Mycobacterium tuberculosis

Background

In HIV-infected individuals, tuberculosis (TB) causes more deaths worldwide than any other condition. A biologic synergy exists between HIV and TB such that HIV-induced immunosuppression increases susceptibility to active TB infection, whereas active TB infection increases HIV progression and risk of death. The populations infected by these two pathogens overlap in many respects, creating epidemiologic synergy. Poverty, crowded living conditions, and inadequate interventions to reduce transmission and treat latent TB infection (LTBI) combine to enhance the transmission of both organisms.

In the United States, more than 60% of TB cases occur in foreign-born individuals, with the majority of these cases attributed to reactivation of LTBI. In 2010, only 8% of active TB cases occurred in patients known to be infected with HIV, and TB is a relatively infrequent AIDS-defining illness. Nevertheless, TB remains important to HIV clinicians in the United States because it can be highly infectious and challenging to diagnose, and because improper treatment may lead to drug resistance both in the infected patient and in individuals to whom that patient transmits. Although other conditions increase the risk of TB disease (e.g., malnutrition, diabetes, end-stage renal disease, pulmonary silicosis, and iatrogenic immunosuppressive drugs [especially inhibitors of tumor necrosis factor]), HIV infection remains an important risk factor.

TB is an infection caused by Mycobacterium tuberculosis (MTB) complex. These organisms grow slowly and can be identified only with special staining techniques, a trait that led to the name "acid-fast bacteria." This chapter focuses on disease caused by M. tuberculosis; other chapters describe diagnosis and management of latent MTB infection (see chapter Latent Tuberculosis Infection) and diagnosis and management of disease caused by Mycobacterium avium (see chapter Mycobacterium avium Complex Disease).

MTB most often causes a chronic pneumonia, but it can affect organs other than the lungs as well. The lung destruction caused by MTB may create cavities, similar to abscesses; these contain huge numbers of organisms. TB is transmitted almost always by persons with active pulmonary TB who release large numbers of organisms in their sputum. Patients with smear-positive sputum are the most infectious; however, transmission from patients with AFB smear-negative, culture-positive sputum has been well documented. Extrapulmonary tuberculosis generally is not considered contagious.

MTB organisms are inhaled and infect the lung. In most people, the initial lung infection is contained by an effective immune response. It usually is asymptomatic but leads to foci in the lung (and sometimes in other organs) of latent TB, which may reactivate and cause active TB disease years later. Shortly after the onset of infection with MTB, before its containment in the lung by the immune system, organisms can spread to other organs and establish latent infection in those areas as well. Reactivation in these other organs can lead to local disease (e.g., in the lymph nodes, meninges, bone, pericardium, peritoneum or intestine, and urogenital tract).

Persons with impaired immunity, such as persons with HIV-associated immunosuppression and very young children, are at high risk of developing progressive primary TB at the time of initial MTB infection. Primary progressive MTB usually causes pulmonary disease, but also can cause meningitis or disseminated disease (blood, liver, spleen, lung, and other organs). Persons who have latent TB infection and then develop immunodeficiency are at high risk of developing reactivation disease. For example, compared with the <10% lifetime risk of developing active TB in immunologically normal persons, an HIV-infected person with latent TB has about a 10% chance each year of developing active disease. Even with immune reconstitution through antiretroviral therapy (ART) and a normalized CD4 cell count, HIV-infected patients remain at elevated risk of reactivation TB, compared with the background community risk of TB.

Classical pulmonary tuberculosis, with upper-lobe infiltrates and cavitary lesions, may occur in HIV-infected persons with relatively intact immunity. As the CD4 count decreases (particularly to <200 cells/µL), TB is more likely to manifest atypically in the chest (without cavitary disease) or with lower-lobe disease, adenopathy, pleural effusions, or interstitial or military infiltrates), and as extrapulmonary or multiorgan disease (particularly in lymph nodes, peritoneum, pericardium, and meninges). Granulomas may be seen in the tissues; in persons with advanced immunodeficiency, these may be poorly formed and non-caseating. Bone, joint, and urogenital TB are less-commonly associated with HIV-induced immunosuppression. Symptoms and signs in HIV-infected persons therefore can vary widely and can be difficult to distinguish from HIV-related opportunistic infections and malignancies.

Appropriate use of modern chemotherapy with rifampin-containing TB treatment applied to drug-susceptible MTB disease cures at least 95% of these patients, including those with HIV coinfection. However, drug resistance seriously reduces the cure rate. Drug resistance usually is caused by improper or erratic treatment. It is spreading rapidly and becoming more severe. Effective diagnosis and cure of drug-susceptible TB not only reduces the disease burden in the individual and reduces further transmission, it also is crucial to avoiding drug resistance.

MTB resistance to a single drug may extend or complicate treatment but usually does not prevent successful treatment of TB. Resistance to both isoniazid and rifampin, with or without resistance to other first-line drugs, is called multidrug resistance (MDR), and it makes treatment especially difficult. Extreme drug resistance (XDR) occurs when, in addition to isoniazid and rifampin resistance, there is resistance to specific second-line drugs: a fluoroquinolone plus an injectable agent (kanamycin, amikacin, or capreomycin). Treatment of drug-resistant TB should be managed by experts or in consultation with experts. MDR TB is uncommon in the United States; it occurred in 1.3% of cases in 2010, and the great majority of these were foreign-born patients (82.6%). XDR is very rare in the United States, with only 4 cases reported in 2010.

