Treatment of Latent Tuberculosis Infection
The preferred first-line regimen for latent TB is 3 months of once-weekly isoniazid plus rifapentine (3HP), which has equivalent efficacy to 9 months of isoniazid but with significantly higher completion rates (82% vs 69%) and better safety profile. 1, 2
Preferred First-Line Regimens
The CDC, American Thoracic Society, and Infectious Diseases Society of America now recommend three shorter regimens over the traditional 9-month isoniazid:
3 months of once-weekly isoniazid plus rifapentine (3HP) - This directly observed regimen is as effective as 9 months of isoniazid in preventing active TB (0.2% vs 0.4% incidence), with 19% higher completion rates and 84% less hepatotoxicity 1, 2, 3
4 months of daily rifampin (4R) - Non-inferior to 9 months of isoniazid for preventing active TB, with 15% higher treatment completion rates and significantly less hepatotoxicity (1.1 percentage point difference in grade 3-5 adverse events) 1, 2, 4
3 months of daily isoniazid plus rifampin (3HR) - Equivalent effectiveness to longer regimens with higher completion rates, particularly useful when directly observed therapy is not feasible 1, 2
Alternative Regimens When Preferred Options Cannot Be Used
9 months of daily isoniazid (9H) - Conditionally recommended when rifamycin-based regimens are contraindicated, with 60-90% protective efficacy if completed 5, 1
6 months of daily isoniazid (6H) - Provides substantial protection but is inferior to 9 months for HIV-positive persons and those with radiographic evidence of prior TB 5, 2
Critical Pre-Treatment Requirements
Active TB disease must be ruled out before initiating LTBI treatment through:
- History and physical examination focusing on TB symptoms (cough, fever, night sweats, weight loss) 5, 2
- Chest radiography to exclude pulmonary TB 5, 2
- Bacteriologic studies (sputum cultures) when clinically indicated 5, 2
Special Population Considerations
HIV-Infected Persons
- 3HP regimen is equally effective in HIV-positive and HIV-negative persons and is preferred 2
- If isoniazid is chosen, use 9 months rather than 6 months 5, 1, 2
- Rifabutin may substitute for rifampin when drug interactions with protease inhibitors or antiretroviral therapy occur 5, 1
Pregnant Women
- For HIV-negative pregnant women, isoniazid (9 or 6 months) is recommended 5
- For women at high risk (HIV-infected or recently infected), treatment should not be delayed based on pregnancy alone, even during the first trimester 5, 2
- Rifampin is not recommended during pregnancy 5, 6
Children and Adolescents
- 3HP is preferred for children ≥2 years old 2
- 4R is preferred for children of all ages as an alternative 2
- 9 months of isoniazid is the traditional pediatric regimen 5
- Short-course rifampin-based regimens (3-4 months) appear superior to 9 months isoniazid in children, with better compliance and fewer radiographic findings suggestive of disease progression 7
Drug-Resistant TB Contacts
- Contacts of isoniazid-resistant, rifampin-susceptible TB: rifampin plus pyrazinamide for 2 months, or rifampin alone for 4 months if pyrazinamide is not tolerated 5
- Contacts of multidrug-resistant TB (isoniazid and rifampin resistant): pyrazinamide plus ethambutol OR pyrazinamide plus a fluoroquinolone (levofloxacin or ofloxacin) for 6-12 months 5
Monitoring and Safety
Baseline Assessment
- Obtain baseline liver function tests for patients with suspected liver disorders, HIV infection, pregnancy/postpartum period, or chronic conditions increasing liver disease risk 2
- Assess for risk factors of hepatotoxicity including age >35 years, alcohol use, chronic liver disease, and concurrent hepatotoxic medications 1
Follow-Up Schedule
- Monthly clinical evaluations for patients on isoniazid or rifampin monotherapy 5, 2
- Evaluations at 2,4, and 8 weeks for patients on rifampin plus pyrazinamide regimens 5
- At each visit, assess for hepatitis symptoms (nausea, vomiting, abdominal pain, jaundice, dark urine) and discontinue treatment if evidence of liver injury occurs 5, 2
Hepatotoxicity Risk by Regimen
- Rifampin plus pyrazinamide has unacceptably high hepatotoxicity risk in HIV-negative adults and is not recommended 1, 2, 8
- 4 months rifampin has significantly lower hepatotoxicity than 9 months isoniazid (1.2 percentage point difference) 4
- 3HP has 84% less hepatotoxicity than 9 months isoniazid 3
Critical Drug Interactions and Pitfalls
Rifamycin Drug Interactions
- Warfarin: rifamycins significantly reduce anticoagulant effect, requiring dose adjustments and close INR monitoring 1
- Oral contraceptives: rifamycins reduce effectiveness; recommend barrier contraception during treatment 1
- HIV antiretroviral therapy: significant interactions with protease inhibitors and NNRTIs; consider rifabutin substitution or alternative LTBI regimen 5, 1
- Antifungals: rifamycins reduce levels of azole antifungals 1
Common Pitfalls to Avoid
- Never use rifapentine as monotherapy - it is only approved in combination with isoniazid 2
- Never use 2-month rifampin-pyrazinamide (2RZ) in HIV-negative adults due to severe hepatotoxicity risk 2, 8
- Never add a single drug to a failing regimen - always add at least 2 drugs to which the organism is susceptible to prevent resistance 5
- Rifampin should be administered 1 hour before or 2 hours after meals with a full glass of water for optimal absorption 6