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🫁 Tuberculosis (TB) - Complete Exam Guide

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1. Etiology & Microbiology

• Causative organism: Mycobacterium tuberculosis (most common) - part of the M. tuberculosis Complex (MTBC)
• Other MTBC members: M. bovis, M. africanum, M. microti, M. canettii
• Key properties:
  • Acid-fast bacillus (AFB) - Ziehl-Neelsen stain (red rods on blue background)
  • Obligate aerobe - explains predilection for upper lobes
  • Slow dividing (18-24 hour generation time)
  • Non-motile, non-spore forming
  • Waxy, lipid-rich cell wall (mycolic acids) - responsible for acid-fastness, resistance to killing, and granuloma formation
  • ESX-1 Type VII secretion system secretes ESAT-6 and CFP-10 (virulence factors, also used in IGRA tests)
• Genome: 4 Mb circular genome, encoding ~4006 proteins; phylogenetically 7 major branches with geographic distribution

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2. Epidemiology

• Leading infectious disease killer worldwide (surpassing HIV)
• High burden countries: India, China, Indonesia, Philippines, Pakistan, Nigeria, South Africa
• Risk factors for infection:
  • Close household contact with active TB case
  • Overcrowding, poor ventilation
  • HIV/AIDS (greatest single risk factor)
  • Poverty, malnutrition, homelessness
  • Healthcare workers
  • Prisoners/institutional settings
• Risk factors for reactivation (LTBI to active TB):
  • HIV (highest risk - 5-10% per year vs 5-10% lifetime in immunocompetent)
  • TNF-alpha antagonists (infliximab, etanercept) - major risk, screen before starting
  • DM, CKD, malnutrition, silicosis
  • Corticosteroids, immunosuppressants
  • Young age (<5 years), old age

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3. Transmission

• Route: Airborne droplet nuclei (1-5 microns diameter)
• Source: Pulmonary/laryngeal TB patients (especially smear-positive, cavitary disease)
• Droplet nuclei survive 3-9 hours in air under standard conditions
• Environmental factors affect risk: ventilation, UV light exposure, air exchanges
• Close household contacts: ~50% become infected; ~15% non-close contacts
• Rate of TB ~15 per 1000 close contacts vs ~3 per 1000 non-close contacts

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4. Pathogenesis

4a. Primary Infection

1. Inhaled droplet nuclei reach alveoli
2. Engulfed by alveolar macrophages (primary host cell)
3. M. tb survives intracellularly - blocks phagosome-lysosome fusion (ESX-3 via EsxH)
4. Bacilli replicate, macrophages spread to regional lymph nodes
5. Ghon focus (parenchymal lesion) + hilar lymphadenopathy = Ghon complex (Ranke complex)
6. Bacilli may enter bloodstream (occult bacteremia) - seeding multiple sites

4b. Granuloma Formation (Key)

• Hallmark: caseating granuloma (caseous necrosis in center)
• Structure: Central caseous necrosis → Epithelioid macrophages → Multinucleated Langhans giant cells → Rim of lymphocytes → Fibroblasts
• Cell-mediated immunity (CD4+ T cells, IFN-gamma, TNF-alpha) critical for containment
• TST/IGRA positivity develops 2-8 weeks after infection

4c. Latent TB Infection (LTBI)

• Bacilli remain dormant within granulomas
• No symptoms, not infectious, positive TST/IGRA
• Reactivation risk when immunity wanes

4d. Post-primary (Reactivation) TB

• Apical and posterior segments of upper lobes (high O2 tension)
• Cavitation occurs - enormously infectious
• Fibrocaseous disease, bronchogenic spread

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5. Clinical Features

Pulmonary TB (most common, ~80%)

• Constitutional symptoms (B symptoms): fever, night sweats, weight loss - classic triad
• Examination: Dullness/bronchial breathing at apex, post-tussive crepitations
• CXR findings: Apical infiltrates, cavities, fibrosis, calcification, pleural effusion, miliary nodules

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6. Extrapulmonary TB (EPTB)

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7. Diagnosis

7a. Tuberculin Skin Test (TST / Mantoux)

• 0.1 mL of 5 TU PPD injected intradermally; read at 48-72 hours
• Interpretation of induration (not erythema):