Effective antiretroviral treatment (ART) is a critical component of the care of persons with TB, and ART should be initiated or optimized in all persons with active TB, regardless of their current CD4 cell count.

This chapter will discuss the evaluation and management of TB in the United States and other high-income settings. For management of TB in resource-limited settings, see the relevant World Health Organization guidelines and other resources.

S: Subjective

Persons with TB generally describe an illness lasting several weeks to months, associated with systemic features such as high fevers, night sweats, loss of appetite, and weight loss. These symptoms are nonspecific, but should raise the possibility of TB.

  • Pulmonary TB presents with a chronic productive cough and sometimes with hemoptysis; shortness of breath occurs late in the disease course.
  • TB adenitis presents with enlarged lymph nodes (usually asymmetric involvement in one region) that may suppurate and drain but usually are not painful, hot, or erythematous.
  • TB meningitis presents with headache, gradual change in mental status, and at times with cranial nerve abnormalities such as double vision or decreased hearing.
  • Disseminated TB may occur with systemic manifestations such as fever, sweats, and weight loss, with no localizing features.

Risk factors for TB infection include known prior contact with an active case, exposure in congregate settings (such as homeless shelters and prisons, but also in health care facilities), travel or residence in countries with high rates of endemic TB, and birth in a TB-endemic county (more than half of foreign-born individuals diagnosed with TB in the United States originated from one of the following five countries: Mexico, the Philippines, Vietnam, India, or China). In the United States, persons with active or past substance-use disorders and persons of color are more likely than others to have had exposure to TB. History of a prior positive tuberculin skin test (TST) or interferon-gamma release assay (IGRA) result provides evidence of previous TB exposure; however, up to 35% of patients with active TB will have a negative TST or IGRA result (see chapter Latent Tuberculosis Infection). Risks for active TB disease include any degree of HIV-associated immunosuppression, immunosuppression associated with other diseases (e.g., leukemia, lymphoma) or caused by medical therapies (e.g., tumor necrosis factor-alpha blockers such as etanercept), and malnutrition.

O: Objective

  • Measure vital signs, including oxygen saturation.
  • Measure weight; compare with previous values.
  • Perform thorough physical examination with particular attention to the lungs, heart, abdomen, lymph nodes, skin, and neurologic system.

Systemic signs of chronic disease and inflammation are common, including cough, fever, night sweats (which may occur without awareness of the high fever that precedes them), and weight loss.

In patients with pulmonary TB, the breath sounds may be normal or focally abnormal; tachypnea and hypoxia occur only with extensive lung damage.

Extrapulmonary TB may present with focal adenopathy without local signs of inflammation, but perhaps with a draining sinus.

TB meningitis presents as subacute or chronic meningitis, with neck stiffness and changes in mental status. Symptoms may include cranial nerve palsies owing to inflammation at the base of the brain or increased intracranial pressure.

Pericardial disease can cause the pain and friction rub of pericarditis or signs of pericardial tamponade.

Infiltration of the bone marrow can produce pancytopenia.

Disseminated TB may cause diffuse adenopathy, hepatic or splenic enlargement, and abnormal liver function, although hepatic failure is rarely attributable to TB alone. Infection of the adrenal glands can cause adrenal insufficiency.

A: Assessment

Note: If pulmonary TB is suspected, the patient should wear a mask while in the medical facility and the care provider should wear an N95 respirator during the examination to reduce transmission risk.

The differential diagnosis of TB is extensive and depends in part on the degree of immunosuppression (as indicated by the CD4 cell count) of the individual. It includes a broad range of bacterial, mycobacterial, viral, and fungal infections in addition to noninfectious causes. A partial differential diagnosis of pulmonary TB includes the following:

  • Bacterial pneumonia
  • Pulmonary Mycobacterium pneumonia (nontuberculous)
  • Pneumocystis jiroveci pneumonia (PCP)
  • Cryptococcus neoformans pneumonia/pneumonitis
  • Pulmonary Kaposi sarcoma
  • Toxoplasma pneumonitis
  • Disseminated histoplasmosis
  • Disseminated coccidioidomycosis
  • Cytomegalovirus pneumonia
  • Bronchogenic carcinoma
  • Non-Hodgkin lymphoma
  • Influenza
  • Pulmonary embolus
  • Chronic obstructive pulmonary disease
  • Reactive airway disease
  • Congestive heart failure
  • Lactic acidosis

P: Plan

Diagnostic Evaluation

Initial evaluation

Suspected TB should be evaluated aggressively.

  • During the initial evaluation, check complete blood count (CBC) and differential, sputum gram stain, sputum acid-fast bacilli (AFB) stain, culture, and nucleic acid amplification (NAA) test (see below), blood cultures, and chest X-ray.
  • For patients with lymphadenopathy, consider fine-needle aspiration biopsy for bacterial and AFB stains and culture, and cytologic evaluation.
  • For patients with meningitis or central nervous system (CNS) abnormalities, perform lumbar puncture (LP) and cerebral spinal fluid (CSF) analysis including cell count, protein, glucose, AFB smear and culture, and bacterial and fungal cultures.
  • Computed tomography (CT) is recommended for all patients with HIV prior to LP, particularly if focal neurologic abnormalities are present.
  • Perform other diagnostic tests as suggested by the clinical presentation.

