Latent Tuberculosis Infection

Background

Latent (or inactive) tuberculosis (TB) infection occurs when an individual has dormant Mycobacterium tuberculosis organisms and no active disease. It can be diagnosed by a tuberculin skin test (TST) or by a blood test called an interferon-gamma release assay (IGRA); both are described below. HIV-infected persons with latent TB infection (LTBI) have a much higher risk of developing active TB (estimated at 10% per year) than the general population (estimated at 10% in a lifetime). Whereas treatment of HIV infection with antiretroviral therapy (ART) reduces the risk of active TB, this risk remains higher than that for HIV-uninfected persons. The risk of an individual with LTBI developing active TB can be reduced 90% with treatment of LTBI. Hence, identifying and treating HIV-infected persons with LTBI is a high priority. Treatment of LTBI not only reduces the risk of disease to the individual but also reduces the risk of further TB transmission within the community. Standard treatment with isoniazid (INH) is effective and safe.

Issues of concern regarding treatment of LTBI among HIV-infected persons include the following:

• Excluding active pulmonary or extrapulmonary TB disease before treatment with INH alone
• Assessing the risk of latent infection with drug-resistant TB
• Avoiding or managing drug interactions if rifamycin-containing regimens are used (rifampin, rifabutin, rifapentine)

S: Subjective

Ask about symptoms of active TB, including fever, cough, and weight loss; see chapter Mycobacterium tuberculosis. Patients with symptoms that could represent active TB must be evaluated for active TB and ruled out by appropriate diagnostic methods before initiating treatment (see "Assessment," below). HIV-infected persons are eligible for LTBI treatment if they have positive LTBI screening results, no symptoms of active TB, and have not been treated previously for active or latent TB (re-treatment of LTBI should be considered if a patient is a close contact to an active TB case).

Persons who have had bacillus Calmette-Guérin (BCG) vaccine can be evaluated by an IGRA (preferably) or by a TST with correct interpretation. Immigrants from many countries will have had childhood BCG vaccination.

Health care providers should ask about a history of potential exposure to TB. Close contact with an active TB case is an indication for LTBI treatment, after active TB has been excluded, regardless of the screening results on TST or IGRA.

O: Objective

Diagnostic Evaluation

Current U.S. Centers for Disease Control and Prevention (CDC) and U.S. Department of Health and Human Services (DHHS) guidelines strongly recommend LTBI testing for all newly diagnosed HIV-infected persons. Repeat testing is recommended for patients whose CD4 lymphocyte count increases from low numbers to counts of >200 cells/µL, and annual testing is suggested for patients whose initial test result is negative and who are considered at high risk of repeated or ongoing exposure to TB (risk factors include incarceration, residence in a congregate setting, active drug use, and residence in or travel to a TB-endemic setting).

The DHHS recommends use of either the TST or one of the three currently available IGRAs (QuantiFERON-TB Gold, QuantiFERON-TB Gold In-tube, or TSPOT-TB). The TST evaluates delayed hypersensitivity to antigens from a number of Mycobacterium species (including non-tuberculosis species). The IGRAs are in vitro tests of lymphocyte recognition and response to antigens more specific to M. tuberculosis, but they still may cross-react with M. kansasii, M. marinum, or M. szulgai. Because the IGRAs use antigens more specific to M. tuberculosis, they generally are thought to have greater specificity and a lower false-positive rate. A positive TST or IGRA result suggests previous contact with M. tuberculosis, and it implies latent or active TB infection. Neither TST nor IGRA screening can distinguish between LTBI and active TB infection.

The CDC recommends that an IGRA can be used in place of a TST in any clinical situation in which TST would be used. Use of an IGRA is preferred for persons with previous BCG exposure and for patient groups at risk of not returning for TST readings. The TST is preferred for children under 5 years of age. The cost of an IGRA is higher than the cost of a TST, and individual clinics should compare the total costs of both testing approaches, including the costs involved in TST protocols of recalling patients who miss visits, repeating TSTs, and treating persons with previous BCG exposure who may have false-positive TST results. Both IGRAs and TST testing have increased rates of anergic test results in HIV-infected patients with advanced immunosuppression (particularly CD4 counts of <100 cells/µL).

Tuberculin skin test

The TST is administered as an intradermal injection of 0.1 mL (5 tuberculin units) of purified protein derivative (PPD), which raises a wheal in the skin. This is sometimes referred to as the Mantoux test. Multiple-puncture tests such as tine tests and the use of other strengths of PPD are considered unreliable. Anergy testing with Candida and mumps antigens is not routinely recommended because a randomized controlled study of HIV-infected patients in the United States did not show an advantage to treating anergic, tuberculin-negative persons.

