What is the recommended treatment regimen for latent tuberculosis (TB) infection?

Treatment of Latent Tuberculosis Infection

The preferred first-line regimen for latent TB is 3 months of once-weekly isoniazid plus rifapentine (3HP), which offers equivalent efficacy to 9 months of isoniazid with superior completion rates and lower hepatotoxicity. 1, 2

Preferred First-Line Regimens

3 Months of Once-Weekly Isoniazid Plus Rifapentine (3HP)

• This is the preferred regimen for HIV-negative adults and children ≥2 years old, demonstrating equivalent efficacy to 9 months of isoniazid but with significantly higher completion rates (82% vs 69%) and dramatically lower hepatotoxicity (0.4% vs 2.4%). 1, 2, 3
• This regimen is equally effective in HIV-positive persons, making it an excellent choice across populations. 1, 2
• Must be administered as directly observed therapy (DOT) once weekly for 12 weeks. 4
• Dosing for adults and children ≥12 years: Weight-based from 300 mg (10-14 kg) up to maximum 900 mg (>50 kg), combined with isoniazid 15 mg/kg up to 900 mg weekly. 4
• Dosing for children 2-11 years: Same weight-based rifapentine dosing, but isoniazid dose is 25 mg/kg up to 900 mg weekly. 4

4 Months of Daily Rifampin (4R)

• This is the alternative preferred regimen for HIV-negative adults and children of all ages, demonstrating clinically equivalent effectiveness to 9 months of isoniazid with significantly lower toxicity and higher completion rates. 1, 2, 5
• A landmark 2018 trial of 6,859 patients showed rifampin was non-inferior to isoniazid for preventing active TB, with 15.1% higher treatment completion and 1.2% fewer hepatotoxic events. 5
• This regimen is particularly useful when DOT is not feasible since it can be self-administered daily. 5
• Dose is 600 mg daily for 4 months in adults. 6

Alternative Regimens

9 Months of Daily Isoniazid (9H)

• For HIV-infected persons, 9 months is strongly preferred over 6 months when rifamycin-based regimens cannot be used. 1, 2, 7
• Efficacy exceeds 90% when completed properly, but completion rates are poor (around 69% in trials, often <50% in real-world practice). 7, 8, 3
• Can be administered daily as self-administered therapy or twice-weekly as DOT. 6, 7
• For children and adolescents, this remains the traditional pediatric regimen, though short-course rifamycin-based regimens appear superior. 6, 2, 9

6 Months of Daily Isoniazid (6H)

• Provides substantial protection but is inferior to 9-month regimens. 6, 2
• Should NOT be used in HIV-infected persons or those with radiographic evidence of prior TB—always use 9 months for these populations. 6, 1, 2
• May be considered for HIV-negative adults and children when longer regimens are not feasible. 1

Critical Pre-Treatment Requirements

Active TB disease must be ruled out before initiating any LTBI treatment through:

• Detailed history focusing on TB symptoms (cough, fever, night sweats, weight loss). 6, 1, 2
• Physical examination checking for signs of active disease. 6, 1, 2
• Chest radiography to exclude pulmonary TB. 6, 1, 2
• Bacteriologic studies (sputum cultures) when clinically indicated by symptoms or radiographic findings. 6, 1, 2

Monitoring During Treatment

Baseline Assessment

• Obtain baseline liver function tests (AST/ALT, bilirubin) for high-risk patients: those with suspected liver disorders, HIV infection, pregnancy or immediate postpartum period (within 3 months of delivery), history of chronic liver disease (hepatitis B/C, alcoholic hepatitis, cirrhosis), regular alcohol use, or other conditions increasing liver disease risk. 6, 1, 2
• Baseline testing is NOT routinely indicated for all patients or based solely on age. 6

Follow-Up Monitoring

• Perform monthly clinical evaluations for patients on isoniazid or rifampin monotherapy, assessing for symptoms of hepatitis and other adverse effects. 6, 1, 2
• For patients on rifampin plus pyrazinamide (if used), evaluate at 2,4, and 8 weeks. 6
• Educate patients to stop treatment immediately and seek medical evaluation if symptoms of liver injury occur (nausea, vomiting, abdominal pain, jaundice, dark urine). 6, 1
• Discontinue treatment if evidence of liver injury develops. 1, 2

Special Population Considerations

Pregnant Women

• For women at high risk (HIV-infected or recently infected), treatment should NOT be delayed based on pregnancy alone, even in the first trimester. 6, 1, 2
• For HIV-negative pregnant women, isoniazid for 9 or 6 months is recommended. 6, 2, 7
• For women whose risk for active TB is lower, some experts recommend waiting until after delivery. 6
• Rifampin is not recommended during pregnancy. 2

HIV-Infected Persons

• The 3HP regimen is equally effective and represents an excellent choice. 1, 2
• If isoniazid is chosen, always use 9 months rather than 6 months. 6, 1, 2, 7
• Isoniazid plus antiretroviral therapy decreases TB incidence more than either intervention alone in high TB incidence areas. 1
• Consider drug interactions: rifapentine should not be used with ritonavir, hard-gel saquinavir, or delavirdine; dose adjustments may be required with other protease inhibitors or NNRTIs. 6

Children and Adolescents

• 3HP is approved for children ≥2 years old with appropriate weight-based dosing. 1, 4
• 4 months of rifampin is preferred for children of all ages. 1
• A 2007 pediatric trial showed 3-4 months of isoniazid plus rifampin was superior to 9 months of isoniazid, with better compliance and fewer radiographic findings suggestive of disease progression. 9
• Traditional 9-month isoniazid regimen remains an option but has lower completion rates. 6, 2

Drug-Resistant Exposure

• For contacts of isoniazid-resistant, rifampin-susceptible TB: Use rifampin plus pyrazinamide daily for 2 months, or rifampin alone for 4 months if pyrazinamide is not tolerated. 6, 2
• For contacts of multidrug-resistant TB (isoniazid and rifampin resistant): Use pyrazinamide plus ethambutol OR pyrazinamide plus a fluoroquinolone (levofloxacin or ofloxacin) for 6-12 months. 6, 2
• Immunocompetent contacts may be observed or treated for at least 6 months; immunocompromised contacts (HIV-infected) should be treated for 12 months. 6

Critical Pitfalls to Avoid

Never Use These Regimens

• NEVER use 2-month rifampin-pyrazinamide (2RZ) in HIV-negative adults due to unacceptably high hepatotoxicity risk (severe liver toxicity rates significantly exceed other regimens). 1, 2, 8
• NEVER use rifapentine as monotherapy—it must always be combined with isoniazid. 1, 2, 4
• NEVER use 6-month isoniazid in HIV-infected persons when 9-month regimens or shorter rifamycin-based regimens are available. 1, 2

Administration Errors to Avoid

• NEVER initiate LTBI treatment without first excluding active TB disease—this is the most critical error that can lead to inadequate treatment of active disease and development of drug resistance. 6, 1, 2
• Rifapentine for 3HP must have an interval of at least 3 days (72 hours) between doses when used for active TB, but is given once weekly for LTBI. 4
• All twice-weekly regimens must be administered as directly observed therapy. 6, 2
• Take rifamycin-containing regimens with meals to increase bioavailability and reduce gastrointestinal side effects. 4