Imaging

Pulmonary TB can be associated with any chest X-ray appearance, including a normal X-ray image. However, the chest X-ray classically demonstrates upper-lobe infiltrates with or without cavities. Patients with HIV infection (especially advanced HIV and low CD4 cell counts) are more likely to have atypical chest X-ray presentations, including absence of cavities, presence of lower-lobe disease, hilar or mediastinal adenopathy, and pleural effusions.

In disseminated TB, the chest X-ray may show a miliary pattern with small nodules ("millet seeds") scattered throughout both lungs.

AFB testing

TB should be diagnosed by identification of the organism in stained sputum smears or stains of tissue and confirmed by culture or NAA test. All positive cultures should undergo drug susceptibility testing. Proof of the diagnosis is important because other opportunistic diseases can mimic TB, and mycobacterial infections other than TB (e.g., MAC) can occur; these require different treatment. TB drug susceptibility testing is necessary to ensure appropriate treatment, to reduce the risk of developing further TB drug resistance, and to decrease the risk of transmission of drug-resistant TB. Three specimens of expectorated sputum should be sent for acid-fast staining and mycobacterial culture. A presumptive diagnosis of pulmonary TB can be made if AFB are seen, but confirmation is required. Sputum induction with nebulized saline (e.g., by respiratory therapists) can be used for patients who do not have spontaneous sputum production. (Sputum induction has been successful in children, but for young children who cannot produce sputum, gastric lavage on three successive mornings can be performed to obtain swallowed sputum for smear [although false-positive results can occur] and culture.)

Current U.S. guidelines for treatment of opportunistic infections recommend NAA testing on at least one respiratory specimen (regardless of smear status) from each patient with signs and symptoms of pulmonary TB. The algorithm in Table 1 is recommended by the U.S. Centers for Disease Control and Prevention (CDC) for interpretation of NAA test results.

Table 1. Nucleic Acid Amplification Testing and Interpretation Algorithm

  1. If the NAA result is positive and the AFB smear result is positive, presume the patient has TB and begin anti-TB treatment while awaiting culture results. The positive predictive value of FDA-approved NAA tests for TB is >95% in AFB smear-positive cases.
  2. If the NAA result is positive and the AFB smear result is negative, use clinical judgment in deciding whether to begin anti-TB treatment while awaiting culture results and determine whether additional diagnostic testing is needed. Consider testing an additional specimen using NAA to confirm the NAA result. A patient can be presumed to have TB, pending culture results, if two or more specimens are NAA positive.
  3. If the NAA result is negative and the AFB smear result is positive, a test for inhibitors should be performed and an additional specimen should be tested with NAA. Sputum specimens (3-7%) might contain inhibitors that prevent or reduce amplification and cause false-negative NAA results.
    1. If inhibitors are detected, the NAA test is of no diagnostic help for this specimen. Use clinical judgment to determine whether to begin anti-TB treatment while awaiting results of culture and additional diagnostic testing.
    2. If inhibitors are not detected, use clinical judgment to determine whether to begin anti-TB treatment while awaiting culture results and determine whether additional diagnostic testing is needed. A patient can be presumed to have an infection with non-TB mycobacteria if a second specimen is smear positive and NAA negative and has no inhibitors detected.
  4. If the NAA result is negative and the AFB smear result is negative, use clinical judgment to determine whether to begin anti-TB treatment while awaiting results of culture and additional diagnostic tests. Currently available NAA tests are not sufficiently sensitive (detecting 50-80% of AFB smear-negative, culture-positive pulmonary TB cases) to exclude the diagnosis of TB in AFB smear-negative patients suspected of having TB.

Sensitivity of the NAA tests in smear-positive specimens is high but decreases to 50-80% in smear-negative, culture-positive specimens. The rapid identification of MTB facilitates appropriate respiratory infection control precautions, contact tracing, and immediate treatment of MTB. NAA tests also are useful in making a presumptive diagnosis in smear-negative patients who are suspected to have active pulmonary TB, pending culture results. However, these tests can yield false-positive results, particularly with persons in whom pulmonary TB is unlikely. Also, false negatives can occur in both smear-positive and smear-negative patients. NAA testing is not available in all laboratories and in some it is restricted to AFB smear-positive specimens.

The Xpert MTB/RIF is a rapid NAA test that was recently reviewed by the FDA and allowed to be marketed the United States. This assay identifies TB and at the same time identifies rifampicin (RIF) resistance from a direct sputum sample. Data from high-prevalence TB settings show a sensitivity of >98% for TB in smear-positive specimens. Sensitivity in smear-negative specimens is 70% with a single test, and up to 90% with three tests, with a specificity of 99%. Other NAA tests can be used to rapidly identify clinically significant non-TB mycobacteria such as MAC and Mycobacterium kansasii. If a non-TB mycobacteria is diagnosed, respiratory precautions can be discontinued, and treatment for the specific or suspected organism can be started.

In patients with suspected pulmonary TB, negative sputum microscopy or NAA results do not rule out TB; and consideration should be given to starting empiric TB treatment while further evaluation is undertaken.