PPD tests are not designed for reading by the patient; a trained health care worker must measure the area of induration (not erythema) 48-72 hours after the test is administered. Induration of 5 mm or more is considered a positive result for HIV-infected persons, other immunosuppressed persons, anyone with recent TB exposure, and anyone with fibrosis on chest X ray that is consistent with previous TB. For HIV-uninfected health care workers, 10 mm of induration is a positive result; in various other populations, either 10 mm or 15 mm of induration may be considered positive. Care providers at many large HIV clinics find it challenging to ensure that their patients return for the PPD reading. One randomized study found that offering incentives (e.g., a fast-food coupon) plus counseling was more effective than counseling alone in obtaining return visits for PPD readings.

Interferon-gamma release assay

IGRA tests performed on peripheral blood samples are available in the United States from two manufacturers. Although the tests are expensive, results are obtained without the patient having to make a return visit to the clinic, and false-positive readings following BCG vaccination do not occur. In addition, IGRAs do not appear to be boosted by prior TST testing and two-step testing is not required. Three test results are possible with IGRA testing: positive, negative, and indeterminate. Unlike the TST, interpretation of IGRA test results does not vary by the risk category of the person tested. An indeterminate test indicates either a high background IFN-gamma level or failure of the mitogen to respond, and should be interpreted as no test result (not as "partially positive"). Repeating the IGRA once may yield interpretable test results. However, if the subsequent IGRA result is indeterminate, no further testing is recommended until there is a change in the patient's immune status, such as reconstitution with ART.

Limited data suggest that the QFT-GIT is the most specific test (lowest rate of false-positive results) and the T-SPOT is the most sensitive test (with the lowest rate of false-negative results). However, few studies have compared the IGRA assays, and there is no reliable "gold standard" for sensitivity or specificity for latent TB infection. Although these tests do not detect previous BCG exposure, they will yield positive results in all three TB-causing species of the M. tuberculosis complex, M. tuberculosis, Mycobacterium bovis, and Mycobacterium africanum, and may yield positive results in persons with exposure to certain mycobacteria other than M. tuberculosis (M. kansasii, M. marinum, and M. szulgai).

There are accumulating data to support the use of IGRA testing in HIV infection. Data suggest that IGRAs are more specific than the TST and correlate more closely with risk factors for TB infection. As with TST, false-negative and indeterminate test results are more likely with advanced immunosuppression. One case series suggests that a significant number of QTF tests may be falsely positive on initial testing but negative on retesting, particularly in patients who were not born in TB-endemic settings. Accordingly, for patients with a positive IGRA result but no risk factors for TB other than HIV infection, it may be reasonable to repeat the IGRA and confirm positivity before treatment.

A: Assessment

A chest X ray should be obtained for all HIV-infected persons with positive TST or IGRA test results. Asymptomatic patients with negative chest X-ray results should be offered treatment for LTBI. (As above, it may be reasonable to repeat the IGRA in HIV-infected patients in non-TB-endemic settings and no other risk factors for TB prior to LTBI treatment.) Persons with symptoms consistent with pulmonary or extrapulmonary TB, and those with abnormal chest radiography, require further assessment before LTBI treatment. This assessment may include sending two to three separate sputum specimens for acid-fast bacilli (AFB) stain, nucleic acid amplification testing if available, and culture, or obtaining other specimens depending on the suspected site of extrapulmonary TB. If suspicion of TB is low, patients with negative sputum smears (or other biopsy or tissue samples) can begin LTBI treatment. If suspicion of active disease is high, treatment for active disease should be started while the culture results are pending (see chapter Mycobacterium tuberculosis). HIV-infected persons with significant exposure to someone with infectious TB should receive a full course of TB prophylaxis regardless of TST or IGRA results. Health departments can assist clinicians in assessing the degree of exposure for an HIV-infected patient and in determining whether there is a need for a full course of treatment.

An HIV-infected person with fibrosis on a chest X ray that is consistent with previous TB and with no history of TB treatment (or a history of inadequate treatment) should be evaluated for active TB regardless of TST or IGRA results. If found not to have active TB, the patient should be treated for LTBI. If the patient is strongly suspected to have active TB, standard treatment for active TB should be given while culture analysis is under way. If cultures are negative, patients may be switched to LTBI treatment. Highly suspect but culture-negative patients may be given a 4-month total course of treatment for active TB. (See chapter Mycobacterium tuberculosis.)