• False negative: HIV/immunosuppression, miliary TB, recent viral illness, malnutrition, improper technique
• False positive: BCG vaccination, NTM infection (Mantoux <15mm usually from BCG)
• Booster effect (two-step testing): for healthcare workers

7b. Interferon-Gamma Release Assays (IGRAs)

• QuantiFERON-TB Gold Plus (QFT-Plus), T-SPOT.TB
• Blood test; measures IFN-gamma response to ESAT-6 and CFP-10 antigens
• Advantages over TST: Not affected by BCG vaccination; more specific; single visit
• Preferred in BCG-vaccinated populations
• Same uses as TST - diagnoses LTBI, NOT active disease

7c. Sputum Microscopy (AFB Smear)

• 3 sputum specimens (at least 2): early morning preferred
• Ziehl-Neelsen (ZN) stain or fluorescent auramine-rhodamine stain
• Sensitivity 60-80% in smear-positive; lower for smear-negative, extrapulmonary
• Grade smear: 1+ to 4+ or scanty
• Requires 5000-10,000 bacilli/mL to be smear positive
• Cannot distinguish M. tuberculosis from NTM

7d. Mycobacterial Culture (Gold Standard)

• Lowenstein-Jensen (LJ) medium: solid, buff-colored, rough, raised colonies; 6-8 weeks
• Middlebrook 7H9/7H10/7H11: liquid and solid
• BACTEC MGIT (automated liquid): faster, 1-3 weeks
• Can distinguish species and perform Drug Susceptibility Testing (DST)

7e. Nucleic Acid Amplification Tests (NAATs)

• Xpert MTB/RIF (CBNAAT/GeneXpert): WHO-recommended first-line rapid test
  • 2-hour turnaround; detects M. tb AND rifampicin resistance (rpoB gene) simultaneously
  • Sensitivity: ~90% smear+, ~70% smear- cases
  • Point-of-care available
• Xpert MTB/RIF Ultra: more sensitive than original (especially smear-negative, TBM)
• Line Probe Assays (LPA): GenoType MTBDRplus - rapid DST for isoniazid and rifampicin resistance; GenoType MTBDRsl for fluoroquinolone/second-line resistance

7f. Additional Investigations

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8. Treatment

First-Line Anti-TB Drugs (RIPE / HRZE)

Standard Treatment Regimen

• 2 HRZE / 4 HR (6 months total)
  • Intensive phase: 2 months - HRZE (Isoniazid + Rifampicin + Pyrazinamide + Ethambutol)
  • Continuation phase: 4 months - HR (Isoniazid + Rifampicin)
• TB Meningitis/Bone/Pericardial: 2 HRZE / 10 HR (12 months total)
• Directly Observed Therapy (DOT) - mandatory to prevent resistance

LTBI Treatment Options

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9. Drug Resistance

• BPaL (Bedaquiline + Pretomanid + Linezolid) - approved for XDR-TB and treatment-intolerant MDR-TB (TB-PRACTECAL/ZeNix trials)
• BPaLM - adds Moxifloxacin (6-month regimen)
• Second-line drugs: Fluoroquinolones (levofloxacin, moxifloxacin), bedaquiline, linezolid, clofazimine, cycloserine, delamanid
• Duration: typically 18-24 months for MDR-TB

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10. TB & HIV Co-infection

• HIV is the biggest risk factor for TB - 20-30x increased risk
• CD4 <200: more atypical presentations (lower lobe, no cavities, miliary)
• IRIS (Immune Reconstitution Inflammatory Syndrome): worsening of TB symptoms after starting ART
• Start ART 2 weeks after anti-TB therapy if CD4 <50; 8 weeks if CD4 >50
• Rifampicin interacts with many ARVs (CYP450 inducer) - substitute rifabutin if on protease inhibitors
• HIV testing is mandatory in all TB patients

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11. TB Meningitis (High-Yield)

• Clinical criteria (max 6 pts): symptom duration >5 days (4 pts), systemic TB symptoms (2 pts), focal deficits (1 pt), CN palsy (1 pt), altered consciousness (1 pt)
• Imaging criteria (max 6 pts): basal meningeal enhancement (2 pts), tuberculoma (2 pts), precontrast basal hyperdensity (2 pts), hydrocephalus (1 pt), infarct (1 pt)
• CSF criteria (max 4 pts): lymphocytosis 10-500/μL, protein >1 g/L, glucose <2.2 mmol/L
• Score: ≥12 = definite; 10-11 = probable; 6-9 = possible; <6 = non-TB
• NAAT for TBM: sensitivity 56%, specificity 98% (meta-analysis)
• Treatment: 2 HRZE + 10 HR + dexamethasone (adjunct, reduces mortality)