A diagnosis of extrapulmonary TB generally requires an examination of infected tissue or body fluid by microscopy and culture. NAA tests are approved for testing of sputum samples, but have been used on tissue and body fluids (such as CSF); specimens that are fresh or frozen generally are preferable to specimens preserved in formalin or a similar chemical. Specimens of organs with suspected TB can be obtained by peripheral lymph node aspiration, CT-guided or other guided aspiration and biopsy, liver biopsy, bone marrow biopsy, or thoracoscopy- or laparoscopy-guided biopsies of pleura or peritoneum. In some cases, surgery is required to obtain appropriate specimens. Blood cultures for mycobacteria (using appropriate mycobacterial media rather than standard blood culture media) may be positive in disseminated TB, particularly with advanced HIV disease; the technique is the same as in culturing blood for MAC organisms. Urine culture is used to diagnose renal TB, although this condition is rare among HIV-infected persons.

Initial growth of MTB on culture may occur within 3-8 weeks. A nucleic acid probe can confirm a positive culture as MTB within few days of culture growth; otherwise, speciation may take several weeks. Susceptibility testing generally takes 3-4 weeks after the initial culture growth, depending on what laboratory procedures are used. Rapid tests for diagnosis of drug resistance allow early identification of resistance and optimization of treatment. The Xpert MTB/RIF assay is available in the United States, and others (including line probe assays, nitrate reductase assay, and phage-based assays) are available in other countries. Some health departments have in-house assays for rifampin resistance. NAA tests for TB drug resistance are efficient at screening for resistance against drugs for which a single mutation (e.g., rifampin) or a few mutations (e.g., isoniazid) are responsible. Rapid assays to detect mutations that confer resistance to other first- and second-line drugs are in development.

Note that a positive TST or IGRA result confirms TB infection but does not prove active disease (see chapter Latent Tuberculosis Infection). Similarly, a negative result may occur in up to 35% of HIV-infected persons with active TB and does not rule out TB disease. When a specific microbiologic diagnosis cannot be made or may be delayed (as with TB meningitis testing, for which CSF culture results may take weeks to obtain or may be negative), a positive TST or IGRA result can help support the diagnosis and implementation of therapy; however, a negative result on these tests does not rule out active TB.

Respiratory Precautions

Respiratory infection control precautions should be implemented for HIV-infected patients with an undiagnosed chronic cough or undiagnosed inflammatory infiltrate on chest X-ray. Individual institutions have specific guidelines that should be followed; patients usually are housed in single negative-pressure rooms and persons entering the rooms are required to wear protective respirators. Patients seen in the outpatient setting should wear a mask while in the medical facility, and providers should wear an N95 respirator when evaluating the patient. If three sputum smears yield negative results on AFB staining, or if a single deep specimen (bronchial lavage or tracheal aspirate) is smear negative, infectious TB is unlikely and respiratory precautions can be discontinued. Patients who are highly suspect for MTB and lack an alternative diagnosis may be kept on precautions and empiric treatment may be started, as transmission of TB from AFB smear-negative, culture-positive TB patients is well documented. Persons who have responded to treatment for an alternative diagnosis (e.g., bacterial pneumonia), and those who cannot produce the requisite three sputum samples, may be released from the TB precautions.

The impact of TB transmission is greater in a health care setting, where immunosuppressed persons may be exposed, than at home, where exposure has occurred prior to the TB evaluation. Of course, children younger than age 5 and immunosuppressed persons in the home are at increased risk.

Treatment

Treatment for TB should be instituted promptly when TB is considered likely and the proper specimens to prove the diagnosis have been obtained. It is ideal to have a positive smear result (and confirmation by NAA testing) prior to initiating treatment, but empiric treatment should be started while the initial specimens are collected from patients in whom the suspicion of TB is high, in severely ill persons, or in circumstances in which positive smear results are unlikely (e.g., suspected TB meningitis with AFB smear-negative CSF).

Randomized trials have demonstrated that ART decreases mortality in HIV-infected persons with active TB regardless of initial CD4 cell count; thus, effective ART should be initiated or optimized in everyone with TB/HIV coinfection; see "Coordinating with antiretroviral therapy," below.

Adherence is the most important treatment issue once the decision to treat is made and an appropriate regimen is selected. It is the responsibility of the treating clinician to ensure that the patient completes a full course of therapy. Therefore, it is strongly recommended that patients be referred to public health departments for TB treatment. Health departments usually can provide free TB treatment and have specific resources and systems to promote adherence. It is recommended that all patients receive directly observed therapy (DOT), an approach by which the taking of every dose of anti-TB medication is observed and documented. Clinical trials have documented that DOT with enhancements to maximize adherence not only improves the rate of completion of therapy but also reduces mortality among HIV-infected TB patients. If a health department manages the TB treatment, the HIV clinician must coordinate with the health department for the following reasons: 1) to coordinate TB and HIV treatment regimens; 2) to avoid or adjust for drug interactions; 3) to assist the health department in avoiding diagnostic or treatment confusion in the event of immune reconstitution inflammatory syndrome (IRIS) or incident opportunistic diseases; and 4) to maximize adherence with the TB medications, ART, opportunistic infection treatment or prophylaxis, and any other medications.

