Update on the Treatment of Tuberculosis & Latent TB Infection - June 6, 2005 JAMA 293:2776

Management of Tuberculosis (Review)  NEJM July 19, 2001  

TB Treatment 2000 (CDC)

New Tuberculosis Guidelines CDC 2000  

MMWR June 09, 2000 / 49(RR06);1-54
Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection

TB Treatment 1997

California Tuberculosis Controllers Association Guidelines  

MMWR March 10, 2000 / 49(09);185-9
Notice to Readers: Updated Guidelines for the Use of Rifabutin or Rifampin for the Treatment and Prevention of Tuberculosis Among HIV-Infected Patients Taking Protease Inhibitors or Nonnucleoside Reverse Transcriptase Inhibitors


Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection 2000  
MMWR June 09, 2000 / 49(RR06);1-54  

This Official Statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. This is a Joint Statement of the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC). This Statement was endorsed by the Council of the Infectious Diseases Society of America (IDSA), September 1999, and the sections of this Statement as it relates to infants and children were endorsed by the American Academy of Pediatrics (AAP), August 1999.


This statement provides new recommendations for targeted tuberculin testing and treatment regimens for persons with latent tuberculosis infection (LTBI) and updates previously published guidelines (1,2).

Isoniazid for 6--12 mo has been the mainstay of treatment for LTBI in the United States for more than 30 years.  However, the application of isoniazid for LTBI has been limited because of poor adherence, due to the relatively long duration of treatment required, and because of concerns about toxicity. Therefore, there has been interest in the development of shorter, rifampin-based regimens as alternatives to isoniazid for the treatment of LTBI. During the past decade, a series of studies of "short-course" treatment of LTBI in persons with human immunodeficiency virus (HIV) infection has been undertaken. The results of these trials have recently become available, and the in-depth analyses of these and prior studies of isoniazid form the scientific basis of the treatment guidelines presented in this report. In addition, many changes to previous recommendations regarding testing for and treatment of LTBI are presented (Table 1).

Targeted Tuberculin Testing

Targeted tuberculin testing for LTBI is a strategic component of tuberculosis (TB) control that identifies persons at high risk for developing TB who would benefit by treatment of LTBI, if detected. Persons with increased risk for developing TB include those who have had recent infection with Mycobacterium tuberculosis and those who have clinical conditions that are associated with an increased risk for progression of LTBI to active TB (see Tables 2 and 3). Following that principle, targeted tuberculin testing programs should be conducted only among groups at high risk and discouraged in those at low risk. Infected persons who are considered to be at high risk for developing active TB should be offered treatment of LTBI irrespective of age.

Based on the sensitivity and specificity of the purified protein derivative (PPD) tuberculin skin test and the prevalence of TB in different groups, three cut-points have been recommended for defining a positive tuberculin reaction: >5 mm, >10 mm, and >15 mm of induration (see Table 7).

For persons who are at highest risk for developing active TB if they are infected with M. tuberculosis (i.e., persons with HIV infection, who are receiving immunosuppressive therapy, who have had recent close contact with persons with infectious TB, or who have abnormal chest radiographs consistent with prior TB), >5 mm of induration is considered positive.

For other persons with an increased probability of recent infection or with other clinical conditions that increase the risk for progression to active TB, >10 mm of induration is considered positive.
These include recent immigrants (i.e., within the last 5 yr) from high prevalence countries; injection drug users; residents and employees of high-risk congregate settings (including health care workers with exposure to TB); mycobacteriology laboratory personnel; persons with clinical conditions such as silicosis, diabetes mellitus, chronic renal failure, leukemias and lymphomas, carcinoma of the head or neck and lung, weight loss of >10% ideal body weight, gastrectomy, and jejunoileal bypass; and children younger than 4 yr of age or infants, children, and adolescents exposed to adults in high-risk categories.

For persons at low risk for TB, for whom tuberculin testing is not generally indicated, >15 mm of induration is considered positive.

Treatment of Latent Tuberculosis Infection

In this report, treatment recommendations use an adaptation of the rating system from recent U.S. Public Health Service documents (3) that grades the strength of the recommendation (A, B, or C) and the quality of evidence supporting the recommendation (I, II, or III). Four regimens are recommended for the treatment of adults with LTBI. (See Tables 8 & 8b and Table10 for detailed recommendations, dosages, and contraindications.)

The isoniazid daily regimen for 9 mo is recommended because prospective, randomized trials in HIV-negative persons indicate that 12 mo of treatment is more effective than 6 mo of treatment. However, in subgroup analyses of several trials the maximal beneficial effect of isoniazid is likely achieved by 9 mo, and minimal additional benefit is gained by extending therapy to 12 mo. When compared with placebo, both 6-mo and 12-mo regimens are effective in HIV-positive patients; however, these regimens have not been compared with each other in randomized trials.

Although a 9-mo regimen of isoniazid is the preferred regimen for the treatment of LTBI, a 6-mo regimen also provides substantial protection and has been shown to be superior to placebo in both HIV-negative and HIV-positive persons. In some situations, treatment for 6 mo rather than 9 mo may provide a more favorable outcome from a cost-effectiveness standpoint.

