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

Treatment of Latent Tuberculosis Infection

The preferred treatment for latent tuberculosis infection is 3 months of once-weekly isoniazid plus rifapentine, which offers equivalent efficacy to 9 months of isoniazid with significantly higher completion rates (82% vs 69%) and lower hepatotoxicity. 1, 2, 3

Preferred First-Line Regimens

The CDC and major guideline bodies recommend three preferred regimens with strong evidence, listed by priority 1, 2:

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

• This is the top-tier recommendation with strong evidence and moderate quality data 1, 2
• Administered as directly observed therapy: adults and children ≥12 years receive weight-based rifapentine (300-900 mg) plus isoniazid 15 mg/kg (900 mg max); children 2-11 years receive weight-based rifapentine plus isoniazid 25 mg/kg (900 mg max) 4
• Demonstrated non-inferiority to 9 months of isoniazid with cumulative tuberculosis rates of 0.19% vs 0.43% 3
• Treatment completion rate of 82.1% compared to 69.0% with 9 months of isoniazid 3
• Hepatotoxicity rate of only 0.4% versus 2.7% with isoniazid monotherapy 3

4 Months of Daily Rifampin

• Strong recommendation with moderate quality evidence for HIV-negative individuals 1, 2
• Rate difference of <0.01 cases per 100 person-years compared to 9 months of isoniazid, meeting non-inferiority criteria 5
• Treatment completion rate 15.1 percentage points higher than 9-month isoniazid (absolute difference) 5
• Grade 3-5 adverse events occurred 1.1 percentage points less frequently, with hepatotoxicity 1.2 percentage points lower 5

3 Months of Daily Isoniazid Plus Rifampin

• Conditional recommendation with very low quality evidence for HIV-negative patients and low quality evidence for HIV-positive patients 1, 2
• Network meta-analysis shows odds ratio of 0.33 (95% CI: 0.20-0.53) for tuberculosis development compared to no treatment 1

Alternative Regimens

When preferred regimens cannot be used:

6 Months of Daily Isoniazid

• Strong recommendation for HIV-negative adults and children; conditional recommendation for HIV-positive individuals 1, 2
• Odds ratio of 0.40 (95% CI: 0.26-0.59) for tuberculosis development versus no treatment 1

9 Months of Daily Isoniazid

• Conditional recommendation with moderate quality evidence for all populations 1, 2
• For HIV-positive patients, 9 months is preferred over 6 months when isoniazid is chosen 2
• Efficacy exceeds 90% when completed properly, but completion rates are poor (69%) 3, 6

Critical Drug Interaction Considerations

Rifamycin-based regimens have extensive drug interactions that must be addressed before prescribing 1, 2:

• Rifamycins interact with warfarin, oral contraceptives, azole antifungals, and HIV antiretroviral therapy 1
• Rifabutin has fewer drug interactions and may substitute for rifampin when drug-drug interactions preclude rifampin use and isoniazid cannot be used 1, 2
• Weekly rifapentine has fewer interactions than daily rifampin and may be considered when rifampin is contraindicated, though clinical data are limited 1
• For HIV-positive patients, consult updated guidelines on rifamycin-antiretroviral interactions at https://aidsinfo.nih.gov/guidelines 1

Pre-Treatment Requirements and Monitoring

Before initiating LTBI treatment, active tuberculosis must be ruled out through history, physical examination, chest radiography, and bacteriologic studies when indicated 2:

• Baseline laboratory testing is recommended for patients with risk factors for hepatotoxicity (HIV infection, chronic liver disease, alcohol use, pregnancy/postpartum period, concurrent hepatotoxic medications) 2
• Monthly follow-up evaluations are recommended for isoniazid or rifampin monotherapy 2
• For rifampin plus pyrazinamide regimens (not recommended as first-line), follow-up at 2,4, and 8 weeks is necessary 2

Special Population Considerations

HIV-Positive Patients

• All preferred regimens can be used, but drug interaction assessment is mandatory 1, 2
• Do not use once-weekly rifapentine-isoniazid continuation phase regimens for active TB in HIV-infected patients due to increased relapse risk 4
• When isoniazid monotherapy is chosen, use 9 months rather than 6 months 2
• Isoniazid plus antiretroviral therapy decreases TB incidence more than either intervention alone 2

Patients with Cavitary Disease or Bilateral Pulmonary Involvement

• Monitor closely for signs of relapse when using rifapentine-based regimens for active TB treatment 4

Common Pitfalls to Avoid

The rifampin-pyrazinamide combination for 2 months is NOT recommended for LTBI treatment in HIV-negative adults 6, 7:

• While this regimen showed excellent efficacy in trials, post-marketing surveillance revealed unacceptably high rates of severe hepatotoxicity in HIV-negative adults 6
• Hepatotoxicity rates of 6.1% were observed with this combination versus 2.0% with isoniazid alone 7
• This regimen may be acceptable in HIV-positive patients and children, but is not a preferred option 6

Rifamycins permanently stain contact lenses and dentures red-orange; patients should be counseled about this and temporary discoloration of body fluids 4

Rifamycins should be avoided in patients with porphyria 4

Administration Considerations

• All regimens should be taken with food 4
• Tablets may be crushed and added to semi-solid food for patients unable to swallow whole tablets 4
• The 3HP regimen requires directly observed therapy, while 4-month rifampin and isoniazid regimens can be self-administered 1, 3