Treatment consists of two phases: intensive and continuation. Several intermittent therapy regimens have been designed to simplify DOT; however, use of TIW and BIW regimens during the intensive phase of treatment have led to higher rates of treatment failure and resistance, as have weekly or BIW continuation phase regimens. Thus, daily (or 5-7 days per week) dosing by DOT is recommended during the intensive phase of treatment, and 5-7 days per week or TIW dosing is recommended during the continuation phase.

Preferred therapy (drug-susceptible pulmonary TB)

  • Intensive Phase: Isoniazid + rifampin (or rifabutin) + pyrazinamide + ethambutol QD (5-7 days per week) for 8 weeks, by DOT
  • Continuation Phase: isoniazid + rifampin or rifabutin 5-7 days per week or TIW
Table 2. Recommended Dosages of First-Line Antituberculosis Drugs for Adults
DrugDaily3 Times Weekly

+ Rifampin is not recommended for patients receiving HIV protease inhibitors, etravirine, nevirapine, rilpivirine, or elvitegravir/cobicistat. Dolutegravir, raltegravir, and maraviroc require dosage adjustment.

* Avoid coadministration of rifabutin with elvitegravir/cobicistat, if possible. If used together, consider therapeutic drug monitoring and dosage adjustment as indicated. Do not coadminister with rilpivirine.

# For patients weighing >90 kg, monitor for therapeutic response can consider therapeutic drug monitoring.

Adapted from Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Accessed December 1, 2013.

Isoniazid5 mg/kg (usual dose 300 mg)15 mg/kg (usual dose 900 mg)
Rifampin+10 mg/kg (usual dose 600 mg)10 mg/kg (usual dose 600 mg)
Rifabutin*
without HIV protease inhibitors, efavirenz, rilpivirine, or elvitegravir/cobicistat5 mg/kg (usual dose 300 mg)5 mg/kg (usual dose 300 mg)
with HIV protease inhibitors150 mg300 mg
with efavirenz450-600 mg450-600 mg
with elvitegravir/cobicistat*150 mg150 mg
Pyrazinamide
40-55 kg body weight1,000 mg (18.2-25.0 mg/kg)1,500 mg (27.3-37.5 mg/kg)
56-75 kg body weight1,500 mg (20.0-26.8 mg/kg)2,500 mg (33.3-44.6 mg/kg)
76-90 kg body weight2,000 mg (22.2-26.3 mg/kg)3,000 mg (33.3-39.5 mg/kg)
>90 kg body weight2,000 mg#3,000 mg#
Ethambutol
40-55 kg body weight800 mg (14.5-20.0 mg/kg)1,200 mg (21.8-30.0 mg/kg)
56-75 kg body weight1,200 mg (16.0-21.4 mg/kg)2,000 mg (26.7-35.7 mg/kg)
76-90 kg body weight1,600 mg (17.8-21.1 mg/kg)2,400 mg (26.7-31.6 mg/kg)
>90 kg body weight1,600 mg#2,400 mg#

Four anti-TB drugs are administered for the first 2 months, then two drugs are administered for an additional 4 months (if the organism is susceptible to standard medications). The initial phase of TB treatment usually consists of isoniazid, rifampin or rifabutin (see below), pyrazinamide, and ethambutol; the continuation phase typically is simplified to isoniazid and rifampin. Pyridoxine (vitamin B6) at a dosage of 10-50 mg QD usually is included to minimize the risk of isoniazid-induced peripheral neuropathy. If drug resistance or MDR is suspected, more drugs can be used initially, and treatment should be directed by experts. Resistance may be suspected among persons exposed to TB in countries with high rates of endemic resistance, those for whom previous treatment has failed, those who have been on and off treatment erratically, those who may have had a specific exposure to drug-resistant TB, and those who have been diagnosed during an outbreak. If drug susceptibility testing shows sensitivity to isoniazid and rifampin, ethambutol can be discontinued during the intensive phase.

In certain circumstances, treatment duration is extended. In cavitary TB or TB in an HIV-infected person that remains sputum culture positive after 2 months of treatment, the two-drug continuation phase should be extended to 7 months for a total treatment course of 9 months. For extrapulmonary TB in HIV-infected persons, a 6- to 9-month course of treatment is recommended. Exceptions include meningeal TB, which is treated for 9-12 months. If cultures obtained prior to treatment demonstrate drug resistance, the regimen and the duration of therapy may need to be changed.

For TB meningitis or pericarditis, a course of corticosteroids may be given in addition to specific anti-TB therapy: dexamethasone 0.3-0.4 mg/kg/day for 2-4 weeks then tapered over the course of 8-10 weeks or prednisone 1 mg/kg/day for 3 weeks followed by a taper over the course of 3-5 weeks. For adrenal insufficiency, replacement corticosteroids should be given.

Considerations during Pregnancy

Pyrazinamide has not been formally proven safe for use during pregnancy; however, it is used during pregnancy in many countries and there have been no reports of problems. Some health departments in the United States avoid the use of pyrazinamide for pregnant women and extend the continuation phase to 7 months, whereas others prescribe the standard regimens shown in Table 2 during pregnancy. Streptomycin and certain second-line drugs should be avoided during pregnancy. HIV-infected women in the United States are instructed not to breast-feed, so there usually are no issues regarding TB treatment of HIV-infected women during breast-feeding. ART should be started as early as possible; consult with an expert.