Thus, based on local conditions, health departments or providers may conclude that a 6-mo rather than a 9-mo course of isoniazid is preferred.

Both the 9-mo and 6-mo isoniazid regimens may be given intermittently (i.e., twice weekly). When isoniazid is given intermittently, it should be administered only as directly observed therapy (DOT).

Treatment of LTBI in HIV-infected persons
The 2-mo daily regimen of rifampin and pyrazinamide is recommended on the basis of a prospective randomized trial of treatment of LTBI in HIV-infected persons that showed the 2-mo regimen to be similar in safety and efficacy to a 12-mo regimen of isoniazid. Twice-weekly treatment with rifampin and pyrazinamide for 2 or 3 mo may be considered when alternative regimens cannot be given. This intermittent regimen should always be administered as DOT. Some experts recommend that the 2-mo regimen of daily rifampin and pyrazinamide also be given by DOT, which can consist of five observed and two self-administered doses each week. In situations in which rifampin cannot be used (e.g., HIV-infected persons receiving protease inhibitors), rifabutin may be substituted.

Rifampin given daily for 4 mo is recommended on the basis of the efficacy of a similar regimen in a) a prospective randomized trial of tuberculin-positive persons with silicosis and b) a nonrandomized trial in persons exposed to individuals with isoniazid-resistant TB. This option may be especially useful for patients who cannot tolerate isoniazid or pyrazinamide.

Before beginning treatment of LTBI, active TB should be ruled out by history, physical examination, chest radiography, and, when indicated, bacteriologic studies.

Special considerations for treatment of LTBI apply to the following populations:

When isoniazid is chosen for treatment of LTBI in persons with HIV infection or those with radiographic evidence of prior TB, 9 mo rather that 6 mo is recommended.

For pregnant, HIV-negative women, isoniazid given daily or twice weekly for 9 or 6 mo is recommended. For women at risk for progression of LTBI to disease, especially those who are infected with HIV or who have likely been infected recently, initiation of therapy should not be delayed on the basis of pregnancy alone, even during the first trimester. For women whose risk for active TB is lower, some experts recommend waiting until after delivery to start treatment.

For children and adolescents, isoniazid given either daily or twice weekly for 9 mo is the recommended regimen.   For contacts of patients with isoniazid-resistant, rifampin-susceptible TB, rifampin and pyrazinamide given daily for 2 mo is recommended, and for patients with intolerance to pyrazinamide, rifampin given daily for 4 mo is recommended.

For persons who are likely to be infected with isoniazid- and rifampin-resistant (multidrug) TB and who are at high risk for developing TB, pyrazinamide and ethambutol or pyrazinamide and a quinolone (i.e., levofloxacin or ofloxacin) for 6--12 mo are recommended. Immunocompetent contacts may be observed or treated for at least 6 mo, and immunocompromised contacts (e.g., HIV-infected persons) should be treated for 12 mo.

Clinical and Laboratory Monitoring

Once patients have been identified and then tested for LTBI, they should receive an initial clinical evaluation. They should also receive follow-up evaluations at least monthly (if receiving isoniazid alone or rifampin alone) and at 2, 4, and 8 wk (if receiving rifampin and pyrazinamide). This evaluation should include questioning about side effects and a brief physical assessment checking for signs of hepatitis. Patients should be educated about the side effects associated with treatment of LTBI and advised to stop treatment and promptly seek medical evaluation when they occur.

Baseline laboratory testing is not routinely indicated for all patients at the start of treatment for LTBI (see Table 8).  Patients whose initial evaluation suggests a liver disorder should have baseline hepatic measurements of serum aspartate aminotransferase (serum glutamic oxaloacetic transaminase) (AST [SGOT]) or alanine aminotransferase (serum glutamic pyruvic transaminase) (ALT [SGPT]) and bilirubin. Baseline testing is also indicated for patients with HIV infection, pregnant women, and women in the im mediate postpartum period (i.e., within 3 mo of delivery), persons with a history of chronic liver disease (e.g., hepatitis B or C, alcoholic hepatitis, or cirrhosis), persons who use alcohol regularly, and persons at risk for chronic liver disease. Baseline testing is not routinely indicated in older persons. However, such testing may be considered on an individual basis, particularly for patients who are taking other medications for chronic medical conditions.

Active hepatitis and end-stage liver disease are relative contraindications to the use of isoniazid or pyrazinamide for treatment of LTBI.

Routine laboratory monitoring during treatment of LTBI is indicated for persons whose baseline liver function tests are abnormal and other persons at risk for hepatic disease. Laboratory testing may also be indicated for the evaluation of possible adverse effects that occur during the course of treatment (e.g., liver function studies for patients with symptoms compatible with hepatotoxicity or a uric acid measurement to evaluate complaints of joint pain). Some experts recommend that isoniazid should be withheld if transaminase levels exceed three times the upper limit of normal if associated with symptoms and five times the upper limit of normal if the patient is asymptomatic.