Clinical Guide > Comorbidities and Complications > >M. tuberculosis

Mycobacterium tuberculosis

January 2011

Chapter Contents

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 TB infection, whereas active TB infection enhances HIV replication through immunologic stimulation. The populations infected by these two pathogens overlap in many respects, creating epidemiologic synergy. Poverty, crowded living conditions, and inadequate efforts to reduce transmission combine to enhance the transmission of both organisms.

In the United States, most cases of TB occur among immigrants, and TB is a relatively infrequent AIDS-defining illness. Nevertheless, TB remains important to HIV clinicians in the United States because it is highly infectious, though curable with proper treatment, and because improper treatment leads to drug resistance both in the infected patient and in those 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 is by far the most important risk factor.

TB is an infection caused by organisms in the Mycobacteria genus. 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 Mycobacterium tuberculosis (MTB); other chapters describe diagnosis and management of latent MTB infection (see chapter Latent Tuberculosis) and diagnosis and management of disease caused by Mycobacteria avium (see chapter Mycobacterium avium Complex).

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. The organisms remain suspended in the air for hours or days, making TB among the most easily transmitted respiratory pathogens. 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 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 limited 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.

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), and disseminated infection. 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.

Before an effective treatment for TB was developed, one half of persons with TB died within a period of about 5 years; others recovered, but relapses sometimes occurred. Appropriate use of modern chemotherapy applied to drug-susceptible MTB disease cured at least 95% of persons in the pre-HIV era. Nowadays, drug-susceptible TB remains highly curable, even for persons with HIV infection. However, drug resistance seriously reduces the cure rate. Drug resistance usually is caused by improper or erratic treatment, and 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 several drugs (polydrug resistance or PDR) requires a longer course of therapy using medications that are less potent and have more side effects, and it markedly reduces the chance of cure. 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 (either kanamycin, amikacin, or capreomycin). Treatment of drug-resistant TB should be managed by experts or in consultation with experts.

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.

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.

The diagnosis is more probable when a patient has a likelihood of both TB infection and a clinical state permissive for MTB disease. 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), or travel or residence in countries with high rates of endemic TB. 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 releasing assay (IGRA) result provides evidence of TB infection (see chapter Latent Tuberculosis). 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, and malnutrition.

O: Objective

Systemic signs of chronic disease and inflammation are common, including 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

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:

P: Plan

Diagnostic Evaluation

Initial evaluation

Suspected TB should be evaluated aggressively.

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) 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 by biopsy 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 can occur; these require different treatment. Drug susceptibility testing is necessary because improper treatment of drug-resistant TB will lead to treatment failure, more severe drug resistance within the patient, and increased risk of transmission of drug-resistant TB.

Three specimens of expectorated sputum should be sent for acid-fast staining and mycobacterial culture on each of three days or at least 8 hours apart, including at least one first-morning specimen. A presumptive diagnosis of pulmonary TB can be made if acid-fast bacilli 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. (Young children cannot produce sputum, so gastric lavage on three successive mornings can be performed to obtain swallowed sputum for smear [although false-positive results can occur] and culture.)

Many laboratories will perform nucleic acid hybridization on acid-fast-positive sputum to identify the species of infecting Mycobacteria, and probes are available to confirm MTB and certain non-TB Mycobacteria. Two NAA tests are licensed in the United States, and some U.S. clinical laboratories use "in-house" NAA tests. Other NAA tests are licensed and available in other countries. These tests confirm M. tuberculosis in sputum smear-positive patients with a specificity of >95%, and results can be available within 24 hours of obtaining a positive smear. 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. Other NAA tests can be used to diagnose non-TB Mycobacteria. If a non-TB Mycobacterium is diagnosed, respiratory precautions can be discontinued, and treatment for the specific or suspected organism can be started.

Patients with suspected pulmonary TB and negative sputum microscopy or NAA should undergo bronchoscopy and transbronchial biopsy (which is more sensitive than bronchoalveolar lavage for TB). The Gen-Probe AMPLIFIED MTD Test also is approved by the U.S. Food and Drug Administration (FDA) for smear-negative cases but sensitivity in this scenario is as low as 66%, whereas specificity remains close to 100%. If the NAA test result is negative, diagnosis of TB may not be excluded, and decisions about treatment must be based on clinical assessment.