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12. Prevention & Control

• BCG vaccine: given at birth; protects against miliary TB and TBM in children (60-80%); does NOT reliably prevent pulmonary TB in adults
• Infection control (4 categories):
  1. Clinician awareness - rapid diagnosis
  2. Administrative controls - respiratory isolation, surgical masks for patients
  3. Environmental controls - ventilation (negative pressure rooms), UV germicidal irradiation, air exchanges
  4. Personal protective equipment (PPE) - N95 respirator for HCWs entering isolation rooms
• Contact tracing: screen all household contacts (TST/IGRA, symptom screen, CXR)
• DOTS strategy (WHO): Directly Observed Therapy, Short-course - cornerstone of national programs
• END TB Strategy (WHO): target <10 cases/100,000 by 2035

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13. Special Scenarios (High Yield for Exams)

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14. Summary: Exam Quick Points

1. AFB stain = Ziehl-Neelsen; Culture = LJ medium (gold standard)
2. Ghon focus = parenchymal lesion; Ghon complex = focus + hilar lymph node
3. CBNAAT (Xpert MTB/RIF) = detects TB + rifampicin resistance simultaneously
4. ADA elevated in pleural, peritoneal, and CSF TB
5. Ethambutol - optic neuritis; INH - peripheral neuropathy (give B6/pyridoxine); Rifampicin - orange urine
6. MDR-TB = resistant to R + H; XDR-TB adds fluoroquinolone + bedaquiline/linezolid resistance
7. BCG protects children from miliary/meningeal TB, NOT adult pulmonary TB
8. IGRA preferred in BCG-vaccinated populations (not affected by BCG)
9. HIV = start ART after 2 weeks if CD4 <50, 8 weeks if CD4 >50
10. DOT (Directly Observed Therapy) = mandatory to prevent resistance

• Murray & Nadel's Textbook of Respiratory Medicine, pp. 1164-1253
• Tintinalli's Emergency Medicine, Ch. 6

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🔬 TB Diagnosis - Made Simple

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STEP 1 - Suspect TB (Clinical)

• Cough for >2 weeks?
• Night sweats + weight loss + fever?
• Contact with a TB patient?
• HIV positive?

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STEP 2 - Take an X-Ray

• White patches at the top of the lungs (upper lobe infiltrates)
• Holes (cavities) - very suspicious
• Miliary TB = "millet seeds" scattered all over

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STEP 3 - Test the Sputum

🔴 Test A - AFB Smear (Fast, Cheap)

• Patient spits sputum (3 samples, early morning best)
• Stain it with Ziehl-Neelsen (ZN) stain
• Seen under microscope as red rods on blue background
• Result in: same day
• Problem: doesn't confirm M. tuberculosis (could be other mycobacteria)

🟡 Test B - CBNAAT / GeneXpert (Fast + Smart)

• Same sputum sample
• Machine detects TB's DNA in 2 hours
• Also tells you if TB is resistant to Rifampicin (MDR-TB)
• WHO recommends this as first test
• Think of it as: "Google search for TB DNA"

🟢 Test C - Culture (Gold Standard but Slow)

• Grow the bacteria on LJ medium in a lab
• Takes 6-8 weeks (bacteria grow very slowly)
• Confirms exact species + which drugs it's sensitive to
• Best test, but too slow for starting treatment

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STEP 4 - Test for Past Exposure / Latent TB

🩺 Mantoux Test (TST)

• Inject a small amount (PPD) under the skin of the forearm
• Come back after 48-72 hours
• Measure the bump (induration) - NOT the redness
• If bump ≥ 10 mm → positive (likely been infected)
• Problem: BCG vaccination can give a false positive

🩸 IGRA / QuantiFERON (Blood Test)

• A blood test - measures immune response to TB proteins
• Not affected by BCG vaccine → more accurate in India
• Same idea as Mantoux but done in a lab

⚠️ Both Mantoux and IGRA only tell you "infected before" - they CANNOT tell if TB is active right now

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ADA Test (Special Situation)

