How does Isoniazid (INH) prevent latent Tuberculosis (TB)?

From the Guidelines

Isoniazid (INH) prevents latent tuberculosis from progressing to active disease by inhibiting mycobacterial cell wall synthesis, and the most effective regimen is 9 months of daily INH, as recommended by the National Tuberculosis Controllers Association and CDC in 2020 1.

Mechanism of Action

INH is a prodrug that is activated by the bacterial enzyme catalase-peroxidase (KatG) to form an active complex with NAD+. This complex then inhibits InhA, an enzyme essential for synthesizing mycolic acids, which are critical components of the tuberculosis bacterium's cell wall. Without proper cell wall formation, Mycobacterium tuberculosis cannot replicate effectively.

Treatment Regimens

For latent TB treatment, INH is typically prescribed at 300mg daily for adults (5mg/kg, maximum 300mg) or 900mg twice weekly for 9 months. Children receive 10-15mg/kg daily (maximum 300mg). The 9-month regimen is preferred for optimal efficacy, though 6-month regimens are sometimes used, as shown in a meta-analysis comparing efficacy and hepatotoxicity among various treatment regimens 1.

Important Considerations

Patients should take vitamin B6 (pyridoxine) 25-50mg daily with INH to prevent peripheral neuropathy, especially in those with diabetes, kidney disease, malnutrition, or alcohol use disorder. Regular liver function monitoring is essential as INH can cause hepatotoxicity, particularly in older adults and those with liver disease. The updated guidelines from 2020 recommend short-course (3- to 4-month) rifamycin-based treatment regimens as preferred over longer-course (6–9 month) isoniazid monotherapy for treatment of LTBI, due to their effectiveness, safety, and high treatment completion rates 1.

Key Points

• INH is effective in preventing latent TB from progressing to active disease
• The 9-month regimen is preferred for optimal efficacy
• Patients should take vitamin B6 with INH to prevent peripheral neuropathy
• Regular liver function monitoring is essential to prevent hepatotoxicity
• Short-course rifamycin-based regimens are preferred over longer-course isoniazid monotherapy for LTBI treatment, as recommended by the National Tuberculosis Controllers Association and CDC in 2020 1.

From the FDA Drug Label

Isoniazid is recommended as preventive therapy for the following groups, regardless of age. Candidates for preventive therapy who have HIV infection should have a minimum of 12 months of therapy. Candidates for preventive therapy who have fibrotic pulmonary lesions consistent with healed tuberculosis or who have pulmonary silicosis should have 12 months of isoniazid or 4 months of isoniazid and rifampin, concomitantly.

The mechanism by which Isoniazid (INH) prevents latent Tuberculosis (TB) is not explicitly stated in the provided drug label. However, it is recommended as preventive therapy for certain groups, including those with HIV infection, close contacts of persons with newly diagnosed infectious tuberculosis, and recent converters, as indicated by a tuberculin skin test.

• The label recommends a minimum of 12 months of therapy for candidates with HIV infection.
• It also recommends 12 months of isoniazid or 4 months of isoniazid and rifampin for candidates with fibrotic pulmonary lesions consistent with healed tuberculosis or pulmonary silicosis. 2

From the Research

Mechanism of Isoniazid (INH) in Preventing Latent Tuberculosis (TB)

• Isoniazid (INH) is a key component in the treatment of latent tuberculosis infection, and its mechanism involves inhibiting the growth of Mycobacterium tuberculosis bacteria [(3,4)].
• The exact mechanism of INH in preventing latent TB is not fully understood, but it is believed to work by killing dormant bacteria, thereby preventing the progression to active TB 4.

Efficacy of INH in Preventing Latent TB

• Studies have shown that INH is effective in preventing latent TB, with a 9-month regimen of daily self-administered INH having an efficacy of more than 90% if completed properly 4.
• However, the 9-month regimen is often limited by toxicity and low rates of treatment completion, leading to the development of shorter, safer, and more effective regimens [(3,4)].

Comparison of INH Regimens

• A 3-month regimen of directly observed once-weekly therapy with rifapentine and INH has been shown to be as effective as 9 months of self-administered daily INH in preventing TB 3.
• The 3-month regimen has also been associated with higher treatment completion rates and lower rates of hepatotoxicity compared to the 9-month regimen [(3,5,6)].
• Other regimens, such as 2 months of rifampin and pyrazinamide, and 4 months of rifampin, have also been studied, but their efficacy and safety profiles vary [(4,7)].

Safety Profile of INH Regimens

• The safety profile of INH regimens varies, with the 9-month regimen associated with a higher risk of hepatotoxicity [(4,6)].
• The 3-month regimen of rifapentine and INH has been associated with a lower risk of hepatotoxicity, but a higher risk of flu-like reactions [(7,6)].
• Overall, the choice of INH regimen depends on various factors, including the patient's risk factors, treatment preferences, and access to directly observed therapy [(5,6)].