A diagnosis of extrapulmonary TB generally requires an examination of infected tissue or body fluid by microscopy and culture. NAA for MTB and some other atypical Mycobacteria also can be performed 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; the technique is the same as in culturing blood for M. avium complex 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. NAA tests for diagnosis of drug resistance are in development and early use internationally but are not yet approved for use in the United States. These are most efficient at testing for resistance against drugs for which a single mutation (e.g., rifampin) or a few mutations (e.g., isoniazid) are responsible for most clinically important drug resistance. 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). Similarly, a negative result may occur in up to 25% 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. 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 alternate diagnosis may be kept on precautions and empiric treatment may be started. 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 already 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) prior to initiating treatment, but empiric treatment can 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., the cerebrospinal fluid smears).

Randomized trials have demonstrated that ART decreases mortality in HIV-infected persons with active TB; 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. The intermittent therapies shown in Table 1 (regimens 1b, 2, and 3) were designed to simplify DOT; however, twice-weekly regimens should not be used for persons with CD4 counts of <100 cells/µL and once-weekly regimens with rifapentine should not be used for anyone with HIV infection.

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.

U.S. guidelines for TB treatment in HIV-infected persons are shown in Table 1; dosages are given in Table 2.

Recommended (drug-susceptible TB):

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 per day 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.

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 twodrug 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 and bone or joint TB, which are 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 tapered over the course of 6-8 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.

Table 1. Regimens for Treatment of Tuberculosis Among HIV-Infected Persons in the United States

Initial Phase Continuation Phase Complete Therapy

* See Table 2 for dosages. See Table 3 for contraindications, substitutions, and dosage adjustments of rifampin. Rifampin should not be used with etravirine, nevirapine, maraviroc, or with protease inhibitors other than ritonavir; rifabutin may be substituted with appropriate dosage adjustments (see U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents; Tables 15a-e. January 10, 2011.).

** In HIV-infected persons with a CD4 count ≤100 cells/µL, twice-weekly regimens should not be used. For these patients, most experts recommend daily treatment during the induction phase.

# For patients who experience slow responses, and those in whom sputum cultures are still positive after the initial 2 months of treatment, the continuation phase may be extended to 7 months, for a total of 9 months of treatment. Pediatric patients should be treated for 7 months in the continuation phase, for a total of 9 months of treatment. TB meningitis caused by susceptible organisms should be treated for 9-12 months. Bone and joint TB should be treated for 9-12 months; the longer time may be prudent when multiple bones and joints are involved or when it is difficult to document a response to treatment. Extrapulmonary disease in other sites should be treated for 6-9 months.

Adapted from American Thoracic Society, CDC, and Infectious Disease Society of America. Treatment of Tuberculosis. Morb Mort Weekly Rpts Recommendations and Reports. June 20, 2003, 52(RR11);1-77.

Drugs Interval and Dosages (minimum duration) Regimen Drugs Interval and Dosages (minimum duration) Range of Total Doses (minimum duration)
1. Preferred Regimen
Isoniazid Rifampin* Pyrazinamide Ethambutol 7 days/week for 56 doses or 5 days/week for 40 doses (8 weeks) For any CD4 count Isoniazid Rifampin* 7 days/week for 126 doses or 5 days/week for 90 doses (18 weeks)# 182-130 doses (26 weeks)
Alternative if CD4 count >100 cells/µL Isoniazid Rifampin* 92-76 doses (26 weeks)
2. Acceptable Alternatives if CD4 >100 cells/µL
Isoniazid Rifampin* Pyrazinamide Ethambutol 7 days/week for 14 doses (2 weeks) followed by twice weekly for 12 doses (6 weeks)

OR

5 days/week for 10 doses (2 weeks) followed by twice weekly for 12 doses (6 weeks)
Isoniazid Rifampin* Twice weekly for 36 doses (18 weeks)**# 62-58 doses (26 weeks)
OR
Isoniazid Rifampin* Pyrazinamide Ethambutol 3 times weekly for 24 doses (8 weeks) Isoniazid Rifampin* 3 times weekly for 54 doses (18 weeks)# 72 doses (26 weeks)

Table 2. Dosages of First-Line Anti-TB Drugs: U.S. Formulary

Daily or 5 Times/Week Dosage (maximum) 2 Times/Week Dosage (maximum) 3 Times/Week Dosage (maximum)

Typical daily dosage for a 60 kg patient is as follows: isoniazid 300 mg (2 tablets), rifampin 600 mg (2 capsules), pyrazinamide 1,500 mg (3 tablets), ethambutol 1,200 mg (3 tablets).

