How should latent tuberculosis infection be diagnosed and treated in an adult without active disease, including preferred regimen, alternative regimens, monitoring for toxicity, and special considerations such as pregnancy, hepatic risk, and drug interactions?

Diagnosis and Treatment of Latent Tuberculosis Infection in Adults

Diagnostic Approach

Either interferon-gamma release assays (IGRAs) or tuberculin skin testing (TST) can be used to diagnose latent TB infection, with IGRAs strongly preferred in BCG-vaccinated individuals due to superior specificity. 1

Testing Methods

• TST interpretation: Positive when induration ≥5 mm in high-risk individuals 2
• IGRA advantages: Not affected by prior BCG vaccination, more specific than TST, and performs better in immunosuppressed patients 1, 3
• Dual testing strategy: Consider performing both TST and IGRA in high-risk situations or high TB burden settings, where a positive result from either test is considered positive 1, 2

Pre-Treatment Evaluation

Active tuberculosis disease must be definitively excluded before initiating any latent TB treatment through chest radiography, clinical history, physical examination, and when indicated, bacteriologic studies. 1, 2

• Obtain three consecutive sputum samples for AFB smear and culture if chest radiograph shows findings suggestive of prior TB or if patient has respiratory symptoms 1
• HIV-infected persons with respiratory symptoms require sputum examination even with normal chest radiography 1
• A normal chest X-ray does not exclude active TB in immunocompromised patients 2

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Preferred Treatment Regimens

The most strongly recommended regimen is 3 months of once-weekly isoniazid (15 mg/kg, max 900 mg) plus rifapentine (weight-based dosing), offering excellent tolerability, shorter duration, and higher completion rates. 4, 5

Alternative Preferred Regimens (in order of preference)

1. 4 months of daily rifampin (10 mg/kg, max 600 mg): Strong recommendation for HIV-negative patients with moderate quality evidence 1, 4

2. 3 months of daily isoniazid (5 mg/kg, max 300 mg) plus rifampin (10 mg/kg, max 600 mg): Conditionally recommended, particularly useful when adherence to longer regimens is uncertain 1

3. 9 months of daily isoniazid (5 mg/kg, max 300 mg): Historically considered standard therapy with >90% efficacy if completed, but lower completion rates 4, 5

4. 6 months of daily isoniazid: Conditional recommendation, less effective than 9-month regimen but may be better tolerated 1, 4

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Baseline Testing and Monitoring

Baseline Laboratory Testing

Baseline liver function tests (AST/ALT and bilirubin) are NOT routinely indicated for all patients. 1, 2

Obtain baseline hepatic measurements only for:

• HIV-infected persons 1, 2
• Pregnant women and women within 3 months postpartum 1, 2
• Persons with history of chronic liver disease (hepatitis B or C, alcoholic hepatitis, cirrhosis) 1, 2
• Persons who use alcohol regularly 1, 2
• Patients whose initial evaluation suggests liver disorder 1, 2
• Baseline testing is NOT routinely indicated based solely on older age 1, 2

Clinical Monitoring Schedule

Monthly clinical evaluations for patients receiving isoniazid alone or rifampin alone. 1, 4

At weeks 2,4, and 8 for patients receiving rifampin plus pyrazinamide. 1, 2

• Assess for fever, malaise, vomiting, jaundice, or unexplained deterioration at each visit 2
• Educate patients to stop treatment immediately and seek medical evaluation if side effects occur 1

Hepatotoxicity Management

Withhold isoniazid if transaminase levels exceed 3 times the upper limit of normal with symptoms, or 5 times the upper limit if asymptomatic. 4, 2

• Active hepatitis and end-stage liver disease are relative contraindications to isoniazid or pyrazinamide 4, 2

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Special Populations

HIV-Infected Patients

For HIV-infected patients, 9 months (not 6 months) of isoniazid is recommended when isoniazid is chosen. 1, 2

• Rifampin-based regimens require careful review of antiretroviral drug interactions 2
• Rifabutin may be substituted when rifampin interactions are problematic 1
• Rifampin is contraindicated or should be used with extreme caution in patients taking protease inhibitors or NNRTIs 1

Pregnancy

For pregnant HIV-negative women, isoniazid daily or twice weekly for 9 or 6 months is recommended. 1, 2

• For women at high risk (HIV-infected or recently infected), initiation should not be delayed even during the first trimester 1, 2
• For lower-risk women, some experts recommend waiting until after delivery 1, 2
• Rifampin-based regimens can be used in pregnant women with careful monitoring 4
• Pyridoxine supplementation should be given with isoniazid to prevent peripheral neuropathy 1

Children and Adolescents

For children and adolescents, isoniazid daily (10-15 mg/kg, max 300 mg) or twice weekly for 9 months is the recommended regimen. 1, 2

• TST is preferred over IGRA for children <5 years 2
• Rifampin-based approaches appear safe and effective in children 4

Contacts of Drug-Resistant TB

For contacts of isoniazid-resistant, rifampin-susceptible TB: rifampin and pyrazinamide daily for 2 months is recommended. 1, 2

• For pyrazinamide intolerance: rifampin alone for 4 months 1, 2

For contacts of multidrug-resistant TB (isoniazid and rifampin resistant): pyrazinamide and ethambutol OR pyrazinamide and a fluoroquinolone (levofloxacin or ofloxacin) for 6-12 months. 1

• Immunocompetent contacts may be observed or treated for at least 6 months 1
• Immunocompromised contacts (e.g., HIV-infected) should be treated for 12 months 1
• Selection of drugs should be guided by susceptibility testing from the source case 1

Patients on Immunosuppressive Therapy

All individuals scheduled to receive anti-TNF therapy, cytotoxic chemotherapy, or other immunosuppressive agents must undergo comprehensive LTBI screening before treatment initiation. 1, 2, 6

• At least 3 weeks of anti-tuberculous therapy should be completed before starting immunosuppressive therapy when feasible 2
• The 3-month once-weekly isoniazid plus rifapentine regimen is preferred due to shorter duration 2
• Consider dual testing (both TST and IGRA) in high-risk situations 1, 6

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Drug Interactions

Rifamycin-based regimens have significant drug interactions with many medications including protease inhibitors, NNRTIs, methadone, warfarin, glucocorticoids, hormonal contraceptives, oral hypoglycemic agents, digitalis, anticonvulsants, and cyclosporine. 1, 4

• Review current interaction guidance before prescribing rifampin or rifapentine 2
• Rifabutin can be substituted when rifampin interactions are problematic, though dose adjustments are often required 1
• Rifampin may permanently discolor soft contact lenses 1

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Critical Pitfalls to Avoid

Never start treatment for latent TB without definitively excluding active TB disease, as single-drug treatment of unrecognized active TB leads to drug resistance. 1, 2

Never assume a normal chest X-ray excludes active TB in immunocompromised patients; maintain high clinical suspicion and obtain sputum cultures when indicated. 2

Never ignore symptoms of hepatotoxicity (fever, malaise, vomiting, jaundice); patients must stop treatment immediately and seek urgent evaluation. 1, 2

Never add a single drug to a failing regimen, as this promotes drug resistance. 4

Always verify antiretroviral compatibility before prescribing rifamycin-based regimens in HIV patients to avoid treatment failure. 2

Do not routinely obtain baseline liver function tests in all patients; target testing to high-risk groups only. 1, 2

BCG vaccination history should NOT influence the decision to treat LTBI; apply standard criteria without modification. 1