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Isoniazid (H) Mono/Poly Drug-Resistant TB — Full Details (15 Marks)

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1. Definition

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2. Diagnosis & Pre-requisite

• NAAT (CBNAAT/Truenat) must confirm Rifampicin resistance NOT detected
• FL-LPA confirms H resistance (katG / inhA mutation)
• Empirical treatment of H mono/poly DR-TB is NOT advised — Rifampicin susceptibility must be excluded first
• Once FL-LPA shows H resistance → LPA deposit sent for SL-LPA and LC-DST to: Mfx, Z, Lzd, Cfz*
• Patient need not be sent to DDR-TBC unless medically necessary; treatment initiated at peripheral health facility level itself while awaiting SL-LPA/LC-DST results
• Results uploaded by microbiologist on Nikshay on the same day

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3. Pre-Treatment Evaluation (PTE)

• PTE valid for 1 month from date of test; can be used for re-initiation
• aDSM (active Drug Safety Management) initiation form completed for all DR-TB patients

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4. Regimen

In exceptional situations where loose R, E or Z is unavailable, 4-FDC (HREZ) + Lfx loose tablets may be used as an alternative rather than delaying treatment.

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5. Dosage (Weight-Band Based)

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6. Inclusion & Exclusion Criteria

• Rifampicin resistance NOT detected (by NAAT) + H resistance detected (by FL-LPA)
• Age ≥ 5 years (weight ≥ 16 kg)
• New or previously treated (not prior treatment failure with FQ-containing regimen)

• R resistance detected/inferred (switch to MDR-TB regimen)
• FQ resistance detected
• Severe hepatic dysfunction
• Prior failure on FQ-containing regimen (without documented susceptibility)
• Children < 5 years (manage differently)

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7. Treatment Duration & Extension

1. Extensive pulmonary disease (bilateral cavitary/extensive parenchymal damage)
2. Uncontrolled comorbidity
3. Extra-pulmonary TB
4. Smear positive at end of Month 4
5. Regimen modification (use of replacement drugs)

In extensive pulmonary TB, prolongation up to 12 months may be considered on an individual basis.

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8. Replacement Sequence (KEY TABLE — PMDT 2021 & 2025)

As per PMDT 2021 Guidelines:

Cfz — DST whenever available. In the first three situations above, treat for a total duration of 9 months. The use of new drugs (Bdq, Pa) is not yet recommended in H mono/poly DR-TB treatment.

As per PMDT March 2025 Guidelines (Updated):

Key Update (2025): Mfx(h) as first replacement for Lfx was in 2021; in 2025 the table directly uses Lzd as first replacement for Lfx or Z, and patients not responding with R/FQ/Z resistance are considered "probable MDR-TB" → evaluated for BPaLM, then shorter 9-month MDR regimen, then longer oral M/XDR-TB regimen.

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9. Follow-Up Monitoring

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10. Adverse Drug Reactions

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11. Special Populations

Children

• Management same as adults; child-friendly formulations used
• Colour vision monitoring every 2 months (Ethambutol)
• Children < 5 years managed differently

Pregnancy & Lactation

• H mono/poly DR-TB regimen may be started or continued in pregnant women
• Rifampicin interacts with oral contraceptives → recommend higher dose estrogen OCP (50 µg) or barrier methods / IUD / depot-medroxyprogesterone

PLHIV

• H mono/poly DR-TB regimen recommended in HIV-reactive TB patients
• ART must be started within 8 weeks of TB treatment initiation regardless of CD4 count

Extra-pulmonary TB

• Close consultation with appropriate specialists (ID physicians, neurologists)
• CNS, skeletal, miliary TB: treatment may be given up to 1 year

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12. Evidence Base

• Addition of fluoroquinolone (Lfx) to (H)REZ regimen:
  • Higher treatment success: aOR 2.8 (95% CI: 1.1–7.3)
  • Reduced deaths: aOR 0.4 (95% CI: 0.2–1.1)
  • Reduced acquisition of additional resistance/MDR-TB progression: aOR 0.10 (95% CI: 0.01–1.2)
• Duration: 6(H)REZ had higher success than >6(H)REZ
• Median FQ duration: 6.1 months (IQR 3.5–8.4); REZ: 9 months

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Summary Mnemonic

"H mono: Lfx-R-Z-E for 6(9) months, peripheral facility, culture-based outcome, replace in sequence (Lzd → Cfz+Cs), never empirical, no new drugs"