How should latent tuberculosis infection be managed in an otherwise healthy adult who is about to start cytotoxic chemotherapy?

Management of Latent Tuberculosis Infection Before Cytotoxic Chemotherapy

All patients about to start cytotoxic chemotherapy should be screened for latent tuberculosis infection, and if positive, must receive at least 3 weeks of anti-tuberculous treatment before initiating chemotherapy, with the preferred regimen being 3 months of once-weekly isoniazid plus rifapentine (3HP). 1, 2

Screening Requirements

Comprehensive TB screening is mandatory before starting chemotherapy and should include: 1, 2

• Patient history: Recent TB exposure, residence/travel in endemic areas, prior TB infection or treatment, and other risk factors 2
• Chest X-ray: To exclude active pulmonary TB, though normal imaging does not definitively rule out active disease in immunocompromised patients 2
• Tuberculin skin test (TST) and/or interferon-gamma release assay (IGRA): IGRAs are preferred in BCG-vaccinated individuals due to superior specificity 1, 2
• Physical examination: To assess for signs of active disease 2

Key Screening Considerations

• TST interpretation: A positive result is defined by induration diameter ≥5 mm 1, 2
• TST limitations: May be false negative in patients on corticosteroids for >1 month or immunomodulators for >3 months; cannot be adequately interpreted unless these medications are discontinued appropriately 1, 2
• IGRA advantages: Not affected by prior BCG vaccination and demonstrate superior specificity in vaccinated individuals 1, 2
• Booster TST: May be appropriate 1-2 weeks after initial negative test in patients on immunomodulators, diagnosing 8-14% additional cases 1, 2

Treatment Regimens for Latent TB

Active tuberculosis disease must be definitively excluded before initiating any latent TB treatment through detailed history, physical examination, chest radiography, and when indicated, bacteriologic studies. 2, 3

Preferred Treatment Options

The most strongly recommended regimen is 3 months of once-weekly isoniazid plus rifapentine (3HP), offering excellent tolerability, shorter duration, and higher completion rates: 2, 3, 4

• Adults and children ≥12 years: Rifapentine dose determined by weight (300-900 mg once weekly) plus isoniazid 15 mg/kg (rounded to nearest 50 or 100 mg) up to maximum 900 mg once weekly 3
• Children 2-11 years: Rifapentine dose determined by weight (300-900 mg once weekly) plus isoniazid 25 mg/kg (rounded to nearest 50 or 100 mg) up to maximum 900 mg once weekly 3

Alternative regimens include: 2, 4

• 4 months of daily rifampin (strong evidence for HIV-negative patients) 2
• 3 months of daily isoniazid plus rifampin (conditional recommendation) 2
• 9 months of daily isoniazid at 5 mg/kg up to 300 mg daily (historically considered standard therapy) 2
• 6 months of daily isoniazid (conditional recommendation with moderate evidence) 2

Timing of Chemotherapy Initiation

When there is latent TB and active underlying disease requiring urgent treatment, chemotherapy should be delayed for at least 3 weeks after starting anti-tuberculous treatment, except in cases of greater clinical urgency and with specialist advice. 1

Risk-Stratified Approach

• Low-risk patients: Chemotherapy can be started after at least 1 month of LTBI treatment 5
• High-risk patients (recent TB contacts, immigrants from high-incidence areas, IV drug users): Complete the full LTBI treatment course before starting chemotherapy 5
• Cases of greater clinical urgency: May proceed with chemotherapy earlier than 3 weeks with specialist infectious disease consultation 1

Monitoring During Treatment

Baseline liver function tests (AST/ALT and bilirubin) are indicated for: 2

• HIV-infected patients 2
• Pregnant women and women within 3 months postpartum 2
• Persons with history of chronic liver disease 2
• Persons who use alcohol regularly 2
• Patients with initial evaluation suggesting liver disorder 2

Baseline testing is NOT routinely indicated for all patients or based solely on older age. 2

Ongoing monitoring schedule: 2

• Monthly evaluations for patients receiving isoniazid alone or rifampin alone 2
• At 2,4, and 8 weeks for patients receiving rifampin plus pyrazinamide 2
• Assess for symptoms of fever, malaise, vomiting, jaundice, or unexplained deterioration at each visit 2

Withhold treatment if: 2

• Transaminase levels exceed 3 times upper limit of normal if symptomatic 2
• Transaminase levels exceed 5 times upper limit of normal if asymptomatic 2

Special Considerations for Chemotherapy Patients

Patients with abnormal liver tests and/or liver disease should only be given LTBI treatment in cases of necessity and under strict medical supervision, with serum transaminase levels obtained prior to therapy and every 2-4 weeks while on therapy. 3

In the context of tuberculosis endemic areas (particularly Asia): 1

• Routine Mantoux test and chest X-ray are recommended for all newly diagnosed cancer patients 1
• A positive Mantoux test (induration >20 mm) requires investigations to isolate Mycobacterium tuberculosis 1
• Early morning gastric aspirate or induced sputum for 3 consecutive days to look for acid-fast bacilli and TB culture is recommended 1
• Prophylactic treatment with rifampin for at least 6 months is commonly practiced in endemic areas, even without definite focus of infection or positive culture 1

Critical Pitfalls to Avoid

Never assume normal chest X-ray excludes TB in immunocompromised patients; maintain high clinical suspicion and proceed with sputum collection if clinical suspicion remains high despite normal imaging. 2

Never start LTBI treatment without excluding active TB, as this risks acquired drug resistance if unrecognized active disease is present. 2

Never delay chemotherapy for prolonged periods when clinically urgent; collaborate with infectious disease specialists to balance TB treatment needs with cancer treatment urgency. 1

Never ignore symptoms of hepatotoxicity; patients should stop treatment immediately and seek evaluation when side effects occur. 2

Active hepatitis and end-stage liver disease are relative contraindications to isoniazid or pyrazinamide for latent TB treatment. 2

Multidisciplinary Collaboration

Collaboration between oncologists and specialists including infectious disease doctors, pulmonologists, and hepatologists is essential for optimal management. 1