• Check ADA (Adenosine Deaminase) level in that fluid
• If ADA > 40 U/L → strongly suggests TB
• Simple blood-like test done on the fluid sample

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🧠 Simple Memory Table

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🎯 One-Line Rule for Exams

Smear = quick screen → GeneXpert = confirm + resistance → Culture = gold standard → Mantoux/IGRA = latent TB only

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💊 First-Line Anti-TB Drugs - Simple Exam Guide

Memory Trick: "RIPE" or "HRZE"

Rifampicin + Isoniazid + Pyrazinamide + Ethambutol

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🔴 Drug 1 - RIFAMPICIN (R)

Classification

• Rifamycin antibiotic - bactericidal (kills bacteria)
• Most powerful sterilizing drug in the regimen

Mechanism (simple)

Blocks the bacteria's ability to make RNA

• Inhibits DNA-dependent RNA polymerase (β-subunit / rpoB gene)
• Without RNA → bacteria cannot make proteins → bacteria die

Common Adverse Effects

Drug Interactions ⚠️

• Rifampicin is a STRONG CYP450 enzyme INDUCER
• It SPEEDS UP the breakdown of many drugs → their levels fall

💡 Exam Tip: "Rifampicin reduces the effect of OCP" is a classic MCQ

Nursing Implications

• ✅ Warn patient urine/tears/sweat will turn orange - this is NORMAL, not blood
• ✅ Warn patients using contact lenses - lenses will stain orange permanently
• ✅ Tell female patients on OCP to use barrier contraception
• ✅ Take on empty stomach (1 hour before or 2 hours after food) for best absorption
• ✅ Monitor liver function tests (LFTs) regularly
• ✅ Do NOT give in severe liver disease

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🟡 Drug 2 - ISONIAZID (H / INH)

Classification

• Isonicotinic acid hydrazide - bactericidal (strongest early-killing drug)
• Prodrug - activated by the bacterial enzyme KatG

Mechanism (simple)

Stops the bacteria from building its protective waxy coat (cell wall)

• Inhibits mycolic acid synthesis (InhA enzyme)
• Without mycolic acid → bacteria's cell wall breaks → bacteria die

Common Adverse Effects

Drug Interactions

Nursing Implications

• ✅ Always give Pyridoxine (Vitamin B6) 25-50 mg/day with INH to prevent peripheral neuropathy
  • Especially important in: diabetics, alcoholics, malnourished, pregnant women, elderly
• ✅ Monitor for tingling/numbness in hands and feet (early neuropathy sign)
• ✅ Monitor liver function tests - warn about signs of hepatitis (yellow eyes, dark urine)
• ✅ Take on empty stomach (food reduces absorption)
• ✅ Avoid alcohol completely
• ✅ Monitor phenytoin levels if patient is on anti-epileptics

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🟢 Drug 3 - PYRAZINAMIDE (Z / PZA)

Classification

• Nicotinamide analogue - bactericidal in acidic environments
• Prodrug - activated by pyrazinamidase to pyrazinoic acid (POA)
• Only drug that works inside acidic macrophages (where TB hides)

Mechanism (simple)

Works inside the acidic environment of macrophages to kill hidden bacteria

• Disrupts mycobacterial membrane energy + inhibits fatty acid synthesis
• Uniquely active at acidic pH (inside phagolysosomes)
• Allows treatment to be shortened from 9 months to 6 months

Common Adverse Effects

Drug Interactions

Nursing Implications

• ✅ Monitor uric acid levels and LFTs regularly
• ✅ Advise patient to report joint pain (gout-like symptoms)
• ✅ Adequate hydration - drink plenty of water (helps uric acid excretion)
• ✅ Avoid sunlight/use sunscreen (photosensitivity)
• ✅ Monitor for jaundice (most hepatotoxic first-line drug)
• ✅ Used only in intensive phase (first 2 months) - not continued phase

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🔵 Drug 4 - ETHAMBUTOL (E / EMB)

Classification

• Synthetic bacteriostatic drug (slows bacteria, doesn't kill - at standard doses)
• Protects against development of rifampicin resistance

Mechanism (simple)

Breaks down the bacteria's cell wall scaffold

• Inhibits arabinosyl transferase (embB gene)
• Blocks synthesis of arabinogalactan (a key cell wall component)
• Without cell wall → bacteria become vulnerable

Common Adverse Effects

🚨 Optic neuritis is the KEY adverse effect of Ethambutol - test red-green color vision before starting!