P: Plan

As with any treatment of TB, adherence to the regimen is required for success. Treatment regimens for LTBI in the United States and other low-prevalence TB countries are presented in Table 1. Treatment should be offered to all HIV-infected persons with evidence of LTBI or close contact with an active TB case, regardless of age.

In some highly TB-endemic settings outside the United States, LTBI treatment given to TST-negative patients or patients of unknown TB status has led to reduction of active TB, although TST- or IGRA-positive patients appear to benefit most from LTBI treatment.

INH is preferred for treatment of LTBI because of extensive data supporting its efficacy and because it has no significant interactions with ARV medications. Treatment with INH for 9 months is recommended. Rifampin-based LTBI treatment is an alternative and is given for 4 months. However, rifampin has substantial drug interactions with a number of ARVs (see "Potential ARV Interactions," below). Rifabutin is an alternative for patients on PI-based regimens, although there are limited data for use in LTBI. Rifapentine, in combination with weekly INH, has been approved as part of a 12-week treatment course for LTBI; however, it is not recommended currently for ART-treated patients outside clinical trials because of limited data on interactions with ARV medications. Rifampin + pyrazinamide is no longer recommended for LTBI treatment owing to unacceptable rates of hepatoxicity.

For treatment of LTBI in persons exposed to drug-resistant TB, there are limited data on efficacy of various regimens in preventing progression to disease; consult with experts.

Length of LTBI Treatment

LTBI treatment is recommended for 9 months with INH (4 months with rifampin/rifabutin) in low-prevalence TB settings such as the United States. Accumulating data suggest that 36 months or indefinite LTBI treatment may be of benefit in some highly TB endemic settings where TB reinfection may be common.

Monitoring on therapy

INH may cause liver toxicity and it should be used cautiously in patients with active alcohol use, liver disease, or chronic hepatitis B or C. INH is contraindicated for use in patients with acute hepatitis or decompensated liver disease. Baseline liver function tests are recommended for all HIV-infected persons prior to starting LTBI treatment. Monthly assessment to screen for signs and symptoms of hepatoxicity (e.g., abdominal pain, jaundice, nausea, vomiting, and fatigue) and neuropathy is recommended. Patients with abnormal hepatic enzymes at baseline and/or liver disease such as viral hepatitis should receive regular checks of transaminases. If patients develop abnormalities in liver transaminases while taking INH (ALT or AST >3 times the upper limit of normal [ULN] with symptoms, or >5 times above the ULN in the absence of symptoms), the INH should be withheld. Obtain expert consultation before treating patients with abnormal liver function or advanced liver disease. All patients should receive pyridoxine (B6), 25-50 mg daily, during INH treatment to reduce the risk of peripheral neuropathy.

Rifampin and rifabutin may cause liver and bone marrow toxicity. Before use, obtain baseline liver and renal function tests and a complete blood count. Given the potential for interaction with ARV and other drugs, a careful review of current medications should be done to assess for possible drug interactions. Follow-up is the same as for INH use.

Other Drug Interactions

Rifampin decreases the blood concentrations of estrogens, anticonvulsants, hypoglycemic agents, and many other drugs. Review all medications a patient is taking before initiating rifampin and make adjustments as necessary. (See Table 12: Clinically significant drug-drug interactions involving the rifamycins.)

Pregnancy

HIV-infected pregnant women with positive LTBI test results and no evidence of active TB should receive standard prophylaxis as soon as possible, even during the first trimester.

The preferred prophylaxis during pregnancy is a 9-month isoniazid regimen (with pyridoxine, as above). Alternative agents, such as rifampin or rifabutin, should be used with caution because of limited experience. Neonates born to women who received rifampin during pregnancy should be given vitamin K (10 mg) to reduce the risk of hemorrhagic disease. Pyrazinamide generally is avoided during pregnancy because of lack of information regarding fetal effects.

