Updated Treatment Regimens for Latent Tuberculosis Infection
The current standard of care prioritizes three short-course rifamycin-based regimens over traditional isoniazid monotherapy: 3 months of once-weekly isoniazid-rifapentine (3HP), 4 months of daily rifampin (4R), or 3 months of daily isoniazid-rifampin (3HR), all of which demonstrate superior completion rates and comparable or better safety profiles compared to longer isoniazid regimens. 1
Preferred First-Line Regimens
The 2020 CDC/NTCA guidelines establish three rifamycin-based regimens as preferred options 1:
3 months of once-weekly isoniazid-rifapentine (3HP): This regimen is as effective as 9 months of isoniazid with significantly higher treatment completion rates (87.5% vs 65.9%) and similar safety profiles 2. It is now approved for adults and children ≥2 years, including persons with HIV on compatible antiretroviral therapy 1.
4 months of daily rifampin (4R): Demonstrates clinically equivalent effectiveness to 9 months of isoniazid with lower toxicity, particularly hepatotoxicity, and higher completion rates 3, 4. This regimen is suitable for all ages including children 3.
3 months of daily isoniazid-rifampin (3HR): Offers equivalent effectiveness to longer isoniazid regimens with the advantage of shorter duration 1, 4.
Alternative Regimens (When Rifamycins Contraindicated)
9 months of daily isoniazid (9H): Provides 60-90% protective efficacy if completed, but has lower completion rates and higher hepatotoxicity risk than rifamycin-based regimens 3. This is the preferred isoniazid duration for HIV-infected persons when rifamycins cannot be used 1, 3, 4.
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 3. Not recommended for these populations 3.
Special Population Considerations
HIV-Infected Persons
- 3HP is equally effective in HIV-positive and HIV-negative persons and is preferred 3, 4
- When using isoniazid monotherapy, 9 months is mandatory rather than 6 months 1, 3, 4
- Rifabutin can substitute for rifampin when drug interactions with antiretroviral medications preclude rifampin use 4
- Management should involve clinicians experienced in both TB and HIV treatment 1
Pregnant Women
- For HIV-negative pregnant women, isoniazid (9 or 6 months) is recommended 3
- For high-risk women (HIV-infected or recently infected), treatment should not be delayed based on pregnancy alone, even in the first trimester 3, 4
- Rifampin is not recommended during pregnancy 3
Children and Adolescents
- 3HP is approved for children ≥2 years old 1
- 4R is suitable for children of all ages 3
- For children aged 2-5 years at higher risk for progression, some experts prefer directly observed therapy (DOT) over self-administered therapy (SAT), though both are acceptable 1
- Short-course rifampin-based regimens appear superior to 9 months isoniazid in children 3
Administration Methods
The choice between DOT and SAT should be based on local practice, patient age, medical history, social circumstances, and risk for progression to severe TB disease 1:
- 3HP can be administered by either DOT or SAT in persons ≥2 years 1
- Intermittent (twice-weekly) isoniazid regimens must always be administered as DOT 3
- For young children (2-5 years) with higher risk for severe disease, DOT may be preferred 1
Critical Pre-Treatment Requirements
Active TB disease must be ruled out before initiating LTBI treatment 3, 4:
- Conduct history and physical examination focusing on TB symptoms (cough, fever, night sweats, weight loss)
- Obtain chest radiography
- Perform bacteriologic studies when clinically indicated 3, 4
Monitoring and Safety Protocols
Baseline Testing
Obtain baseline hepatic chemistry tests (at least AST) for patients with 1:
- HIV infection
- Liver disorders or suspected liver disease
- Postpartum period (≤3 months after delivery)
- Regular alcohol use
- Injection drug use
- Medications with known hepatic interactions
- Pregnancy or immediate postpartum period 3, 4
Ongoing Monitoring
- Monthly evaluations (in-person or telephone) for all patients to assess adherence and adverse effects 1, 3, 4
- Educate patients at each visit about adverse effects and instruct them to seek immediate medical attention for symptoms 1
- Discontinue treatment if AST ≥5 times upper limit of normal without symptoms, or ≥3 times upper limit of normal with symptoms 1
3HP-Specific Adverse Events
- Approximately 4-5% experience flu-like systemic drug reactions (fever, headache, dizziness, nausea, muscle pain, rash) typically occurring after the first 3-4 doses, beginning ~4 hours post-ingestion 1
- Hypotension and syncope occur rarely (2 per 1,000 persons) 1
- If systemic drug reaction occurs, stop 3HP while determining cause; symptoms usually resolve within 24 hours without treatment 1
- Neutropenia and liver enzyme elevation occur uncommonly 1
Critical Drug Interactions and Contraindications
Rifapentine and rifampin are potent enzyme inducers affecting multiple medications 1, 4:
- Monitor closely when prescribed with methadone or warfarin 1
- Rifapentine reduces effectiveness of hormonal contraceptives; women should add or switch to barrier methods 1
- Check antiretroviral drug interactions before prescribing to HIV-infected persons 1, 4
- Women should inform providers if planning pregnancy or becoming pregnant during treatment 1
Common Pitfalls to Avoid
- Never use rifapentine as monotherapy—it is only approved in combination with isoniazid 4
- Never use 2 months of rifampin-pyrazinamide (2RZ) in HIV-negative adults due to unacceptably high hepatotoxicity risk 1, 4
- Do not confuse rifampin and rifapentine—they are not interchangeable and have different dosing schedules 1
- Never add a single drug to a failing regimen—always add at least 2 drugs to prevent resistance 3
- Do not use 6-month isoniazid for HIV-infected persons or those with radiographic evidence of prior TB—9 months is required 3
- Report any LTBI treatment-associated adverse event leading to hospitalization or death to local/state health departments and FDA MedWatch 1