Drug Interactions

Nursing Implications

• ✅ Baseline visual acuity test + red-green color vision test before starting
• ✅ Ask about vision changes at every visit - blurred vision, difficulty distinguishing red from green
• ✅ If patient reports any visual changes → STOP DRUG IMMEDIATELY and refer ophthalmology
• ✅ Avoid in children <5 years (cannot report visual symptoms reliably)
• ✅ Reduce dose in renal failure (drug accumulates → more eye toxicity)
• ✅ Do NOT give with antacids at the same time

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⚡ QUICK COMPARISON TABLE (Most Important for Exam)

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🎯 HEPATOTOXICITY - All 3 Can Cause It!

Rifampicin + Isoniazid + Pyrazinamide ALL cause liver damage

• ALT/AST > 3x normal WITH symptoms (nausea, jaundice, abdominal pain)
• ALT/AST > 5x normal even WITHOUT symptoms

• Yellow eyes/skin (jaundice)
• Dark urine (like tea)
• Pale/clay-coloured stools
• Right upper abdomen pain

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🧠 NURSING IMPLICATIONS - COMMON TO ALL DRUGS

1. DOT (Directly Observed Therapy) - watch patient swallow every dose
2. Never miss a dose - skipping doses causes drug resistance
3. Take medicines at the same time daily
4. Monitor LFTs, CBC, renal function regularly
5. Report side effects immediately - especially vision, numbness, yellow eyes
6. HIV test for all TB patients
7. Complete the full course even if feeling better
8. Sputum tests at 2 months, 5 months, end of treatment

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🔑 Classic Exam MCQ Clues

• Lippincott Illustrated Reviews: Pharmacology, Ch. 32
• Murray & Nadel's Textbook of Respiratory Medicine, p. 2106-2122

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🆕 MDR-TB Treatment Guidelines - 2024-2025 Update

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🔑 The Big Picture - What Changed?

Old approach: Long 18-24 month regimens with painful injectable drugs (kanamycin, amikacin) New approach: Short 6-month all-oral regimens - simpler, safer, more effective

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📋 Three Categories of MDR-TB Regimens (WHO 2025)

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🥇 TIER 1 - PREFERRED: 6-Month All-Oral Regimens

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🟢 Regimen 1: BPaLM

• Who gets BPaLM: MDR-TB/RR-TB patients sensitive to fluoroquinolones
• Duration: 6 months
• Moxifloxacin dropped if fluoroquinolone-resistant → becomes just BPaL (also 6-9 months)
• Success rate: ~76% (TB-PRACTECAL trial, Lancet 2024) vs 51% with old injectable regimen

• Bedaquiline: 400 mg daily x 2 weeks → 200 mg 3x/week x 24 weeks
• Pretomanid: 200 mg daily x 26 weeks
• Linezolid: 600 mg daily x 26 weeks (600 mg better tolerated than 1200 mg - ZeNix trial)

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🟡 Regimen 2: BDLLfxC

• Key advantage: Suitable for groups excluded from BPaLM:
  • ✅ Children of any age
  • ✅ Adolescents
  • ✅ Pregnant women
  • ✅ Breastfeeding women
• Duration: 6 months
• Delamanid replaces pretomanid (better safety profile in these populations)

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🥈 TIER 2: 9-Month All-Oral Regimen

• For MDR-TB without fluoroquinolone resistance
• All-oral, shorter than old regimens
• Still widely used - 99 countries using it by end of 2024
• Includes: bedaquiline, fluoroquinolone, ethionamide/prothionamide, ethambutol, pyrazinamide, clofazimine

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🥉 TIER 3 - LAST RESORT: 18-20 Month Regimens

• Only when shorter regimens fail or are not feasible
• May include amikacin (injectable) as a last option
• Still used in 54% of MDR-TB patients globally in 2024 (due to limited access to new drugs)

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📊 Global Uptake (WHO 2025 Report)

• A 6x increase in one year - the fastest scale-up in TB history
• By 2024, African Region (45%) and Eastern Mediterranean (57%) had highest 6-month regimen use

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⚠️ Where 6-Month Regimens Are NOT Recommended (2025)

Both BPaLM and BDLLfxC have limitations in certain complex TB forms:

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💊 New Drug Side Effects to Know

🚨 QTc prolongation is the most critical monitoring concern in BPaLM - multiple drugs in the regimen all prolong QTc (bedaquiline + moxifloxacin + clofazimine). ECG monitoring is mandatory.