* Add pyridoxine 10-25 mg per dose of isoniazid.

** See Table 3 for dosage adjustments or rifabutin substitution based on combination with antiretroviral therapy.

# Suitable for daily dosing during continuation phase.

## May be part of daily initial phase combined with ethambutol tablets.

Adapted from: Centers for Disease Control and Prevention. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents. Table 3. Recommendations from the Centers for Disease Control, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. April 10, 2009.

Agent Adults Children Adults Children Adults Children
Isoniazid* (tablets: 100 and 300 mg) 5 mg/kg (300 mg maximum) 10-15 mg/kg (300 mg max) 15 mg/kg (900 mg maximum) 20-30 mg/kg (900 mg maximum) 15 mg/kg (900 mg maximum) NA
Rifampin** (capsules: 150 and 300 mg) 10 mg/kg (600 mg maximum) 10-20 mg/kg (600 mg max) 10 mg/kg (600 mg maximum) 10-20 mg/kg (600 mg maximum) 10 mg/kg (600 mg maximum) NA
Pyrazinamide (tablets: 500 mg) 10-30 mg/kg (2 g max) 10-30 mg/kg (2 g max) NA
40-55 kg body weight 1,000 mg 2,000 mg 1,500 mg
56-75 kg body weight 1,500 mg 3,000 mg 2,500 mg
>75 kg body weight 2,000 mg 4,000 mg 3,500 mg
Ethambutol (tablets: 100 and 400 mg) 10-20 mg/kg (1 g max) 10-20 mg/kg (1 g max) NA
40-55 kg body weight 800 mg 2,000 mg 1,200 mg
56-75 kg body weight 1,200 mg 2,800 mg 2,000 mg
>75 kg body weight 1,600 mg 4,000 mg 2,400 mg
Rifamate# (capsules: isoniazid 150 mg, rifampin 300 mg) 2 capsules daily NA NA NA NA NA
Rifater## (tablets: isoniazid 50 mg, rifampin 120 mg, pyrazinamide 300 mg) ≤44 kg: 4 tablets
45-54 kg: 5 tablets
55-90 kg: 6 tablets
NA NA NA NA NA

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 1 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 indicated for all adults and adolescents with active TB, and both metaanalyses and randomized trials have demonstrated reduction in mortality when ART is combined with anti-TB chemotherapy.

The optimal timing of ART initiation in relation to TB therapy is not well established, but recent studies have shown that the risk of death is substantially lower if ART is initiated early, particularly in patients with low CD4 cell counts. Recent recommendations for the timing of ART initiation are based on CD4 thresholds. Adults and adolescents with active TB and CD4 counts of <200 cells/µL should start ART within 2-4 weeks of starting TB treatment. Those with CD4 counts of 200-350 cells/µL should start ART within 2-4 weeks, or at least within 8 weeks of starting TB therapy, and those with CD4 counts >500 cells/µL should start ART within 8 weeks of starting TB therapy. In all cases, TB treatment should be started immediately.

Although paradoxical immune responses (i.e., "Immune reconstitution inflammatory syndrome," see below) may 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), the integrase inhibitor raltegravir, 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. The safest ARV combination to use with rifampin is a two-drug NRTI backbone with efavirenz (see Table 3). Some clinicians increase the efavirenz dosage to 800 mg/day because efavirenz blood levels may be reduced 25% by concomitant rifampin. 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 patients on efavirenz.

To avoid rifampin-ARV interactions, rifabutin typically is used in place of rifampin. Rifabutin has fewer marked effects on the pharmacokinetics 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. Rifabutin is expensive; some public health systems do not provide rifabutin as part of TB treatment and it generally 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.

Table 3. Interactions Between Antiretroviral Medications and Rifampin or Rifabutin: Contraindicated Combinations and Dosage Adjustments

Antiretroviral Agent Rifampin Rifabutin* (Preferred in combination with PIs, boosted or unboosted)

Note: NRTIs are given in standard dosages with either rifampin or rifabutin.

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

** Avoid use of efavirenz during 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. Barrier methods are recommended for women who are infertile, in order to reduce HIV transmission.

*** Cases of inadequate rifabutin levels and rifamycin resistance in patients on rifabutin 150 mg QOD or TIW and ritonavir-boosted PIs. Consider rifabutin 150 mg QD or 300 mg TIW. Monitor rifabutin drug levels, if possible.

