Treatment of Latent Tuberculosis Infection
The preferred first-line treatment 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 and less hepatotoxicity. 1, 2
Preferred First-Line Regimens
The CDC and American Thoracic Society recommend three preferred short-course regimens that have revolutionized LTBI treatment 1, 2:
3 months of once-weekly isoniazid plus rifapentine (3HP): This is the top-tier recommendation for HIV-negative adults and children ≥2 years old, with completion rates superior to traditional 9-month isoniazid and equivalent efficacy 1, 2
4 months of daily rifampin (4R): This is strongly recommended as a preferred alternative for HIV-negative adults and children of all ages, demonstrating non-inferiority to 9 months of isoniazid with significantly better safety profiles and higher completion rates 1, 2, 3
3 months of daily isoniazid plus rifampin: This regimen offers excellent efficacy with higher completion rates than longer regimens 2
The landmark NEJM trial comparing 4 months of rifampin versus 9 months of isoniazid demonstrated that rifampin was non-inferior for preventing active TB, with a 15.1 percentage point higher completion rate and 1.2 percentage points lower rate of hepatotoxic events 3.
Alternative Regimens When Rifamycins Cannot Be Used
9 months of daily isoniazid (9H): This is conditionally recommended when rifamycin-based regimens are contraindicated, with 60-90% protective efficacy if completed 1
6 months of daily isoniazid (6H): This provides substantial protection but is explicitly NOT recommended for HIV-positive persons or those with radiographic evidence of prior TB, where 9 months is required 1, 2
Critical Pre-Treatment Requirements
Active TB disease MUST be ruled out before initiating any LTBI treatment through history and physical examination focusing on TB symptoms (cough, fever, night sweats, weight loss), chest radiography, and bacteriologic studies when clinically indicated 4, 1, 2.
Special Population Considerations
HIV-Infected Persons
- The 3HP regimen is equally effective in HIV-positive and HIV-negative persons and is preferred 1, 2
- If isoniazid monotherapy is chosen, 9 months is required rather than 6 months 4, 1, 2
- Rifabutin may be substituted for rifampin when drug interactions with antiretroviral medications (particularly protease inhibitors) preclude rifampin use 4, 2
Pregnant Women
- For HIV-negative pregnant women, isoniazid given daily or twice weekly for 9 or 6 months is recommended 4
- For women at high risk (HIV-infected or recently infected), treatment should NOT be delayed based on pregnancy alone, even during the first trimester 4, 1
- For women at lower risk, some experts recommend waiting until after delivery 4
- Rifampin is not recommended during pregnancy 1
Children and Adolescents
- 9 months of isoniazid given daily or twice weekly is the traditional pediatric regimen 4
- Short-course rifampin-based regimens (3-4 months) appear superior to 9 months of isoniazid in children, with better completion rates and fewer radiographic findings suggestive of disease progression 1, 5
Drug-Resistant Source Cases
Isoniazid-resistant, rifampin-susceptible TB contacts: Rifampin plus pyrazinamide for 2 months, or rifampin alone for 4 months if pyrazinamide is not tolerated 4, 1
Multidrug-resistant TB contacts: Pyrazinamide plus ethambutol OR pyrazinamide plus a fluoroquinolone (levofloxacin or ofloxacin) for 6-12 months 4, 1
- Immunocompetent contacts: treat for at least 6 months or observe
- Immunocompromised contacts (HIV-infected): treat for 12 months 4
Clinical and Laboratory Monitoring
Baseline Testing
Baseline liver function tests (AST/ALT and bilirubin) are NOT routinely indicated for all patients but ARE required for 4, 2:
- Patients with suspected liver disorders
- HIV-infected persons
- Pregnant women and women in the immediate postpartum period (within 3 months of delivery)
- Persons with chronic liver disease (hepatitis B or C, alcoholic hepatitis, cirrhosis)
- Persons who use alcohol regularly
- Persons at risk for chronic liver disease
- Patients taking other medications for chronic conditions (consider on individual basis)
Follow-Up Monitoring
- Monthly clinical evaluations for patients receiving isoniazid alone or rifampin alone 4, 1
- Evaluations at 2,4, and 8 weeks for patients receiving rifampin plus pyrazinamide 4, 1
- Each evaluation should include questioning about side effects and brief physical assessment checking for signs of hepatitis 4
- Patients should be educated to stop treatment and promptly seek medical evaluation if symptoms of hepatotoxicity develop (nausea, vomiting, abdominal pain, jaundice, dark urine) 4
Laboratory Monitoring During Treatment
Routine laboratory monitoring is indicated for 4:
- Persons with abnormal baseline liver function tests
- Persons at risk for hepatic disease
- Evaluation of possible adverse effects during treatment
Some experts recommend withholding isoniazid if transaminase levels exceed 3 times the upper limit of normal with symptoms, or 5 times the upper limit of normal if asymptomatic 4.
Critical Pitfalls to Avoid
NEVER use 2-month rifampin-pyrazinamide (2RZ) in HIV-negative adults: This regimen has unacceptably high hepatotoxicity risk, with a threefold increased risk compared to isoniazid and documented severe hepatotoxicity (ALT >1,600 U/L) in 5% of patients 1, 6
NEVER use rifapentine as monotherapy 1
NEVER add a single drug to a failing regimen: Always add at least 2 drugs to which the organism is susceptible to prevent resistance 1
Beware of rifamycin drug interactions: Rifamycins interact with warfarin, oral contraceptives, antifungals, and HIV antiretroviral therapy, requiring dose adjustments or alternative agents 2
Intermittent (twice-weekly) isoniazid regimens MUST be administered as directly observed therapy (DOT) 1
Active hepatitis and end-stage liver disease are relative contraindications to isoniazid or pyrazinamide 4