Coordinating with Antiretroviral Therapy

ART and TB treatment must be coordinated for both to be successful. ART is strongly recommended for all adults and adolescents with active TB, and both randomized and nonrandomized trials have demonstrated reduction in mortality when ART is combined with anti-TB chemotherapy.

The optimal timing of ART initiation in relation to TB treatment has been established with several randomized controlled trials. Adults and adolescents with active TB and CD4 counts of <50 cells/µL should start ART within 2 weeks of starting TB treatment. All patients with CD4 counts of ≥50 cells/µL should start ART within 8-12 weeks of starting TB therapy, but those who have CD4 counts of 50-200 cells/µL and severe disease should start within 2-4 weeks, if possible. Further, current HHS ARV guidelines recommend consideration of early ART (within 2-4 weeks) for patients with CD4 counts of >200 cells/µL and severe disease. In all cases, TB treatment should be started immediately.

Timing of ART initiation in CNS TB infection is not clear. In one randomized trial, there was not a mortality benefit to starting ART at 2 weeks after TB treatment initiation compared with starting after 2 months of TB treatment, and more severe adverse events occurred in the earlier ART arm. Given the capacity for close monitoring that exists in the United States, many experts recommend initiating ART as with non-CNS TB.

Although paradoxical immune response (i.e., IRIS, see below) appears to be more common in patients who start ART earlier in the course of TB treatment, IRIS generally is not fatal.

Drug-drug interactions

Drug interactions between TB medications and ARVs may require dosage adjustments or modifications in treatment (see Table 3). Rifampin is a potent inducer of cytochrome P450 enzymes and has many clinically important drug interactions. It reduces the blood levels of nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase inhibitors, and the CCR5 antagonist maraviroc, but does not affect nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) or the fusion inhibitor enfuvirtide. Triple-nucleoside regimens can be administered safely during rifampin treatment but are less potent than first-line ARV combinations and generally are not recommended. Current guidelines recommend the use of efavirenz plus a two-drug NRTI backbone if cotreatment with rifampin is planned (see Table 3). Efavirenz blood levels may be reduced 25% by concomitant rifampin, but the majority of available clinical data suggest that that the standard efavirenz dosage of 600 mg/day is appropriate for rifampin coadministration, particularly in African-American and Asian populations. Limited clinical data support the use of nevirapine at standard dosages in combination with rifampin. This is not a favored approach because nevirapine levels are reduced up to 50% when combined with rifampin. In one study, 20% of patients on ARV and TB treatment with rifampin had trough nevirapine levels that were below target, although they achieved the same rates of HIV RNA suppression as did patients on efavirenz. Plasma levels of the integrase inhibitors raltegravir and dolutegravir also are reduced when they are given with rifampin but the interaction can be overcome by increasing the dosage of the integrase inhibitor; few clinical data are available on the use of integrase inhibitors with rifampin.

To avoid rifampin-ARV interactions, rifabutin typically is used in place of rifampin. Rifabutin has fewer marked effects on the pharmaco-kinetics of other drugs, although its own blood concentrations can be affected by certain ARVs. Dosing recommendations for rifabutin with ARVs are found in Table 3. Acquired rifamycin resistance has been reported with coadministration of rifabutin with protease inhibitors, leading to the recommendation that the rifabutin dosage be at least 150 mg daily when given with ritonavir-boosted PIs and that monitoring of serum rifabutin levels be considered. Rifabutin is expensive; some public health systems do not provide rifabutin as part of TB treatment and it often is not available in resource-limited countries. The FDA characterizes rifabutin in pregnancy category B: it has been safe in animal studies of pregnancy but has not been proven safe for humans. For pregnant women who require both TB and ARV therapy, the use of rifabutin rather than rifampin allows the use of non-efavirenz-based ARV regimens.

Persons who are already on ART when TB treatment is begun must have their ARV regimens reassessed; the appropriate dosages of rifampin or rifabutin must be chosen or the ARV regimen must be modified, at least until completion of TB treatment (see Table 3).

Table 3. Interactions Between Antiretroviral Medications and Rifampin or Rifabutin: Contraindicated Combinations and Dosage Adjustments*
AntiretroviralAgentRifampinRifabutin*
(Preferred in combination with PIs)

Note: Rifapentine should not be coadministered with NNRTIs, PIs, or maraviroc.

* If available, rifabutin may be substituted for rifampin when TB treatment and ART are combined.

** Avoid use of efavirenz during early pregnancy and with women who may become pregnant while on therapy. Both rifampin and rifabutin significantly reduce estrogen and progestin levels for women on hormonal contraceptives; efavirenz raises estrogen levels moderately. Two forms of birth control, including one barrier method and either a mid- to high-dose hormonal contraceptive or an intrauterine device, are recommended most often.

Adapted from Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Accessed December 1, 2013.

Nonnucleoside Reverse Transcriptase Inhibitors
Efavirenz** ↓ efavirenz AUC; use standard efavirenz dosage 600 mg QD with monitoring for virologic efficacy (consider 800 mg QD if weight >60 kg).Use standard efavirenz dosage. Increase rifabutin to 450-600 mg daily.
Etravirine↓ etravirine levels expected; do not coadminister.

Etravirine without ritonavir-boosted PI: rifabutin 300 mg QD.

Etravirine with a boosted PI: avoid, or consider therapeutic drug monitoring or rifabutin.