Adapted from U.S. Centers for Disease Control and Prevention. Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis; and U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. January 10, 2011.

Nonnucleoside Reverse Transcriptase Inhibitors
Delavirdine Never combine Never combine
Efavirenz** (Preferred in combination with rifampin, see exceptions) Rifampin dosage unchanged; efavirenz dosage 600-800 mg daily Use standard efavirenz dosage. Increase rifabutin to 450-600 mg daily or 600 mg TIW.
Etravirine Never combine Etravirine without ritonavir-boosted PI: dose rifabutin at 300 mg daily. Etravirine with a boosted PI: DO NOT use with rifabutin.
Nevirapine Do not combine; 25-50% reduction in nevirapine levels Use standard dosage of nevirapine. Dose rifabutin at 300 mg daily or TIW.
Protease Inhibitors, Nonboosted
Atazanavir Never combine Use atazanavir at standard dosage. Dose rifabutin at 150 mg QOD or TIW.
Fosamprenavir Never combine Use PIs at standard dosage. Dose rifabutin 150 mg daily or 300 mg TIW.
Indinavir Never combine Increase indinavir dosage to 1,000 mg Q8H. Dose rifabutin at 150 mg daily or 300 mg TIW.
Nelfinavir Never combine Increase nelfinavir dosage to 1,000 mg Q8H. Dose rifabutin at 150 mg daily or 300 mg TIW.
Ritonavir May be used at standard dosages; limited clinical experience Use ritonavir at standard dosage. Dose rifabutin at 150 mg QOD or TIW.
Protease Inhibitors, Ritonavir-Boosted
Lopinavir/ritonavir (Kaletra) Lopinavir/ritonavir must be supplemented with additional ritonavir 300 mg BID; high rates of hepatotoxicity; should not be used Use standard dosage of lopinavir/ritonavir. Usual rifabutin dosage: 150 mg QOD or TIW.***
Saquinavir/ritonavir Owing to high rates of hepatotoxicity, this combination should not be used Use standard dosage of saquinavir/ritonavir. Usual rifabutin dosage: 150 mg QOD or TIW.***
All other ritonavir-boosted PIs Should not be used (adequate dosing regimens not defined) Use standard dosage of PI/ritonavir. Usual rifabutin dosage: 150 mg QOD or TIW.***
Integrase Inhibitors
Raltegravir Increase raltegravir dosage to 800 mg BID; monitor for virologic response No dosage adjustment.
CCR5 Receptor Antagonists
Maraviroc Not recommended; if used without a strong CYP 3A4 inhibitor: 600 mg BID; if used with a strong CYP 3A4 inhibitor: 300 mg BID Without a strong CYP 3A4 inhibitor: 300 mg BID. With a strong CYP 3A4 inhibitor: 150 mg BID.
Fusion Inhibitors
Enfuvirtide No 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. 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 central nervous system 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, and usually is accompanied by a sharp drop in HIV viral load and at least a twofold increase in the CD4 lymphocyte count. 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. If IRIS is diagnosed, TB and HIV treatment should be continued and symptoms managed with nonsteroidal antiinflammatory drugs or, in severe cases, with a short course of corticosteroids. (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

Medication Common Toxicity Rare 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
Isoniazid Transient aminotransferase elevation, hepatitis, positive antinuclear antibody (ANA) Peripheral neurotoxicity, lupus-like syndrome, central nervous system effects, hypersensitivity, rash, monoamine poisoning
Rifampin Transient bilirubin elevation, anorexia, nausea, vomiting, hepatitis, red-orange discoloration of urine and tears Acute renal failure, shock, thrombocytopenia, rash, "flu" syndrome from intermittent doses, pseudomembranous colitis, pseudoadrenal crisis, osteomalacia, hemolytic anemia
Rifabutin Elevated liver function tests, nausea, red-orange discoloration of urine and tears Cytopenias, uveitis, rash
Ethambutol Optic neuritis Skin rash, joint pains, peripheral neuropathy
Pyrazinamide Joint pains, gout, hepatitis Gastrointestinal symptoms, skin rash, sideroblastic anemia
Streptomycin Auditory and vestibular nerve damage, renal injury Rash
Second-Line Agents
Moxifloxacin Nausea, diarrhea, dizziness Tendon rupture, hepatoxicity, renal damage, prolonged QT interval, skin reactions
Amikacin/Kanamycin Auditory, vestibular, renal injury

Patient Education

References