The grades of evidence supporting the treatment recommendation (I–III) and the strength of the recommendations (A–E) are defined at the end of the Major Recommendations.
Note from the National Guideline Clearinghouse (NGC):
To reduce the risk for liver injury associated with rifampin-pyrazinamide therapy for latent tuberculosis infection, the American Thoracic Society and the Centers for Disease Control (CDC), with the endorsement of the Infectious Diseases Society of America, prepared recommendations on August 31, 2001 that supercede previous guidelines. These follow:
Revised recommendations on selecting appropriate latent tuberculosis infection therapy for patients and monitoring the use of rifampin-pyrazinamide to treat latent tuberculosis infection
- The 2-month rifampin-pyrazinamide treatment regimen for latent tuberculosis infection should be used with caution, especially in patients concurrently taking other medications associated with liver injury, and those with alcoholism, even if alcohol use is discontinued during treatment. Rifampin-pyrazinamide is not recommended for persons with underlying liver disease or for those who have had isoniazid-associated liver injury. Persons being considered for treatment with rifampin-pyrazinamide should be informed of potential hepatotoxicity and asked whether they have had liver disease or adverse effects from isoniazid.
- For persons not infected with HIV, 9 months of daily isoniazid remains the preferred treatment for latent tuberculosis infection; 4 months of daily rifampin is an acceptable alternative. Two months of daily rifampin-pyrazinamide may be useful when completion of longer treatment courses is unlikely and when the patient can be monitored closely.
- Available data do not suggest excessive risk for severe hepatitis associated rifampin-pyrazinamide treatment among HIV-infected persons. In a large multinational trial, HIV-infected patients treated with rifampin-pyrazinamide had lower rates of serum aminotransferase elevations than those given isoniazid alone. The rifampin-pyrazinamide regimen also was well tolerated when given twice weekly to HIV-infected persons in Zambia and Haiti. However, experience from trials may not translate to all clinical practice settings, and it may be prudent to use 9 months of daily isoniazid for treatment of HIV-infected persons with latent tuberculosis infection when completion of treatment can be assured.
- No more than a 2-weeks supply of rifampin-pyrazinamide (with a pyrazinamide dose <20 mg/kg/d and a maximum of 2 gm/d) should be dispensed at a time to facilitate periodic clinical assessments. Patients should be reassessed in person by a health-care provider at 2, 4, and 6 weeks of treatment for adherence, tolerance, and adverse effects, and at 8 weeks to document treatment completion. At each visit, health-care providers conversant in the patients' language should instruct patients to stop taking rifampin-pyrazinamide immediately and seek medical consultation if abdominal pain, emesis, jaundice, or other hepatitis symptoms develop. Provider continuity is recommended for monitoring.
- A serum aminotransferase and bilirubin should be measured at baseline and at 2, 4, and 6 weeks of treatment in patients taking rifampin-pyrazinamide. Because some side effects may occur in the second month of treatment, patients should be monitored throughout the entire course of treatment. Asymptomatic serum aminotransferase increases are expected and usually do not require that treatment be stopped. However, treatment should be stopped and not resumed for any of these findings: aminotransferase greater than five times the upper limit of normal range in an asymptomatic person, aminotransferase greater than normal range when accompanied by symptoms of hepatitis, or a serum bilirubin greater than normal range.
The following considerations are crucial in deciding whom to test and treat for latent tuberculosis infection:
- The purpose of targeted testing is to find and treat
persons who have both latent tuberculosis infection and high risk for
tuberculosis disease (e.g., recent exposure to a contagious case). Persons at
low risk for developing tuberculosis and who have had a tuberculin skin test
for other reasons, such as baseline tuberculin skin test of health-care
workers, are not necessarily candidates for treatment if found to be infected.
- Treatment is recommended for foreign-born persons from
countries with a high prevalence of tuberculosis who have latent tuberculosis
infection and who have been in the United States <5 years [as indicated
below]. After 5 years, treatment decisions should be made on the same basis as
other patients.
- Because sporadic severe isoniazid-associated liver injury still occurs, patients taking isoniazid should be monitored as recommended [below].
CDC is collecting reports of severe liver injury (i.e., leading to hospital admission or death) in persons receiving any regimen for latent tuberculosis infection. Reports are being analyzed to assess contributing factors. Report possible cases to the Division of Tuberculosis Elimination; telephone (404) 639-8125.
Note from the National Guideline Clearinghouse:
The following recommendations, issued on June 9, 2000 by the Centers for Disease Control, have been superceded by revised recommendations issued on August 31, 2001 [see above].