Patient Education

• Patients should know that TB bacteria in their bodies cannot be passed to others while the TB is latent. However, because they have HIV infection, the TB bacteria is more likely to make them sick at some point in the future.
• Treatment for LTBI will help kill the TB bacteria and reduce patients' chances of becoming sick with active TB.
• Patients must take all of their medicine, every day, to prevent the TB from spreading and making them sick.
• Advise patients to contact their health care provider immediately if they have adverse effects to the medication, such as rash or itching. Occasionally, INH can cause tingling or numbness in the hands or feet. The pyridoxine (vitamin B6) they are taking should help prevent that, but they should let their provider know if it occurs.
• Advise patients to avoid the use of alcohol while taking INH. The medicines for TB are processed by the liver and, when combined with alcohol, they easily can overload the liver. Acetaminophen (Tylenol) also is processed by the liver, so patients should keep their intake to a minimum. (Patients with hepatitis C, liver disease, or chronic alcohol use should not take more than 3 grams per day.)
• Tell patients that blood tests may be done regularly to make sure the liver is working well, so it is important to keep follow-up appointments. They should take all their medications, vitamins, and supplements with them to the clinic so that their health care provider can review them and make sure there are no drug interactions.
• If patients experience nausea, vomiting, poor appetite, or abdominal pain; if they notice their urine darkening or becoming cola colored; or if they notice their eyes or skin yellowing, they should contact the clinic immediately. These problems may indicate that the liver is being overwhelmed, and it is important to find out before permanent damage is done.
• Rifampin and rifabutin will cause sweat, tears, urine, and plastic contact lenses to turn orange.
• Rifampin and rifabutin can make birth control pills ineffective. Patients should use a backup method of contraception until treatment is complete. Condoms can help prevent HIV transmission and reduce the likelihood of pregnancy.

References

• Akolo C, Adetifa I, Sheppard S, et al. Treatment of latent tuberculosis infection in persons with HIV infection. Cochrane Database Syst Rev. 2004;(1):CD000171.
• American Thoracic Society. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR Recomm Rep. 2000 Jun 9;49(RR-6):1-51.
• Blumberg HM, Leonard MK, Jasmer RM. Update on the treatment of tuberculosis and latent tuberculosis infection. JAMA. 2005 Jun 8;293(22):2776-84.
• Centers for Disease Control and Prevention. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. April 10, 2009.
• Centers for Disease Control and Prevention. Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis. 2007.
• Centers for Disease Control and Prevention. Recommendations for use of an isoniazid-rifapentine regimen with direct observation to treat latent Mycobacterium tuberculosis infection. MMWR Morb Mortal Wkly Rep. 2011 Dec 9;60(48):1650-3.
• Centers for Disease Control and Prevention, American Thoracic Society. Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection--United States, 2003. MMWR Morb Mortal Wkly Rep. 2003 Aug 8;52(31):735-9.
• Golub JE, Pronyk P, Mohapi L, et al. Isoniazid preventive therapy, HAART, and tuberculosis risk in HIV-infected adults in South Africa: a prospective cohort. AIDS. 2009 Jul 17;23(11):1444-6.
• Golub JE, Saraeini V, Cavalcante SG, et al. The impact of antiretroviral therapy and isoniazid preventive therapy on tuberculosis incidence in HIV-infected patients in Rio de Janeiro, Brazil. AIDS. 2007 Jul 11;21(11):1441-8.
• Innes C, Charalambous S, Felix M, et al. Effectiveness of isoniazid preventive therapy in reducing mortality in patients on ART. In: Program and abstracts of the 17th Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco. [Oral abstract]; Paper 102.
• Mazurek GH, Jereb J, Lobue P, et al; Division of Tuberculosis Elimination, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention. Guidelines for using the QuantiFERON-TB Gold Test for detecting Mycobacterium tuberculosis infection, United States. MMWR Recomm Rep. 2005 Dec 16;54(RR-15):49-55.
• Mazurek GH, Jereb J, Vernon A, et al.; IGRA Expert Committee; Centers for Disease Control and Prevention. Updated guidelines for using Interferon Gamma Release Assays to detect Mycobacterium tuberculosis infection -- United States, 2010 . MMWR Recomm Rep. 2010 Jun 25;59(RR-5):1-25.
• National Tuberculosis Controllers Association; Centers for Disease Control and Prevention. Guidelines for the investigation of contacts of persons with infectious tuberculosis. Recommendations from the National Tuberculosis Controllers Association and CDC. MMWR Recomm Rep. 2005 Dec 16;54(RR-15):1-47.
• Pai M, Zwerling A, Menzies D. Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: an update. Ann Intern Med. 2008 Aug 5;149(3):177-84.
• Samandari T, Mosimaneotsile B, Agizew T, et al. Randomized, placebo-controlled trial of 6 vs 36 months isoniazid TB preventive therapy for HIV-infected adults in Botswana. In: Program and abstracts of the 17th Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco. Abstract 104LB.