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CDC's Core Curriculum on Tuberculosis

Core Curriculum on Tuberculosis

Chapter 6 - Treatment of Latent TB Infection (LTBI)

Regimens
(See Tables 1 and 2)

There are several treatment regimens available for the treatment of LTBI, and providers should discuss options with their patients. For persons who are at especially high risk for TB and are either suspected of nonadherence or are on an intermittent dosing regimen, directly observed therapy (DOT) of LTBI should be considered. This method of treatment is especially appropriate when a household member is on DOT for active disease, or in institutions and facilities where treatment for infection can be observed by a staff member.

Isoniazid
In clinical trials, daily isoniazid treatment for latent infection for 12 months reduced the risk for TB disease by more than 90% in patients who completed a full course of therapy. ¹ There is evidence that 6 months of treatment for LTBI with isoniazid can also confer a high degree of protection (approximately 70% in patients who complete the regimen) against the progression of TB infection to TB disease. ¹ The protection conferred by taking at least 9 months of isoniazid is greater than that conferred by taking 6 months.

Isoniazid is normally used alone for treatment of LTBI in a single daily dose of 300 mg in adults and 10-15 mg/kg body weight in children, not to exceed 300 mg per dose. Isoniazid can be given two times a week at a dosage of 15 mg/kg as DOT of LTBI. ^2,3 When isoniazid is given alone to persons with active TB disease, resistance to isoniazid is likely to develop. For this reason, persons suspected of having TB disease should receive the recommended multidrug regimen for treatment of disease until the diagnosis is confirmed or ruled out.

A 9-month regimen (minimum of 270 doses administered within 12 months) is considered optimal treatment for both HIV-positive and HIV-negative adults. A 6-month regimen (minimum of 180 doses administered within 9 months) may also provide sufficient protection. HIV-positive and HIV-negative children should receive 9 months of isoniazid treatment for infection. Twice-weekly regimens should consist of at least 76 doses administered within 12 months for the 9-month regimen and 52 doses within 9 months for the 6-month regimen. Treatment for LTBI for 6 months rather than 9 months may be more cost-effective and result in greater adherence by patients, therefore, local programs may prefer to implement the 6-month regimen rather then the 9-month regimen. Every effort should be made to ensure that patients adhere to treatment for infection for at least 6 months.

Peripheral neuropathy is associated with the use of isoniazid but is uncommon at doses of 5 mg/kg. Persons with conditions in which neuropathy is common (e.g., diabetes, uremia, alcoholism, malnutrition, HIV-infection), as well as pregnant women and persons with a seizure disorder, may be given pyridoxine (vitamin B₆) (10-50 mg/day) with isoniazid.

Rifampin/Pyrazinamide
Two- and three-month regimens with daily rifampin in combination with pyrazinamide and/or isoniazid have recently been evaluated in HIV-positive adult patients and appear to be as effective as longer courses of isoniazid. ^2,3 Clinical trials of rifampin and pyrazinamide have not been conducted in HIV-negative persons. Therefore, the strength of the recommendation for use of this regimen is less for this population than for those who are HIV-positive. Regimens consisting of 2 months of rifampin and pyrazinamide are not recommended for pregnant women. Pyrazinamide’s effect on the fetus is unknown.

HIV-Negative Persons
The recommended 2-month treatment-of-latent-infection regimen (60 doses to be administered within 3 months) includes daily rifampin and pyrazinamide. Rifampin is given in a daily dose of 10 mg/kg (maximum dose 600 mg) and pyrazinamide is given in a daily dose of 15-20 mg/kg (maximum dose 2 g). Rifampin and pyrazinamide may also be given two times a week (16 doses to be administered for 2 months or 24 doses to be administered for 3 months). However, this regimen has not been studied in this population and should be used only when other effective regimens cannot be given. Like all intermittent regimens, this regimen must always be administered under DOT.

HIV-Positive Persons
Two-month regimens for treatment of LTBI that include rifampin or rifabutin are appropriate for HIV-positive adults who are likely to be infected with TB organisms susceptible to rifamycins.

The administration of rifampin is contraindicated with some protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) used for HIV therapy. For these patients, a substitution of rifabutin for rifampin is generally recommended. Clinicians are advised to consider potential drug interactions when prescribing rifamycins to patients receiving HIV therapy with PIs and NNRTIs. Daily regimens of a rifamycin (rifampin or rifabutin) and pyrazinamide should consist of at least 60 doses to be administered for 2 months or up to 3 months. This regimen may also be given two times a week (16 doses to be administered for 2 months or 24 doses to be administered for 3 months).