Changes from Prior Recommendations on Tuberculin Testing and Treatment of Latent Tuberculosis Infection (LTBI)
Tuberculin Testing
- Emphasis on targeted tuberculin testing among persons
at high risk for recent latent tuberculosis infection or with clinical
conditions that increase the risk for tuberculosis (TB), regardless of age;
testing is discouraged among persons at lower risk
- For patients with organ transplants and other
immunosuppressed patients (e.g., persons receiving the equivalent of >15 mg/d
prednisone for 1 month or more), 5 mm of induration rather than 10 mm of
induration as a cut-off level for tuberculin positivity
- A tuberculin skin test conversion is defined as an increase of >10 mm of induration within a 2-yr period, regardless of age
Treatment of Latent Tuberculosis Infection
- For human immunodeficiency virus (HIV)-negative
persons, isoniazid given for 9 months is preferred over 6-month regimens
- For HIV-positive persons and those with fibrotic
lesions on chest x-ray consistent with previous tuberculosis, isoniazid should
be given for 9 months instead of 12 months
- For HIV-negative and HIV-positive persons, rifampin
and pyrazinamide should be given for 2 months
- For HIV-negative and HIV-positive persons, rifampin should be given for 4 months
Clinical and Laboratory Monitoring
- Routine baseline and follow-up laboratory monitoring
can be eliminated in most persons with latent tuberculosis infection, except
for those with HIV infection, pregnant women (or those in the immediate
postpartum period), and persons with chronic liver disease or those who use
alcohol regularly
- Emphasis on clinical monitoring for signs and symptoms
of possible adverse effects, with prompt evaluation and changes in treatment,
as indicated.
Targeted Tuberculin Testing
Targeted tuberculin testing for latent tuberculosis infection is a strategic component of tuberculosis (TB) control that identifies persons at high risk for developing tuberculosis who would benefit by treatment of latent tuberculosis infection, if detected. Persons with increased risk for developing tuberculosis 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 latent tuberculosis infection to active tuberculosis. 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 tuberculosis should be offered treatment of latent tuberculosis infection irrespective of age.
Based on the sensitivity and specificity of the purified protein derivative (PPD) tuberculin skin test and the prevalence of tuberculosis in different groups, three cut-points have been recommended for defining a positive tuberculin reaction: >5 mm, >10 mm, and >15 mm of induration. For persons who are at highest risk for developing active tuberculosis 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 tuberculosis, or who have abnormal chest radiographs consistent with prior tuberculosis), >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 tuberculosis, >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 tuberculosis); 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 tuberculosis, for whom tuberculin testing is not generally indicated, >15 mm of induration is considered positive.
Treatment of Latent Tuberculosis Infection
In the guideline, treatment recommendations use an adaptation of the rating system from recent U.S. Public Health Service documents 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 latent tuberculosis infection.
Recommended drug regimens for treatment of latent tuberculosis (TB) infection in adults
|
|
|
|
Rating (Evidence)
|
|
Drugs |
Interval and Duration |
Comments |
HIV-
|
HIV+
|
|
Isoniazid |
Daily for 9 mos#& |
In human immunodeficiency virus (HIV)-infected patients, isoniazid may be administered concurrently with nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors, or non-nucleoside reverse transcriptase inhibitors (NNRTIs)
|
A (II) |
A (II) |
|
|
Twice weekly for 9 mos#& |
Directly observed therapy (DOT) must be used with
twice-weekly dosing |
B (II) |
B (II) |
|
Isoniazid |
Daily for 6 mos & |
Not indicated for HIV-infected persons, those with
fibrotic lesions on chest radiographs, or children |
B (I) |
C (I) |
|
Twice weekly for 6 mos& |
Directly observed therapy must be used with
twice-weekly dosing |
B (II) |
C (I) |
|
Rifampin plus pyrazinamide |
Daily for 2 mos |
May also be offered to persons who are contacts of pyrazinamide patients with isoniazid-resistant, rifampin-susceptible tuberculosis
In HIV-infected patients, protease inhibitors or
NNRTIs should generally not be administered concurrently with rifampin;
rifabutin can be used as an alternative for patients treated with
indinavir, nelfinavir, amprenavir, ritonavir, or efavirenz, and possibly
with nevirapine* or soft-gel saquinavir** |
B (II) |
A (II) |
|
Twice weekly for 2-3 mos |
Directly observed therapy must be used with twice-weekly dosing |
C (II) |
C (I) |
|
Rifampin |
Daily for 4 mos |
For persons who cannot tolerate pyrazinamide
For persons who are contacts of patients with
Isoniazid-resistant, rifampin-susceptible tuberculosis who cannot tolerate
pyrazinamide |
B (II) |
B (III) |
# Recommended regimen for children younger than 18 years of age.
& Recommended regimens for pregnant women. Some experts would use rifampin and pyrazinamide for 2 months as an alternative regimen in HIV-infected pregnant women, although pyrazinamide should be avoided during the first trimester.
