What is the recommended preventive treatment for latent Tuberculosis (TB) infection?

TB Preventive Treatment for Latent Tuberculosis Infection

For latent TB infection, the preferred regimens are short-course rifamycin-based treatments: 3 months of once-weekly isoniazid plus rifapentine, or 4 months of daily rifampin, both of which are superior to the traditional 6-9 months of isoniazid monotherapy in terms of completion rates and safety. 1

Preferred Regimens (in order of priority)

1. Three Months of Isoniazid Plus Rifapentine (Once Weekly)

• Dosing: Once weekly for 12 weeks, administered as directly observed therapy (DOT) 2
• Adults and children ≥12 years: Weight-based rifapentine dosing up to 900 mg weekly plus isoniazid 15 mg/kg (max 900 mg) 2
• Children 2-11 years: Weight-based rifapentine dosing up to 900 mg weekly plus isoniazid 25 mg/kg (max 900 mg) 2
• Advantages: Equivalent effectiveness to 9 months of isoniazid with higher completion rates and less hepatotoxicity in HIV-negative persons 1, 3
• Caution: Associated with systemic drug reactions (flu-like syndrome, syncope, hypotension) requiring hospitalization in 20.1% of cases, though self-limited and no deaths reported 1

2. Four Months of Daily Rifampin

• Dosing: 600 mg daily for 4 months 1
• Population: Strongly recommended for HIV-negative adults and children of all ages 1
• Advantages: Non-inferior effectiveness compared to 9 months of isoniazid with 15.1 percentage point higher completion rate and significantly lower hepatotoxicity (1.2 percentage point reduction in hepatotoxic events) 3
• Particularly useful: For patients who cannot tolerate isoniazid or pyrazinamide 1

Alternative Regimens

Six Months of Daily Isoniazid

• Strongly recommended for HIV-negative adults and children when shorter regimens cannot be used 1
• Conditionally recommended for HIV-positive adults and children 1
• Dosing: Daily administration for at least 270 doses over 6-9 months 1
• Rationale: Provides substantial protection superior to placebo, though less favorable completion rates than shorter regimens 1

Nine Months of Daily Isoniazid

• Conditionally recommended for both HIV-negative and HIV-positive adults and children when preferred regimens are contraindicated 1
• Dosing: Daily administration for at least 270 doses over 9-12 months if interruptions occur 1
• Historical standard: More than 90% efficacy if completed properly, but poor acceptance and adherence limit public health impact 4

Special Population Considerations

HIV-Infected Patients

• Preferred: 9-month isoniazid regimen (not 6 months) when isoniazid is chosen 1
• Alternative: 3 months of isoniazid plus rifapentine showed no significant difference compared to 6 or 9 months of isoniazid 1
• Avoid: Two-month rifampin plus pyrazinamide due to unacceptable hepatotoxicity risk in non-HIV adults, though acceptable safety profile in HIV-infected persons 4

Pregnant Women

• HIV-infected pregnant women: Initiation should not be delayed based on pregnancy alone, even in first trimester; 9-month isoniazid regimen is the only recommended option 1
• HIV-negative pregnant women: Isoniazid daily or twice weekly for 6-9 months; for high-risk women (HIV-positive or recent infection), do not delay treatment; for lower-risk women, some experts recommend waiting until after delivery 1

Children

• HIV-infected children: 12-month isoniazid regimen recommended by American Academy of Pediatrics 1
• General pediatric population: Isoniazid for 9 months is recommended regimen 1
• Evidence: Short-course isoniazid plus rifampin for 3-4 months appears superior to 9-month isoniazid monotherapy with better compliance and fewer radiographic findings suggestive of disease (11-13.6% vs 24%) 5

Drug-Resistant Exposure

Isoniazid-resistant, rifamycin-susceptible TB:

• Preferred: 2-month rifamycin (rifampin or rifabutin) plus pyrazinamide 1
• Alternative (if pyrazinamide intolerance): 4-6 months of rifamycin alone 1

Multidrug-resistant TB (isoniazid and rifampin resistant):

• Combination of at least two drugs to which the strain is susceptible (e.g., ethambutol plus pyrazinamide, or levofloxacin plus ethambutol) 1
• Review drug-susceptibility pattern from source patient before choosing regimen 1
• Duration: Immunocompetent contacts treated for at least 6 months; immunocompromised contacts (HIV-infected) treated for 12 months 1

Monitoring Requirements

Monthly Clinical Evaluation

• All patients: Monthly assessment of adherence and medication side effects required 1
• Education: Patients must be informed about side effects (especially hepatitis symptoms), advised to stop treatment and seek immediate evaluation if symptoms develop 1

Baseline Laboratory Testing

• Not routinely indicated for all patients 1
• Required for: Patients with abnormal liver tests, pre-existing liver disease, HIV infection, pregnant women, heavy alcohol users, or history of liver injury 1
• Frequency when indicated: Serum transaminases prior to therapy and every 2-4 weeks during therapy 2

Directly Observed Therapy (DOT)

• Always required: For all intermittent dosing regimens 1
• Strongly recommended: For 2-month preventive therapy regimens, institutional settings, community outreach programs, and household contacts of active TB patients receiving home-based DOT 1
• 3-month isoniazid plus rifapentine: Highest completion with DOT, though self-administered therapy is approved option 1

Treatment Completion Criteria

• Based on total doses administered, not duration alone 1
• Isoniazid daily: At least 270 doses over 9 months (up to 12 months if interruptions) 1
• Isoniazid twice weekly: At least 76 doses over 9 months (up to 12 months if interruptions) 1
• Rifamycin plus pyrazinamide daily: At least 60 doses over 2 months (up to 3 months if interruptions) 1

Interruptions in Therapy

• If interruption ≥2 months: Medical examination to rule out active TB disease is required before restarting 1
• Options: Continue original regimen to complete recommended duration, or completely renew entire regimen 1

Critical Contraindications and Precautions

Before Initiating Treatment

• Active TB disease must be ruled out by history, physical examination, chest radiography, and bacteriologic studies when indicated 1, 2
• Rifapentine contraindicated: In patients with hypersensitivity to rifamycins 2

Drug Interactions

• Rifamycins cannot be used concurrently with certain antiretrovirals (protease inhibitors, NNRTIs including ritonavir, hard-gel saquinavir, delavirdine) 1
• Rifabutin may be substituted for rifampin in situations where rifampin cannot be used (e.g., HIV-infected persons on protease inhibitors) 1

Hepatotoxicity Risk

• Discontinue immediately if evidence of liver injury occurs 2
• Two-month rifampin plus pyrazinamide: Not recommended for LTBI due to unacceptably high severe liver toxicity rate in non-HIV-infected adults 1, 4
• Rifampin monotherapy: Significantly less hepatotoxic than isoniazid 3

Post-Treatment Follow-Up

• No routine follow-up required (including chest x-rays and medical evaluations) for patients who complete treatment, unless they develop TB symptoms or are re-exposed to infectious TB 1
• For those who do not receive preventive therapy: Assess periodically (intervals <6 months) for TB symptoms as part of ongoing management; educate about symptoms (cough with/without fever, night sweats, weight loss) and advise immediate medical attention if symptoms develop 1