For HIV-positive patients receiving PIs or NNRTIs, an alternative 2-month regimen includes rifabutin and pyrazinamide administered daily. However, the concurrent administration of rifabutin is contraindicated with hard-gel saquinavir and delavirdine. An alternative is the use of rifabutin with indinavir, nelfinavir, amprenavir, ritonavir, efavirenz, and possibly soft-gel saquinavir and nevirapine. Caution is advised when using rifabutin with soft-gel saquinavir and nevirapine, because data regarding the use of rifabutin with soft-gel saquinavir and nevirapine are limited. Rifabutin is given in a daily dose of 5 mg/kg (maximum dose 300 mg) and pyrazinamide is given in a daily dose of 15-20 mg/kg (maximum dose 2 g). The dosage of rifabutin may need to be adjusted when given with certain PIs and NNRTIs (see Table 2).

For HIV-positive patients not receiving PIs or NNRTIs, the recommended 2-month treatment-of-latent-infection regimen includes daily rifampin and pyrazinamide. Rifampin is given in a daily dose of 10-20 mg/kg (maximum dose 600 mg) and pyrazinamide is given in a daily dose of 15-20 mg/kg (maximum dose 2 g).

Rifampin
For both HIV-negative and HIV-positive patients who cannot tolerate isoniazid or pyrazinamide, an alternative treatment regimen is 4-months (minimum of 120 doses administered within 6 months) of rifampin.

Contacts of Isoniazid-Resistant TB
For persons who are known to be contacts of patients with isoniazid-resistant, rifampin-susceptible TB, a 2-month regimen of rifampin and pyrazinamide is recommended. For patients who are unable to tolerate pyrazinamide, a 4-month regimen of daily rifampin alone is recommended. In situations where rifampin cannot be used, rifabutin may be substituted. For HIV-positive persons, a 2-month regimen with a rifamycin and pyrazinamide is recommended.

Contacts of Multidrug-Resistant TB
For persons likely to have been infected with a strain of M. tuberculosis resistant to both isoniazid and rifampin, alternative regimens should be considered. Alternative regimens should consist of two drugs to which the infecting organism has demonstrated susceptibility. Potential alternative regimens include either 6-12 months of daily ethambutol and pyrazinamide or 6-12 months of pyrazinamide and a quinolone (i.e, levofloxacin, ofloxacin, or ciprofloxacin). Immunocompetent contacts may be treated for 6 months or observed without treatment. Immunocompromised contacts (e.g., HIV-positive persons) should be treated for 12 months. Persons receiving pyrazinamide and a quinolone antibiotic should be monitored closely for adverse effects. Some evidence suggests that the combination of pyrazinamide and ofloxacin may be poorly tolerated. ⁴ All persons with suspected multidrug-resistant LTBI should be followed for 2 years regardless of the treatment regimen.

Ethambutol at the usual dose is safe for children. The regimen of pyrazinamide and ethambutol for 9-12 months is recommended for children if the infecting organism has demonstrated susceptibility. When pyrazinamide and/or ethambutol cannot be used, a combination of two other drugs to which the infecting organism is likely susceptible is recommended.

Persons with Fibrotic Lesions
Patients who have a chest radiograph suggestive of old fibrotic lesions thought to represent previous TB, a positive tuberculin skin test (³5 mm), no evidence of active disease, and no history of treatment for TB should be treated for LTBI. Acceptable regimen options include

• 9 months of isoniazid
• 2 months of rifampin plus pyrazinamide or
• 4 months of rifampin (with or without isoniazid)

Patients who have a positive tuberculin skin test and radiographic findings suggestive of healed, primary TB (calcified solitary pulmonary nodules, calcified hilar lymph nodes, and apical pleural capping) are not at significantly increased risk of TB. Their risk for progression to TB disease and the need for treatment of LTBI should be determined by other risk factors and the size of the tuberculin reaction.

Pregnancy and Breast-feeding
Isoniazid administered either daily or twice-weekly are the preferred regimens for the treatment of LTBI in pregnant women. Such women taking isoniazid should also take pyridoxine (vitamin B₆) supplementation. Although rifampin may be safe, there are no efficacy data supporting its use in this population.

For women who are at high risk for the progression of LTBI to active disease, especially those who are HIV-positive or who have been recently infected, initiation of therapy should not be delayed on the basis of pregnancy alone, even during the first trimester. For these women, careful clinical monitoring and/or lab monitoring should be conducted.

Breast-feeding is not contraindicated when a mother is being treated for LTBI. Likewise, the amount of isoniazid provided by breast milk is inadequate for the treatment of an infant. Infants whose breast-feeding mothers are taking isoniazid should receive supplemental pyridoxine.