** Rifabutin should not be used with hard-gel saquinavir or delavirdine. When used with other protease inhibitors or NNRTIs, dose adjustments or rifabutin may be required (see Table 8 in the guideline document).
*Note from the National Guideline Clearinghouse: On January 19, 2005, the U.S. Food and Drug Administration (FDA) issued a public health advisory about recent safety-related changes to the nevirapine (Viramune®) label and about appropriate use of HIV triple combination therapy containing nevirapine. The Indications and Usage section now recommends against starting nevirapine treatment in women with CD4+cell counts greater than 250 cells/mm3 unless benefits clearly outweigh risks. This recommendation is based on a higher observed risk of serious liver toxicity in patients with higher CD4 cell counts prior to initiation of therapy. See the FDA Web site for more information.
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 month regimen of isoniazid is the preferred regimen for the treatment of latent tuberculosis infection, a 6 month 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 months rather than 9 months 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 month rather than a 9 month course of isoniazid is preferred.
Both the 9 month and 6 month 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).
The 2 month daily regimen of rifampin and pyrazinamide is recommended on the basis of a prospective randomized trial of treatment of latent tuberculosis infection in HIV-infected persons that showed the 2 month regimen to be similar in safety and efficacy to a 12 month regimen of isoniazid. Twice-weekly treatment with rifampin and pyrazinamide for 2 or 3 months may be considered when alternative regimens cannot be given. This intermittent regimen should always be administered as directly observed therapy. Some experts recommend that the 2 months regimen of daily rifampin and pyrazinamide also be given by directly observed therapy, 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 months 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 tuberculosis. This option may be especially useful for patients who cannot tolerate isoniazid or pyrazinamide.
Before beginning treatment of latent tuberculosis infection, active tuberculosis should be ruled out by history, physical examination, chest radiography, and, when indicated, bacteriologic studies.
Special considerations for treatment of latent tuberculosis infection apply to the following populations:
- When isoniazid is chosen for treatment of latent
tuberculosis infection in persons with HIV infection or those with
radiographic evidence of prior tuberculosis, 9 months rather that 6 months is
recommended.
- For pregnant, HIV-negative women, isoniazid given
daily or twice weekly for 9 or 6 months is recommended. For women at risk for
progression of latent tuberculosis infection 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 tuberculosis 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 months is the recommended regimen.
- For contacts of patients with isoniazid-resistant,
rifampin-susceptible tuberculosis, rifampin and pyrazinamide given daily for 2 months is recommended, and for patients with intolerance to pyrazinamide, rifampin
given daily for 4 months is recommended.
- For persons who are likely to be infected with isoniazid- and rifampin-resistant (multidrug) tuberculosis and who are at high risk for developing tuberculosis, pyrazinamide and ethambutol or pyrazinamide and a quinolone (i.e., levofloxacin or ofloxacin) for 6 to 12 months are recommended. Immunocompetent contacts may be observed or treated for at least 6 months, and immunocompromised contacts (e.g., HIV-infected persons) should be treated for 12 months.
Clinical and Laboratory Monitoring
Once patients have been identified and then tested for latent tuberculosis infection, 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 weeks (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 latent tuberculosis infection 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 latent tuberculosis infection. 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 immediate postpartum period (i.e., within 3 months 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 latent tuberculosis infection.
Routine laboratory monitoring during treatment of latent tuberculosis infection 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.
Definitions:
Treatment recommendations use an adaptation of the rating system from recent U.S. Public Health Service documents that grades the strength of the recommendation and the quality of the evidence.
Strength of the recommendation
- Preferred; should generally be offered
- Alternative; acceptable to offer
- Offer when preferred (A) or alternative (B) regimens
cannot be given
- Should generally not be offered
- Should never be offered
Quality of evidence supporting the recommendations
- At least one randomized trial with clinical endpoints
- Clinical trials that either are not randomized or were
conducted in other populations
- Expert opinion