Nevirapine↓ nevirapine levels; avoid if possible. If used, initiate nevirapine at 200 mg BID (no lead-in dosage); do not use nevirapine extended-release formulation.↓ nevirapine and ↑ rifabutin levels. No dosage adjustment recommended; use cautiously.
Rilpivirine↓ rilpivirine levels; do not coadminister.↓ rilpivirine levels; do not coadminister.
Protease Inhibitors
All protease inhibitors↓ protease inhibitor levels; do not coadminister.↑ rifabutin levels; adjust rifabutin dosage to 150 mg QD. Monitor for anti-TB efficacy, consider therapeutic drug monitoring.
Integrase Inhibitors
Dolutegravir↓ dolutegravir levels; increase dolutegravir to 50 mg BID for integrase-naive patients (avoid if integrase resistance).No dosage adjustment.
Elvitegravir/cobicistat↓ elvitegravir and cobicistat levels expected; do not coadminister↓ elvitegravir and ↑ rifabutin levels; do not coadminister.
RaltegravirIncrease raltegravir dosage to 800 mg BID; monitor for virologic response.No dosage adjustment.
CCR5 Receptor Antagonists
Maraviroc↓ maraviroc levels; coadministration not recommended. If maraviroc must be used: Without a strong CYP 3A4 inhibitor: maraviroc 600 mg BID. With a strong CYP 3A4 inhibitor: maraviroc 300 mg BID.Possible ↓ maraviroc levels. Without a strong CYP 3A4 inhibitor: maraviroc 300 mg BID. With a strong CYP 3A4 inhibitor: maraviroc 150 mg BID.
Fusion Inhibitors
EnfuvirtideNo dosage adjustment.No dosage adjustment.

Monitoring for efficacy

Ideally, every dose of anti-TB therapy is observed and documented by a health care agent or responsible individual, particularly during the intensive phase. Patients' adherence should be evaluated by a health care team member at least weekly during the initial phase of treatment and at least weekly or monthly during the continuation phase. If gaps in medication use occur, the cause must be evaluated and a plan to improve adherence must be implemented.

In treatment of pulmonary TB, monthly sputum specimens should be obtained for smear and culture until two sequential specimens are sterile on culture. Patients with extrapulmonary and disseminated TB usually are monitored clinically and with imaging studies. Biopsies are not repeated but other specimens (CSF and other body fluids) may be obtained for repeat AFB smear and culture. Monitoring of patients with extrapulmonary and disseminated TB should be done in consultation with an expert.

Immune reconstitution inflammatory syndrome

Patients on treatment for active TB who begin ART may experience a paradoxical increase in signs and symptoms of TB (fever, dyspnea, increased cough, enlarging lymph nodes, worsening chest X-ray findings, increased inflammation at other involved sites, or enlargement of CNS tuberculomas). These often are attributable to an enhanced immune response against remaining MTB organisms that occurs because of immunologic improvement from ART. IRIS may occur at any point from within 2 weeks up to several months after ART is initiated. TB treatment failure (potentially owing to an inappropriate treatment regimen, inadequate adherence, or drug resistance) must be ruled out, and the possibility of drug toxicity should be considered. In addition, new presentation of opportunistic infection or malignancies should be considered. Paradoxical IRIS is a clinical diagnosis, and it can be made only after alternative diagnoses are excluded. If IRIS is diagnosed, TB and HIV treatment should be continued and symptoms can be managed with nonsteroidal antiinflammatory drugs or, in severe cases, with corticosteroids. Many experts recommend the use of corticosteroids particularly in the case of TB IRIS involving the CNS (see chapter Immune Reconstitution Inflammatory Syndrome).

Adverse effects of anti-TB medications

Anti-TB medications may have significant adverse effects. The most important adverse reactions reported for the commonly used anti-TB medications are listed in Table 4. The most frequent toxicities of first-line TB medications include hepatic enzyme elevations. Before initiating TB treatment, conduct a complete blood count with platelet count, serum creatinine count, liver function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], bilirubin, alkaline phosphatase), and hepatitis B and C serology. Newly diagnosed TB patients with unknown HIV status should be tested for HIV infection.

Patients should be monitored monthly with a symptom review to assess possible toxicity, and laboratory tests should be performed if symptoms suggest adverse effects. For patients with liver disease, it may be prudent to perform routine laboratory monitoring after 1 month on treatment and every 3 months thereafter. Persons with symptoms and aminotransferase elevations ≥3 times the upper limit of normal, and asymptomatic persons with aminotransferase elevations ≥5 times the upper limit of normal, should have therapy interrupted and should be managed thereafter in consultation with an expert.

Patients should be monitored for isoniazid-induced peripheral neuropathy; this adverse effect is rare if pyridoxine is administered with isoniazid, as recommended. Testing of visual acuity and red-green color vision is recommended at the start of therapy with ethambutol. Persons on standard ethambutol dosages with normal baseline examinations should be asked monthly about visual disturbances. Patients on higher ethambutol dosages and those who have been on ethambutol for more than 2 months should have periodic eye examinations for acuity and color discrimination.

Table 4. Adverse Events Associated with Common Anti-TB Medications
MedicationCommon ToxicityRare Toxicity

Adapted from American Thoracic Society; CDC; Infectious Diseases Society of America. Treatment of Tuberculosis. MMWR Recomm Rep. 2003 Jun 20;52(RR-11):1-77; and Harries A, Maher D, Gramm S; World Health Organization. HIV/TB: A Clinical Manual, 2nd Edition. Geneva: World Health Organization; 2004:131-2.

