Latent Tuberculosis Treatment

Aka: Latent Tuberculosis Treatment, Latent Tuberculosis, Latent Tb, Tuberculosis Prophylaxis, Tb Prophylaxis, LTBI

1. See Also
   1. Tuberculosis
   2. Tuberculosis Screening in Children
   3. Tuberculosis Risk Factors (Tuberculosis Screening Indications)
   4. Tuberculosis Risk Factors for progression from Latent to Active Disease (Latent Tuberculosis Treatment Indications)
   5. Tuberculosis Related Chest XRay Changes
   6. Extrapulmonary Tuberculosis
   7. Tuberculin Skin Test (TST, Purified Protein Derivative, PPD)
   8. Mycobacterium Tuberculosis Antigen-Specific Interferon-Gamma Release Assay (IGRA)
   9. Active Tuberculosis Treatment
   10. Susceptible Tuberculosis Treatment
   11. Possibly Resistant Tuberculosis Treatment
   12. Multiple Drug Resistant Tuberculosis Treatment
   13. Tuberculosis Resources
2. Epidemiology
   1. Concurrent HIV Infection confers a 10% conversion to Active Tuberculosis per year (highest rate)
   2. Overall rate of progression from Latent Tuberculosis to Active Tuberculosis: 5-15%
      1. Latent Tuberculosis progression is responsible for >80% of Active Tuberculosis cases in the United States
      2. Half of latent to Active Tuberculosis progressions occur within the first 2 years following infection
         1. Progression within 2 years in otherwise healthy patient (e.g. non-HIV): 5%
         2. Progression after 2 years in otherwise healthy patient (e.g. non-HIV): 5%
3. Precautions
   1. Latent Tuberculosis is a lab diagnosis based on positive Screening Tests (IGRA, PPD)
      1. Latent Tuberculosis patients are asymptomatic, noninfectious and without Chest XRay findings of Tuberculosis
      2. Do not treat Latent Tuberculosis patients with single agent until Active Tb is excluded by history and imaging
   2. Active Tuberculosis patients are symptomatic (Chronic Cough >3 weeks, Hemoptysis, Night Sweats, weight loss)
      1. Active Tuberculosis requires 3 Sputum samples for acid-fast bacilli smear, PCR and Culture
      2. Active Tuberculosis patients are treated with multi-drug regimens to prevent resistance
   3. Latent Tb management requires provider vigilence
      1. Educate and monitor compliance (important to complete course)
      2. Be alert for hepatotoxicity (Isoniazid, rifamycins) and limit Alcohol and other Hepatotoxins
      3. Observe for Thrombocytopenia with rifamycins
      4. See specific agents for additional recommendations (e.g. Vitamin B6 and Isoniazid, Rifamycin Drug Interactions)
   4. Give adjunctive Vitamin B6 (Pyridoxine) 25-50 mg daily
      1. Indicated for Neuropathy risk due to Isoniazid (e.g. Diabetes Mellitus, Alcoholism)
      2. See Isoniazid for details
4. Indications: Strongest Indications for Latent Tuberculosis Treatment
   1. See Tuberculosis Screening (Tuberculin Skin Test or IGRA)
   2. See Tuberculosis Risk Factors for progression from Latent to Active Disease
   3. Risk of serious disease or Extrapulmonary Tuberculosis (e.g. Miliary Tuberculosis, Tuberculous Meningitis)
5. Contraindications: Latent Tuberculosis Treatment
   1. Age over 35 years (risk of hepatitis) is no longer an absolute contraindication
   2. Prophylaxis indications regardless of age
      1. Recent PPD conversion
      2. Chest XRay shows healed Tuberculosis (see Tuberculosis Related Chest XRay Changes)
      3. Immunocompromised patient (e.g. HIV)
6. Protocols: First-Line Short Courses
   1. Background
      1. Short courses for 3-4 months are preferred for Latent Tuberculosis management over traditional 6-9 month courses
         1. Similar efficacy as with Isoniazid 6-9 month monotherapy course
         2. Higher compliance and completion rates compared with longer courses
         3. Less hepatotoxicity compared with longer courses
   2. Isoniazid and Rifapentine for 3 months (3HP)
      1. Indications
         1. Preferred regimen for adults and children >2 years
         2. Also preferred in HIV positive patients (unless Rifampin Drug Interactions prohibit)
         3. Rifapentine has multiple Drug Interactions but less than with Rifampin
         4. Requires observed therapy (patient must come to clinic weekly for administered dose)
      2. Combination of both Isoniazid (INH) and Rifapentine both taken weekly for 12 weeks
         1. Each dose must be physician observed (due to risk of drug resistant Tuberculosis if stopped early)
      3. Protocol (Age >=2 years)