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🆕 What's New in Drug-Susceptible TB (2025)

• Isoniazid (H) + Rifapentine (P) + Moxifloxacin (M) + Pyrazinamide (Z) x 2 months
• Then: Isoniazid + Rifapentine + Moxifloxacin x 2 months
• Rifapentine dose: 1200 mg, Moxifloxacin: 400 mg - daily dosing
• NOT recommended yet for extrapulmonary TB, children <12 years, HIV with CD4 <100, or pregnancy

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🆕 WHO 2025 New Guidelines on TB & Undernutrition

• Released October 2025 as Module 6 of consolidated TB guidelines
• Addresses undernutrition as a major driver of TB epidemic
• Recommends integrating nutritional support and food assistance into TB care

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🧠 Exam Summary Table

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📌 Key Facts for Exam MCQs

1. MDR-TB = resistant to Rifampicin + Isoniazid
2. Pre-XDR-TB = MDR + resistant to any fluoroquinolone
3. XDR-TB = MDR + fluoroquinolone + bedaquiline OR linezolid resistant
4. BPaLM = first-line preferred 6-month regimen since WHO 2022
5. BDLLfxC = second 6-month option added in 2024, safe in children/pregnancy
6. Linezolid 600 mg (not 1200 mg) - current recommendation (ZeNix trial)
7. ECG monitoring mandatory with BPaLM (QTc)
8. Clofazimine causes harmless skin discolouration (pink-brown)
9. Only 2 in 5 MDR-TB patients accessed treatment globally in 2024 (treatment gap remains huge)
10. DOT remains mandatory for all MDR-TB regimens

• Davoli et al., 2025 - 6-month MDR-TB regimens review (PMID: 40953688)
• Michalik et al., 2025 - DR-TB treatment advances (PMID: 40657634)
• WHO Global TB Report 2025

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🧠 TBM Treatment 2025 - Quick Reference

💊 Anti-TB Regimen (WHO 2025)

Children: Same 12-month regimen, weight-adjusted doses ⚠️ BPaLM and BDLLfxC are NOT recommended for TBM - poor CNS drug penetration

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🔴 Adjunctive Dexamethasone (Always Add)

• Dose: 0.3-0.4 mg/kg/day IV → taper over 6-8 weeks
• Reduces mortality and neurological disability
• 🆕 2026 Landmark RCT (Donovan et al., Nature Medicine): Dexamethasone benefit is genotype-dependent (LTA4H gene):
  • TT genotype → clear survival benefit from dexamethasone
  • CC/CT genotype → benefit uncertain (trial did not establish noninferiority of placebo)
  • Clinical implication: Dexamethasone remains standard of care for ALL patients until genotyping becomes routine - do NOT omit

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🧪 CSF Findings in TBM

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⚠️ Complications to Monitor

• Hydrocephalus - most common; needs VP shunt if severe
• Cranial nerve palsies - CN III, IV, VI (eye movement), VII (facial)
• Cerebral infarction - vasculitis of basal vessels
• SIADH - hyponatremia, fluid restriction needed
• Raised ICP - manage with head elevation, mannitol if severe

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🔑 5 Must-Know Points

1. Start treatment immediately on clinical suspicion - never wait for culture (takes weeks)
2. 12 months, not 6 - TBM needs longer treatment than pulmonary TB
3. Rifampicin + Isoniazid have the best CSF penetration of first-line drugs
4. Dexamethasone is mandatory - reduces death and disability (still standard of care 2025)
5. BPaLM/BDLLfxC = NOT for TBM - new short MDR regimens do not reach the CNS adequately

• Donovan et al., Nature Medicine 2026 - landmark Phase 3 RCT on dexamethasone genotyping (PMID: 41540106)
• Rosen's Emergency Medicine, p. 4418
• WHO Consolidated Guidelines Module 4: Treatment and Care, 2025

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🧠 Bottom-Line Memory Points

⚠️ Hepatotoxicity Alert: Rifampicin + Isoniazid + Pyrazinamide ALL three can damage the liver. Check LFTs before starting and regularly during treatment. Stop ALL drugs if ALT >3x ULN with symptoms, or >5x ULN even without symptoms.