Treatment of Latent Tuberculosis Infection (LTBI)
The preferred first-line treatment for LTBI 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 lower hepatotoxicity. 1, 2
Preferred First-Line Regimens
3 months of once-weekly isoniazid plus rifapentine (3HP) is the CDC's top recommendation for HIV-negative adults and children ≥2 years old, offering the best balance of efficacy, safety, and completion rates 1, 2
4 months of daily rifampin (4R) is strongly recommended as a preferred alternative for HIV-negative adults and children of all ages, with clinically equivalent effectiveness to 9 months of isoniazid but lower toxicity 1, 3
The 3HP regimen demonstrates superior hepatotoxicity profile compared to 9 months of isoniazid (pooled OR 0.18,95% CI 0.12-0.26), better efficacy in preventing active TB (OR 0.38,95% CI 0.18-0.80), and higher completion rates (OR 2.30,95% CI 2.10-2.53) 4
The 4-month rifampin regimen showed a 15.1 percentage point higher completion rate than 9 months of isoniazid, with significantly fewer grade 3-5 adverse events (rate difference -1.1 percentage points) and hepatotoxic events (rate difference -1.2 percentage points) 3
Alternative Regimens When Rifamycins Cannot Be Used
9 months of daily isoniazid (9H) is conditionally recommended when rifamycin-based regimens are contraindicated, with 60-90% protective efficacy if completed 1, 5
6 months of isoniazid provides substantial protection but is explicitly not recommended for HIV-infected persons or those with radiographic evidence of prior TB—these populations require the full 9-month course 1, 2
The 9-month isoniazid regimen can be administered daily as self-administered therapy or twice-weekly under directly observed therapy (DOT) 5, 6
HIV-Infected Patients: Critical Distinctions
The 3HP regimen is equally effective in HIV-positive and HIV-negative persons and is preferred 1, 2
If isoniazid monotherapy is chosen for HIV-infected persons, 9 months is mandatory rather than 6 months 7, 2
Combining isoniazid with antiretroviral therapy decreases TB disease incidence more than either intervention alone 2
Rifabutin can substitute for rifampin when drug interactions with protease inhibitors or other antiretrovirals preclude rifampin use 7, 2
Pregnant Women: Specific Guidance
For HIV-negative pregnant women, isoniazid (9 or 6 months) is the recommended regimen 7, 1
For women at high risk (HIV-infected or recently infected), treatment should not be delayed based on pregnancy alone, even during the first trimester 1
Rifampin is not recommended during pregnancy 1
Streptomycin is absolutely contraindicated in pregnancy due to risk of congenital deafness 6
Pyrazinamide is not routinely recommended in pregnancy due to inadequate teratogenicity data 6
Children and Adolescents
9 months of isoniazid has been the traditional pediatric regimen 7
Short-course rifampin-based regimens (3HP or 4R) appear superior to 9 months of isoniazid in children and are now preferred 1
For children <2 years old, 4 months of rifampin is preferred since 3HP is only approved for children ≥2 years 1
Ethambutol should not be used in children whose visual acuity cannot be monitored 6
Drug-Resistant TB Contacts: Tailored Approaches
Contacts of isoniazid-resistant, rifampin-susceptible TB: Use rifampin plus pyrazinamide for 2 months, or rifampin alone for 4 months if pyrazinamide is not tolerated 7, 1
Contacts of multidrug-resistant TB (resistant to both isoniazid and rifampin): Use pyrazinamide plus ethambutol OR pyrazinamide plus a fluoroquinolone (levofloxacin or ofloxacin) for 6-12 months 7, 1
Immunocompetent contacts may be treated for 6 months, but immunocompromised contacts (especially HIV-infected) require 12 months of treatment 7
Critical Pre-Treatment Requirements
Active TB disease must be ruled out before initiating LTBI treatment through history focusing on TB symptoms (cough, fever, night sweats, weight loss), physical examination, chest radiography, and bacteriologic studies (sputum cultures) when clinically indicated 7, 2
This step is non-negotiable—treating active TB as LTBI with monotherapy or short-course regimens will lead to drug resistance 1
Monitoring During Treatment
For isoniazid or rifampin monotherapy: Monthly clinical evaluations assessing for hepatitis symptoms (nausea, vomiting, abdominal pain, jaundice, dark urine) 7, 1
For rifampin plus pyrazinamide regimens: More intensive monitoring at 2,4, and 8 weeks due to higher hepatotoxicity risk 7, 1
Baseline liver function tests are recommended for patients with suspected liver disorders, HIV infection, pregnancy or immediate postpartum period, chronic alcohol use, or conditions increasing liver disease risk 1, 2
Discontinue treatment immediately if evidence of liver injury occurs (transaminases >3 times upper limit of normal with symptoms, or >5 times without symptoms) 1
Regimens to Avoid: Critical Safety Warnings
2 months of rifampin plus pyrazinamide (2RZ) should NOT be used in HIV-negative adults due to unacceptably high hepatotoxicity risk, including reports of severe liver injury and death 7, 2
This regimen may still be considered in HIV-infected persons based on randomized trial data showing acceptable safety in this population, but only after consultation with a TB expert 7, 5
Rifapentine should never be used as monotherapy 1
Directly Observed Therapy (DOT) Indications
All intermittent regimens (twice-weekly or thrice-weekly) must be administered as DOT 7
The 3HP regimen (once-weekly) should be administered as DOT 1, 2
Highest priority for DOT includes HIV-infected persons and recent contacts of infectious pulmonary TB patients 7
DOT should be used with daily dosing whenever feasible, as nonadherence to intermittent dosing results in larger proportions of missed doses 7
Common Pitfalls to Avoid
Never add a single drug to a failing regimen—always add at least 2 drugs to which the organism is susceptible to prevent resistance development 1
Do not use 6 months of isoniazid for HIV-infected persons or those with radiographic evidence of prior TB—these populations require 9 months 1, 2
Be aware of rifamycin drug interactions with warfarin, oral contraceptives, antifungals, and HIV antiretroviral therapy—dose adjustments or alternative agents may be necessary 2
Persons with previously completed LTBI treatment (>6 months isoniazid, 4 months rifampin, or another regimen) do not need retreatment unless reinfection is suspected 7
Active hepatitis and end-stage liver disease are relative contraindications to isoniazid or pyrazinamide—if treatment is necessary, baseline and follow-up liver function monitoring is essential 7