What is the recommended treatment for a patient with latent tuberculosis (TB) infection?

Treatment of Latent Tuberculosis Infection

The preferred first-line treatment for latent TB infection is 3 months of once-weekly isoniazid plus rifapentine (3HP) for most patients, or 4 months of daily rifampin (4R) as an equally effective alternative, both offering superior completion rates and lower toxicity compared to traditional 9-month isoniazid regimens. 1, 2

Preferred First-Line Regimens

3 Months of Once-Weekly Isoniazid Plus Rifapentine (3HP)

• This is the CDC's preferred regimen for HIV-negative adults and children ≥2 years old, demonstrating equivalent efficacy to 9 months of isoniazid but with significantly higher completion rates and less hepatotoxicity 1, 2
• The regimen is equally effective in HIV-positive and HIV-negative persons, making it broadly applicable 1
• Dosing is weight-based up to a maximum of 900 mg rifapentine once weekly, combined with isoniazid 15 mg/kg (up to 900 mg) for adults and children ≥12 years, or 25 mg/kg isoniazid for children 2-11 years 3
• Must be administered as directly observed therapy (DOT) 3

4 Months of Daily Rifampin (4R)

• Strongly recommended as a preferred alternative for HIV-negative adults and children of all ages, with clinically equivalent effectiveness to 9 months of isoniazid and demonstrably lower toxicity 1, 2
• A landmark 2018 randomized trial of 6,859 adults demonstrated non-inferiority to 9-month isoniazid, with treatment completion rates 15.1 percentage points higher and significantly fewer grade 3-5 adverse events (rate difference -1.1 percentage points) and hepatotoxic events (rate difference -1.2 percentage points) 4

3 Months of Daily Isoniazid Plus Rifampin (3HR)

• Recommended by the CDC as another preferred option, offering excellent efficacy with higher completion rates than longer regimens 2
• A pediatric randomized trial over 11 years showed this regimen was superior to 9-month isoniazid monotherapy, with better compliance and fewer new radiographic findings suggestive of disease (11.8% vs 24%, P=.001) 5

Alternative Regimens When Rifamycins Are Contraindicated

9 Months of Daily Isoniazid (9H)

• Conditionally recommended when rifamycin-based regimens are contraindicated, with 60-90% protective efficacy if completed 1
• For HIV-infected persons, 9 months is strongly preferred over 6 months when isoniazid is chosen 1, 2
• The major limitation is poor completion rates and higher hepatotoxicity risk compared to shorter rifamycin-based regimens 4

6 Months of Daily Isoniazid (6H)

• Not recommended for HIV-infected persons or those with radiographic evidence of prior TB, as it provides inferior protection compared to 9 months in these populations 1
• May be considered for HIV-negative adults and children when other regimens cannot be used 2

Critical Pre-Treatment Requirements

Active TB disease must be ruled out before initiating any LTBI treatment through:

• History and physical examination focusing specifically on TB symptoms (cough, fever, night sweats, weight loss) 1, 3
• Chest radiography 1, 3
• Bacteriologic studies (sputum cultures) when clinically indicated 1, 3

Special Population Considerations

HIV-Infected Patients

• The 3HP regimen is equally effective and preferred 1
• If isoniazid monotherapy is chosen, use 9 months rather than 6 months 1, 2
• Isoniazid plus antiretroviral therapy decreases TB incidence more than either intervention alone 2
• Rifabutin may substitute for rifampin when drug interactions with antiretroviral medications preclude rifampin use 2

Pregnant Women

• For women at high risk (HIV-infected or recently infected), treatment should not be delayed based on pregnancy alone, even in the first trimester 1
• Isoniazid (9 or 6 months) is recommended for HIV-negative pregnant women 1
• Rifampin is not recommended during pregnancy 1

Children and Adolescents

• Short-course rifamycin-based regimens (3HP, 4R, 3HR) appear superior to 9-month isoniazid in children 1, 5
• Weight-based dosing is essential for the 3HP regimen in children 2-11 years 3

Monitoring During Treatment

Baseline Assessment

• Obtain baseline liver function tests for patients with:
  • Suspected liver disorders 1
  • HIV infection 1
  • Pregnancy or immediate postpartum period 1
  • Chronic conditions increasing liver disease risk 1

Ongoing Monitoring

• Monthly clinical evaluations for all patients on isoniazid or rifampin monotherapy, assessing for hepatitis symptoms 1, 2
• More frequent evaluations (at 2,4, and 8 weeks) for patients on rifampin plus pyrazinamide regimens 1, 2
• Discontinue treatment immediately if evidence of liver injury occurs 1
• For patients with abnormal baseline liver tests, obtain serum transaminases every 2-4 weeks during therapy 3

Management of Drug-Resistant Exposure

Isoniazid-Resistant, Rifampin-Susceptible TB Contacts

• Treat with rifampin plus pyrazinamide for 2 months, or rifampin alone for 4 months if pyrazinamide is not tolerated 1

Multidrug-Resistant TB Contacts

• Treatment is suggested for MDR-TB contacts versus observation alone 6
• Use 6-12 months of a later-generation fluoroquinolone alone or with a second drug based on source-case susceptibility 6
• Pyrazinamide should not be routinely used as the second drug due to increased toxicity, adverse events, and discontinuations 6
• Alternatively, pyrazinamide plus ethambutol or pyrazinamide plus a fluoroquinolone for 6-12 months 1

Critical Pitfalls to Avoid

• Never use rifapentine as monotherapy 1, 3
• Never use 2-month rifampin-pyrazinamide (2RZ) in HIV-negative adults due to unacceptably high hepatotoxicity risk 1, 7, 8
• Do not use 3HP or other rifamycin-based regimens in individuals presumed exposed to rifamycin-resistant organisms 3
• Intermittent (twice-weekly) isoniazid regimens must always be administered as directly observed therapy 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
• Be aware of significant drug interactions with rifamycins, particularly with warfarin, oral contraceptives, antifungals, and HIV antiretroviral therapy 2

Administration Considerations

• Take rifapentine with meals to increase oral bioavailability and reduce gastrointestinal upset 3
• For patients unable to swallow tablets, tablets may be crushed and added to semi-solid food, which should be consumed immediately 3
• All once-weekly regimens must be given as directly observed therapy 3
• For twice-weekly rifapentine in active TB treatment, maintain an interval of at least 3 consecutive days (72 hours) between doses 3