         1. Isoniazid (INH) 15 mg/kg (25 mg/kg if age 2-11 years) up to 900 mg weekly for 12 weeks AND
         2. Rifapentine (Priftin) weekly for 12 weeks
            1. Weight 10 to 14 kg: Rifapentine 300 mg weekly
            2. Weight 14.1 to 25 kg: Rifapentine 450 mg weekly
            3. Weight 2.5.1 32 kg: Rifapentine 600 mg weekly
            4. Weight 32.1 to 49.9 kg: Rifapentine 750 mg weekly
            5. Weight >50 kg (and adults): Rifapentine 900 mg weekly
      4. Efficacy: 90% effective
         1. As effective and safe as other Latent Tb regimens with significantly higher completion rates
            1. Njie (2018) Am J Prev Med 55(2):244-252 +PMID: 29910114 [PubMed]
      5. References
         1. Sterling (2011) N Engl J Med 365:2155-2166 [PubMed]
   3. Rifampin for 4 months (4R)
      1. Indications
         1. Short course self-administered monotherapy
         2. Cost was previously prohibitive, but now Rifampin cost is $70 for 120 of the 300 mg capsules
      2. Contraindications
         1. Do not use as monotherapy in HIV Infection
         2. Review Drug Interactions before use (multiple rifampin Drug Interactions, but less with Rifabutin)
      3. Allows for shorter course and lower hepatotoxicity risk
      4. Rifampin Routine Dosing (intermittent dosing not recommended when used alone)
         1. Adults 10 mg/kg up to 600 mg orally daily for 4 months
         2. Child 15-20 mg/kg/day (max 600 mg/day) for 4 months
      5. Efficacy: 60% effective
         1. Not inferior to Isoniazid for 9 months, and better completion rates with less adverse effects
            1. Menzies (2018) N Engl J Med 379(5):440-53 +PMID: 30067931 [PubMed]
   4. Isoniazid and Rifampin for 3 months (3HR)
      1. Indications
         1. Adults and children of all ages including HIV positive patients
      2. Contraindications
         1. Rifampin Drug Interactions
      3. Protocol: Taken daily for 3 months
         1. Isoniazid (INH) 5 mg/kg in adults (10-20 mg/kg in children) up to 300 mg daily AND
         2. Rifampin 10 mg/kg in adults (15-20 mg/kg in children) up to 600 mg daily
7. Protocols: Latent Tuberculosis Long Course Treatment
   1. See Isoniazid for specific precautions and Vitamin B6 supplementation guidelines
   2. Typical long course: 9 months (unless otherwise noted - see below)
   3. Course of 9 months is now also recommended in cases previously treated for 12 months
      1. Human Immunodeficiency Virus (HIV)
      2. Immunosuppression
      3. Chest XRay showing healed Tuberculosis (e.g. apical fibronodular changes)
   4. Protocol
      1. Duration
         1. Standard therapy: 9 months (90% effective)
         2. Shorter course: 6 months (60-80% effective, but better compliance)
      2. Isoniazid Routine Dosing
         1. Adults 5 mg/kg up to 300 mg orally daily
         2. Child 10-20 mg/kg/day (max 300 mg/day)
      3. Isoniazid Alternative Dosing
         1. Adult: 15 mg/kg up to 900 mg twice weekly supervised
         2. Child: 20-40 mg/kg twice weekly (maximum 900 mg) supervised
8. Protocols: Resistant Exposures
   1. Isoniazid Resistant Tuberculosis Exposure
      1. Rifampin 600 mg qd
      2. Ethambutol for 6-12 months
   2. Multi-drug resistant Tb Exposure:
      1. Pyrazinamide 25-30 mg/kg/day and
      2. Ethambutol 15-25mg/kg/day and
      3. Fluoroquinolones
         1. Ofloxacin 400mg bid or
         2. Ciprofloxacin 750 mg bid
9. Protocols: Discontinued - Rifampin and Pyrazinamide
   1. No longer recommended for Latent Tuberculosis Treatment due to hepatotoxicity
   2. Details listed for historical purposes only
      1. Rifampin 600 mg qd for 2 months
      2. Pyrazinamide 25mg/kg qd for 2 months
   3. Higher risk of hepatotoxicity than with 6 months INH
      1. Observe serial Liver Function Tests closely
      2. Jasmer (2002) Ann Intern Med 137:640-7 [PubMed]
10. Monitoring
    1. See Isoniazid for toxicity related to Neuropathy and Hepatotoxicity
    2. See Rifampin regarding Drug Interactions
11. Resources
    1. Treatment Regimens for Latent Tuberculosis or LTBI (CDC)
       1. https://www.cdc.gov/tb/topic/treatment/ltbi.htm
12. References
    1. Orman, Moran and Swaminathan in Herbert (2016) EM:Rap 16(11): 2-3
    2. Hartman-Adams (2014) Am Fam Physician 89(11): 889-96 [PubMed]
    3. Hartman-Adams (2022) Am Fam Physician 106(3): 308-15 [PubMed]
    4. Sterling (2020) MMWR Recomm Rep 69(1): 1-11 [PubMed]