What is a latent infection?

Latent Tuberculosis Infection: Definition and Management

Latent tuberculosis infection (LTBI) is characterized by the presence of immune responses to Mycobacterium tuberculosis infection without clinical evidence of active tuberculosis disease. 1 Individuals with LTBI are asymptomatic, have a normal chest radiograph, and are not infectious, but they remain at risk for developing active TB disease in the future.

Understanding Latent TB Infection

Definition and Characteristics

• LTBI represents a state where M. tuberculosis bacteria are present in the body but remain dormant, with the immune system containing the infection 1
• Individuals with LTBI:
  • Have no clinical, bacteriological, or radiological signs of active disease
  • Cannot transmit the infection to others
  • Have a positive tuberculin skin test (TST) or interferon-gamma release assay (IGRA)
  • Are at risk for progression to active TB disease if their immune system weakens

Epidemiology

• Approximately one-third of the world's population is estimated to be infected with M. tuberculosis 1
• The lifetime risk of progression from LTBI to active TB disease is estimated at 5-15%, with the majority developing disease within the first 5 years after initial infection 1

Diagnosis of LTBI

Two main diagnostic tests are available to identify LTBI:

1. Tuberculin Skin Test (TST)

• In vivo test using a mixture of antigens from M. tuberculosis
• Interpretation varies based on risk factors:
  • ≥5 mm induration: HIV-infected persons, recent contacts of TB cases, persons with immunosuppression, persons with chest radiograph suggestive of prior TB 1
  • ≥10 mm induration: Recent immigrants from high TB prevalence countries, injection drug users, residents of congregate settings, children <4 years old 1
  • ≥15 mm induration: Persons with no known risk factors 1
• Less specific in BCG-vaccinated individuals 1

2. Interferon-Gamma Release Assays (IGRAs)

• Ex vivo blood tests that measure T-cell response to M. tuberculosis antigens
• Higher specificity than TST (92-97% vs 56-95%) 1
• Less affected by prior BCG vaccination 1
• Examples include QuantiFERON-TB Gold and T-SPOT.TB test 1

Important Diagnostic Considerations

• Neither test can distinguish between latent infection and active disease
• Neither test can confirm the presence of living bacilli in persons with LTBI 1
• Before LTBI treatment, active TB must be ruled out through:
  • Symptom screening (cough, fever, night sweats, weight loss)
  • Chest radiography 1, 2
  • Further investigation for those with TB symptoms or radiological abnormalities 1

Management of LTBI

Who Should Be Tested and Treated

The WHO strongly recommends systematic testing and treatment of LTBI in:

• People living with HIV
• Adult and child contacts of pulmonary TB cases
• Patients initiating anti-TNF treatment
• Patients receiving dialysis
• Patients preparing for organ or hematological transplantation
• Patients with silicosis 1

Conditional recommendations for testing and treatment in:

• Prisoners
• Healthcare workers
• Immigrants from high TB burden countries
• Homeless persons
• Illicit drug users 1

Preferred Treatment Regimens

The CDC recommends the following regimens for LTBI treatment due to their similar efficacy with better completion rates and fewer hepatotoxic events compared to traditional isoniazid regimens: 2

1. 3 months of once-weekly isoniazid plus rifapentine (strong recommendation, moderate quality evidence)

   • Better completion rates
   • Lower hepatotoxicity
   • Excellent tolerability and efficacy 2

2. 4 months of daily rifampin (strong recommendation, moderate quality evidence)

   • Significantly less hepatotoxicity than isoniazid regimens
   • Higher completion rates than 9-month isoniazid 2

3. 3 months of daily isoniazid plus rifampin 2

Alternative regimens include:

• 6 months of daily isoniazid
• 9 months of daily isoniazid 1

Monitoring During Treatment

• Regular monthly clinical monitoring for all patients on LTBI treatment
• Patient education on potential adverse effects and when to seek medical attention
• Baseline laboratory testing recommended for:
  • Patients with suspected liver disorders
  • HIV-infected persons
  • Pregnant women
  • Persons with history of chronic liver disease or regular alcohol use 2

Special Considerations

Drug Interactions

• Rifamycin-based regimens have numerous drug interactions, including:
  • Warfarin
  • Oral contraceptives
  • Azole antifungals
  • HIV antiretroviral therapy 2

Risk of Drug Resistance

• Studies show no significant difference in the incidence of isoniazid-resistant TB between those treated with isoniazid preventive therapy versus no treatment or placebo 1

Challenges in LTBI Management

• Inability to directly confirm the presence of viable bacteria
• Difficulty predicting which individuals will progress to active disease
• Treatment adherence challenges due to lengthy regimens
• Limited evidence for preventive therapy in contacts of MDR-TB cases 2

Conclusion

Identifying and treating LTBI is a critical component of TB elimination strategies, particularly in low-incidence countries. While current diagnostic tests cannot confirm the presence of living bacilli, they remain valuable tools for identifying individuals who would benefit from preventive treatment. Shorter rifamycin-based regimens are now preferred due to better completion rates and fewer adverse events.