 16–29 kg).
  • Mfx 400 mg OD wk1-26/39 (kept even if FQ-R).

Lzd Dose Reduction

  • Try to keep 600 mg through 9 wk.
  • Grade 3-4 toxicity after 9 wk → may reduce to 300 mg and extend regimen to 39 wk.
  • If 600 mg cannot be given within first 9 wk → declare treatment failed.

Regimen Change

  • If baseline DST shows resistance to Bdq/Pa/Lzd: outcome “Treatment regimen changed” → shift to longer regimen.

Extension / Modification

  • Grade 3-4 Mfx intolerance → drop Mfx, continue BPaL for 39 wk.
  • Treatment interruptions: must finish 182 (or 273) days of all core drugs within 30 (43) wk; otherwise declare failure.

Monitoring

  • Clinical & adherence monthly; CBC & ECG Day 15, 30, then monthly; LFT & CXR Month 3 & EOT.
  • Cultures monthly from Month 2; additional culture if no improvement by Week 9.
  • Ophthalmic exam Weeks 9, 13 & 26.

Ineligible Patients

  • Consider 9–11 m or 18–20 m regimens per criteria.

2. Nine-to-Eleven-Month Shorter Oral MDR/RR-TB Regimen (Bdq + Lzd)

Eligibility

  • RR detected, FQ susceptible, no prior use of Bdq/Lfx/Cfz/Lzd >1 mo, non-extensive disease, no severe EP-TB.
  • Lzd version safe in pregnancy; Eto version only if ≥32 wk gestation or non-pregnant.

Dosing (Adults)

  • First 4–6 mo (IP): Bdq (6 mo), Lzd 600 mg × 9 wk, Lfx (dose-banded), Cfz, Z, E, Hh.
  • CP (5 mo): Lfx + Cfz + Z + E.

Monitoring

  • CBC at baseline, Weeks 2, 4, 8 for Lzd AE.
  • Ophthalmology Week 9, 13, 26.

Modifications

  • Missed Lzd ≤14 days → add missed doses before end of 2 mo.
  • Permanent Lzd stop within 2 mo → replace with Eto for remaining IP duration; failure if regimen cannot continue.
  • If Z/E intolerance drop one drug; stopping ≥2 core drugs → switch to longer regimen.

3. Eighteen-to-Twenty-Month Longer Oral M/XDR-TB Regimen

  • Core: Bdq (6 mo, can extend), Lfx, Lzd (600 mg first 6 mo → 300 mg), Cfz, Cs.
  • Replace per priority list (Mfx-h, Dlm, Z, Eto, PAS, Am, carbapenems+Amx-Clv) when resistance/intolerance.
  • Total treatment ≤20 mo; if culture +ve Month 8 → declare failure.
  • Bdq extension allowed if <2 Group A/B drugs otherwise.

4. Six-Month Hr-TB Regimen

  • 06\;\text{Lfx} R E Z (directly extend to 9 mo in extensive disease, EP, smear + at Month4, etc.).
  • Replacement: if Lfx or Z unusable → add Lzd; if both unusable → Lzd + Cfz ± Cs.

Switching Rules

  • From shorter → longer when resistance emerges, intolerance, ≥2 missed core drugs, or interruption >2 wk.
  • From longer → shorter allowed if ≤1 mo therapy and baseline DST suits; Bdq loading need not repeat if already completed.
  • Outcome “Treatment regimen changed” recorded; patient removed from earlier denominator.

Supply Chain & Logistics

  • NTEP procures; drugs move SDS → DDS → TUDS/NDR-TBC.
  • Patient-wise box (PwB) packed at SDS.

BPaLM PwB 26 wk

  • Bdq 100 mg × 200 (188 in bottle + 12 in pouch) or 20 strips.
  • Pa 200 mg × 182.
  • Lzd 600 mg × 182.
  • Mfx 400 mg × 182.
  • Pdx for full course.

Extension PwB 27-39 wk

  • Bdq 78 tabs; Pa 91; Lzd 91; Mfx 91; Pdx 91.
    • Child-friendly Bdq 20 mg DT bio-equivalent; adult tablets can be crushed.
    • Dlm 25 mg DT approved for ≥10 kg.

