What are the guidelines for the treatment of latent tuberculosis (TB)?

Treatment Guidelines for Latent Tuberculosis Infection

The preferred first-line treatment for latent TB infection is 3 months of once-weekly isoniazid plus rifapentine given as directly observed therapy, which has strong evidence and offers superior completion rates compared to traditional 9-month isoniazid regimens. 1

Preferred Treatment Regimens (in order of priority)

Option 1: 3 Months of Isoniazid Plus Rifapentine (Once Weekly)

• Dosing for adults and children ≥12 years: Weight-based rifapentine (300-900 mg) plus isoniazid 15 mg/kg (maximum 900 mg) once weekly for 12 weeks 1, 2
• Dosing for children 2-11 years: Weight-based rifapentine (300-900 mg) plus isoniazid 25 mg/kg (maximum 900 mg) once weekly for 12 weeks 2
• Administration: Must be given as directly observed therapy with at least 3 days between doses 1, 2
• Evidence: Strong recommendation with moderate quality evidence; demonstrated non-inferiority to 9 months isoniazid with 82% completion rate versus 69% for isoniazid alone 1, 3
• Advantages: Shortest duration, highest completion rates, lower hepatotoxicity (0.4% vs 2.7% with isoniazid) 3

Option 2: 4 Months of Daily Rifampin

• Dosing: 10 mg/kg daily (450 mg if <50 kg, 600 mg if ≥50 kg) for 4 months 1
• Evidence: Strong recommendation with moderate quality evidence in HIV-negative patients 1
• Advantages: Network meta-analysis shows odds ratio of 0.25 for TB development versus no treatment; significantly better completion (15.1 percentage points higher) and lower hepatotoxicity than 9-month isoniazid 1, 4
• Efficacy: Non-inferior to 9 months isoniazid with rate difference <0.01 cases per 100 person-years 4

Option 3: 3 Months of Daily Isoniazid Plus Rifampin

• Dosing: Isoniazid 5 mg/kg (maximum 300 mg) plus rifampin 10 mg/kg (maximum 600 mg) daily for 3 months 1
• Evidence: Conditional recommendation with very low quality evidence in HIV-negative patients, low quality in HIV-positive patients 1
• Network meta-analysis: Odds ratio 0.33 for TB development versus no treatment 1

Alternative Regimens

6 Months of Daily Isoniazid

• Dosing: 5 mg/kg (maximum 300 mg) daily for 6 months 1, 5
• Evidence: Strong recommendation with moderate quality evidence in HIV-negative patients; conditional in HIV-positive patients 1
• Limitations: Lower completion rates (approximately 66-69%) and higher hepatotoxicity (2.7%) compared to rifamycin-based regimens 1, 3

9 Months of Daily Isoniazid

• Dosing: 5 mg/kg (maximum 300 mg) daily for 9 months 1, 5
• Evidence: Conditional recommendation with moderate quality evidence for all patients 1
• Historical standard: Efficacy >90% if completed, but poor adherence limits real-world effectiveness 1, 6

Critical Pre-Treatment Requirements

Active TB disease must be ruled out before initiating LTBI treatment through: 1, 7

• Detailed symptom review (cough, fever, night sweats, weight loss)
• Physical examination
• Chest radiography
• Bacteriologic studies when indicated (sputum cultures if any symptoms present)

Baseline laboratory monitoring: 7

• Liver function tests (AST, ALT, bilirubin) required before starting treatment
• Particularly important in patients with pre-existing liver disease, concurrent hepatotoxic medications, or alcohol use

Monitoring During Treatment

For Rifamycin-Based Regimens

• Monthly clinical evaluations to assess adherence and adverse effects 7
• Monitor for signs/symptoms of hepatitis: jaundice, dark urine, light stools, nausea, vomiting, abdominal pain 1
• No routine laboratory monitoring needed unless symptoms develop or baseline abnormalities present 1