First-Line Agents
IsoniazidTransient transaminase elevation, hepatitis, positive antinuclear antibody (ANA)Peripheral neurotoxicity, lupus-like syndrome, CNS effects, hypersensitivity, rash, monoamine poisoning
RifampinTransient bilirubin elevation, transaminase elevations, anorexia, nausea, vomiting, hepatitis, red-orange discoloration of urine and tearsAcute renal failure, shock, thrombocytopenia, rash, "flu" syndrome from intermittent doses, pseudomembranous colitis, pseudoadrenal crisis, osteomalacia, hemolytic anemia
RifabutinElevated liver function tests, nausea, red-orange discoloration of urine and tearsCytopenias, uveitis, rash
EthambutolOptic neuritisSkin rash, joint pains, peripheral neuropathy
PyrazinamideJoint pains, gout, hepatitisGastrointestinal symptoms, skin rash, sideroblastic anemia
StreptomycinAuditory and vestibular nerve damage, renal injuryRash
Second-Line Agents
MoxifloxacinNausea, diarrhea, dizzinessTendon rupture, hepatoxicity, renal damage, prolonged QT interval, skin reactions
Amikacin/KanamycinAuditory, vestibular, renal injury 

Patient Education

  • All patients with TB-positive sputum or bronchoscopy specimens can infect others with TB. All close contacts, especially children, should be screened for TB as soon as possible and given medication to prevent (or treat) active disease.
  • The health department will be notified of each TB case and will provide the required follow-up care.
  • Patients must take all medicines exactly as prescribed. If doses are missed, or if the medication is stopped and restarted, the TB bacteria can develop resistance to even the best medications and become even more dangerous. If patients are having trouble taking the medication on schedule, they should contact their health care provider immediately.
  • If patients become ill, if their skin or eyes turn yellow, or if their urine darkens to a "cola" color, they should contact their health care provider immediately.
  • Patients must keep all follow-up appointments. Blood tests will be done regularly to ensure that the liver is working well, and patients will be checked for medication adverse effects. They should show their health care provider all medications, vitamins, and supplements they are taking so that the provider can check for drug interactions.
  • Rifampin and rifabutin will make urine, sweat, and tears turn orange; this is not harmful. They will cause staining of plastic contact lens; patients should avoid wearing contact lenses if they are taking rifamycins.
  • Rifampin and rifabutin may cause birth control pills to become ineffective. An alternative method of contraception should be used when the patient is undergoing treatment.
  • The use of alcohol should be avoided during treatment with TB drugs to avoid the risk of liver damage.

References

  • Abdool Karim SS, Naidoo K, Grobler A, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med. 2011 Oct 20;365(16):1492-501.
  • Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviral drugs during tuberculosis. N Engl J Med. 2010 Feb 25;362(8):697-706.
  • American Thoracic Society; Center for Disease Control and Prevention; Infectious Diseases Society of America. Treatment of Tuberculosis. MMWR Recomm Rep. 2003 Jun 20;52(RR-11):1-77. Accessed December 1, 2013.
  • Blanc FX, Sok T, Laureillard D, et al.; CAMELIA (ANRS 1295-CIPRA KH001) Study Team. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med. 2011 Oct 20;365(16):1471-81.
  • Centers for Disease Control and Prevention. Trends in tuberculosis - United States, 2011. MMWR Morb Mortal Wkly Rep. 2012 Mar 23;61(11):181-5.
  • Centers for Disease Control and Prevention. Updated guidelines for the use of nucleic acid amplification tests for the diagnosis of tuberculosis. MMWR Morb Mortal Wkly Rep. 2009 Jan 16;58(1):7-10.
  • Havlir D. International randomized trial of immediate vs. early ART in HIV+ patients treated for TB: ACTG 5221 STRIDE study. In: Program and abstracts of the 18th Conference on Retroviruses and Opportunistic Infections; February 27-March 2, 2011; Boston. [Oral abstract].
  • Mandell G, Bennett JE, Dolin R, et al. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th Edition. Philadelphia: Churchill Livingstone Elsevier; 2010.
  • Manosuthi W, Sungkanuparph S, Tantanathip P, et al; N2R Study Team. A randomized trial comparing plasma drug levels and efficacies between 2 nonnucleoside reverse transcriptase-inhibitor therapies in HIV-infected patients receiving rifampin: the N2R study. Clin Infect Dis. 2009 Jun 15;48(12):1752-9.
  • Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Accessed December 1, 2013.
  • Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Accessed December 1, 2013.
  • Török ME, Yen NT, Chau TT, et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)-associated tuberculous meningitis. Clin Infect Dis. 2011 Jun;52(11):1374-83.

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Abbreviations for Dosing Terminology

BID
twice daily
BIW
twice weekly
IM
intramuscular (injection), intramuscularly
IV
intravenous (injection), intravenously
PO
oral, orally
Q2H, Q4H, etc.
every 2 hours, every 4 hours, etc.
QAM
every morning
QD
once daily
QH
every hour
QHS
every night at bedtime
QID
four times daily
QOD
every other day
QPM
every evening
TID
three times daily
TIW
three times weekly