Management in Special Situations

Pregnancy & Lactation

  • BPaLM only if <20/24 wk & MTP chosen; Pa contraindicated in breastfeeding.
  • 9–11 m regimen with Lzd preferred in pregnancy; Eto avoided <32 wk.
  • Monitor CBC monthly, foetal USG anomaly (18 wk) & growth (32 wk); aDSM strict.

Children

  • BPaLM not yet for <14 yr (pending data); use shorter or longer oral regimens; Bdq approved ≥5 yr; Dlm 25 mg DT for ≥10 kg.

Older (>65 yr)

  • Assess comorbidities; closer monitoring on BPaLM.

PLHIV

  • Efavirenz reduces Bdq & Pa exposures → avoid; prefer DTG (few data) or boosted PIs with ECG monitoring.
  • Avoid Zidovudine + Lzd (additive myelosuppression).

Renal Insufficiency

  • Bdq, Lzd, Mfx largely safe; monitor electrolytes, anaemia.

Liver Disorders

  • Z, H, R, Eto, Bdq, Pa hepatotoxic; routine LFT Month 3 and PRN; manage per flowchart.

Diabetes

  • Monitor sugars; risk of neuropathy ↑; avoid high-dose metformin with Lzd (lactic acidosis).

Anaemia

  • Baseline Hb

Adverse Events

Peripheral Neuropathy (Annex-3)

  • Screening tool & DAIDS grades; manage with pyridoxine, pregabalin, gabapentin, duloxetine (avoid with Lzd due serotonin syndrome); consider dose reduction/stop Lzd.

QTc Prolongation (Annex-4)

  • Culprits: Bdq, Pa, Dlm, Mfx, Cfz.
  • Management table:
    • Grade 1 (QTcF ≤480 ms) → observe.
    • Grade 2 (481–500 ms) → correct electrolytes, weekly ECG.
    • Grade 3 (>500 ms) → hold QT drugs, admit, restart sequentially after normalization.
    • Grade 4 + arrhythmia → stop offending drug permanently.

Hepatotoxicity Flow (Annex-4)

  • AST/ALT <5× ULN asymptomatic → continue.
  • Symptomatic or >5× ULN → stop Pa/Bdq/Z/H/Eto as per regimen, manage, re-introduce sequentially when AST/ALT <2× ULN.

Treatment Interruptions

  • Missed doses in BPaLM: compensate within 30–43 wk window; >2 wk consecutive or >4 wk cumulative core-drug gap → switch to longer regimen.
  • Interruption <9 wk in other regimens: extend course; ≥9 wk → outcome LTFU, reassess.
  • Bdq interruption rules: reload if >7 days during loading or >2 wk during maintenance (≤8 wk); >8 wk stop & switch.

Patient Support

  • Ambulatory care via Ayushman Arogya Mandirs/HWC; CHO tracks contacts, adverse events, Ni-Kshay updates.
  • Counselling at every touchpoint; Nikshay Sampark call centre & TB Aarogya Saathi app for adherence & education.
  • Nutrition: Ni-Kshay Poshan Yojana – ₹1000/month DBT; assess BMI, MUAC, Hb; manage SAM/MAM per 2017 guidance.
  • Community support via “Pradhan Mantri TB Mukt Bharat Abhiyan” – patients linked to Ni-Kshay Mitra donors.

Recording, Reporting, Monitoring

  • Ni-Kshay modules: enrolment, test request, PTE, dispensation, aDSM, outcome, transfer, long-term follow-up (6, 12, 18, 24 mo).
  • Indicator 1: Proportion of R-susceptible TB patients with valid H & FQ DST.
  • Indicator 2: Sustained treatment success at 6, 12 mo (DS & DR) and 18, 24 mo (DR only).

Annexure Highlights

  • Chronology of Pa introduction: US FDA 2019 → CDSCO conditional access 2020 → Indian pragmatic mBPaL trial 2021→ programmatic roll-out 2024.
  • SOP for EP specimen: divide sterile vs contaminated; decontamination protocols (NALC-NaOH, 2–4 % NaOH) and MGIT processing.
  • Peripheral neuropathy tool: 0–10 faces scale, vibration & ankle reflex grading.
  • QT & Hepatotoxicity algorithms (flow charts reproduced in chapter 3 & Annex-4).

Ethical & Practical Considerations

  • Emphasis on informed decision-making, patient-centred care, pharmaco-vigilance (PvPI) and difficult-to-treat clinics (DT3C).
  • Guidelines will be refined as global/national evidence evolves; implement across public & engaged private sector.