For Isoniazid Regimens

• Monthly clinical monitoring mandatory 1
• Serum transaminases every 2-4 weeks if abnormal baseline liver tests or liver disease present 2
• Higher risk populations (age >35 years, alcohol use, concurrent medications) require closer monitoring 1

Drug Interaction Management

Rifamycin-based regimens have significant interactions with: 1

• Warfarin (requires INR monitoring and dose adjustment)
• Oral contraceptives (use alternative contraception)
• Azole antifungals (may require dose adjustments)
• HIV antiretrovirals (consult current guidelines at aidsinfo.nih.gov)

Rifabutin alternatives: 1

• Use when rifampin contraindicated due to drug interactions and isoniazid cannot be used
• Fewer drug interactions than rifampin but more than rifapentine

Rifapentine (once weekly) has fewer interactions than daily rifampin and may be preferred when drug interactions are a concern 1

Special Population Considerations

HIV-Infected Patients

• All preferred regimens are appropriate with specific caveats 1
• 4-month rifampin has strong evidence in HIV-negative patients but conditional in HIV-positive 1
• Check antiretroviral drug interactions before prescribing rifamycins 1
• In low CD4 counts, consider immune reconstitution inflammatory syndrome risk 1

Pregnant Women

• Rifampin is not recommended during pregnancy 1
• Isoniazid 9 months is preferred, though hepatotoxicity risk may be increased 1
• Pyrazinamide should not be used due to inadequate teratogenicity data 1

Children

• For children <12 years: Only 3-month isoniazid/rifapentine (ages 2-11) or 9-month isoniazid are recommended 1, 2
• Weight-based dosing essential: isoniazid 10-15 mg/kg (up to 300 mg) daily for 9-month regimen 5
• Children have lower hepatotoxicity risk than adults 1

Patients with Fibrotic Lesions on Chest X-ray

• Represent high-risk subset with inactive TB 1
• 6-12 months therapy more effective than 2-3 months in this population 1
• Consider longer duration regimens (6-9 months isoniazid) 1

Common Pitfalls and Critical Caveats

Do NOT confuse LTBI regimens with active TB treatment: 1, 8

• Active TB requires 6-month multi-drug regimens (2HRZE/4HR)
• LTBI uses shorter, simpler regimens
• Never add a single drug to a failing regimen—this creates drug resistance 1

Do NOT use these regimens if: 1, 2

• Rifamycin-resistant or isoniazid-resistant M. tuberculosis suspected
• Active TB disease has not been adequately excluded
• Patient has documented hypersensitivity to rifamycins 2

Hepatotoxicity warning signs requiring immediate discontinuation: 1, 2

• AST/ALT >3 times upper limit of normal with symptoms
• AST/ALT >5 times upper limit of normal without symptoms
• Total bilirubin elevation
• Clinical jaundice

Pyrazinamide plus rifampin for 2 months is NOT recommended: 1

• Previously used but abandoned in 2003 due to unacceptably high severe hepatotoxicity rates in HIV-negative adults 1
• Hepatotoxicity rate of 6.1% with moderate-to-severe events 9

Treatment Completion Definitions

Completion criteria: 1

• 3-month rifapentine/isoniazid: 11 of 12 doses within 16 weeks
• 4-month rifampin: at least 120 doses within 6 months
• 3-month isoniazid/rifampin: at least 90 doses within 4 months
• 6-month isoniazid: at least 180 doses within 9 months
• 9-month isoniazid: at least 270 doses within 12 months

Expected completion rates: 1

• Performance indicator of 75% completion within one year after initiation is the minimum standard
• Rifamycin-based regimens achieve 77-82% completion versus 66-69% for isoniazid 4, 3, 9

Administration Recommendations

Take all medications with food to increase bioavailability and reduce gastrointestinal side effects 2

For patients unable to swallow tablets: Crush tablets and mix with small amount of semi-solid food; consume immediately 2

Directly observed therapy (DOT) is mandatory for: 1, 2

• 3-month isoniazid/rifapentine regimen (once weekly)
• Strongly recommended for all regimens to ensure adherence, though self-administered therapy acceptable for daily regimens in selected patients 1