Update on the Treatment of Tuberculosis and Latent Tuberculosis Infection

Tuberculosis (TB) has emerged as a global public health epidemic. The World Health Organization estimates that there will be approximately 9 million individuals who develop active TB disease and more than 2 million deaths due to TB this year.^{1 - 2} The global epidemic of TB has affected the United States where the majority of cases now occur among non–US-born persons. In the United States, there were 14 511 cases reported in 2004 (4.9 cases per 100 000 individuals).³ Despite decreasing numbers of cases since 1992, TB remains a serious public health problem among certain patient populations and is highly prevalent in many urban areas.⁴ Given the decline in TB cases in the United States, there has been renewed interest in the treatment of those with latent TB infection as a TB-control strategy for eliminating the large reservoir of individuals at risk for progression to TB.

The treatment of TB and the treatment of latent TB infection in the United States are reviewed in this article. National evidence-based guidelines for the treatment of TB⁵ and latent TB infection^{6 - 7} have been developed in collaboration by the American Thoracic Society, the Centers for Disease Control and Prevention (CDC), and the Infectious Diseases Society of America. Additional guidelines for the treatment of latent TB infection in children and adolescents have also been published.⁸

Successful treatment of TB depends on more than the science of chemotherapy and should be provided within a clinical and social framework based on the patient’s circumstances.⁵ The responsibility for prescribing an appropriate drug regimen and ensuring that treatment is completed is assigned to the public health program or the clinician not to the patient.⁵ The initial prescribed regimen usually consists of isoniazid, rifampin, pyrazinamide, and ethambutol. Providing medications directly to the patient and watching him/her swallow the anti-TB drugs, which is termed directly observed therapy, is recommended for all patients diagnosed with TB and can help ensure higher completion rates (Figure 1), prevent the emergence of drug-resistant disease, and enhance TB control.^{5 ,9} The infrastructure to provide directly observed therapy is generally only available through public health agencies. Tuberculosis should never be treated with a single drug and a single drug should never be added to a failing regimen because of the risk of emergence of drug-resistant disease. Thus, multidrug therapy is required. The minimum length of therapy for the treatment of drug-susceptible TB is 6 to 9 months (often termed short-course therapy) with a rifampin-based regimen.

The decision to initiate combination anti-TB chemotherapy (eg, 4-drug therapy) should be based on epidemiological information; clinical, pathological, and radiographic findings; and the results of microscopic examination of acid-fast bacilli (AFB)–stained sputum smears as well as other appropriately collected diagnostic specimens and cultures for mycobacteria.⁵ Empirical therapy with an appropriate multidrug regimen (Table 1) needs to be initiated when there is a high clinical suspicion for active disease prior to culture confirmation and in some cases before AFB smear microscopy results are known. The use of nucleic acid amplification tests may be useful in selected cases in providing an immediate definitive diagnosis (eg, confirmation of AFB smear-positive respiratory specimens).¹¹ The threshold for initiating empirical therapy should be low for patients with potentially rapid, life-threatening conditions such as tuberculous meningitis, pericarditis, or miliary disease.

The goals of anti-TB therapy include ensuring a cure without relapse, preventing death, stopping transmission of Mycobacterium tuberculosis, and preventing the emergence of drug-resistant disease.¹ Therapy is initiated with a multidrug regimen to kill tubercle bacilli rapidly, to minimize or prevent development of drug resistance in M tuberculosis, and to eliminate persistent organisms from the host’s tissue to prevent relapse. The first randomized trial was published in 1946 and explored the use of streptomycin for the treatment of TB.¹² Subsequent randomized trials performed by the British Medical Research Council, the US Public Health Service, and other investigators have helped to define regimens for the treatment of TB including rifampin-based short-course therapy regimens, which are now the standard of care.^{12 - 17} Article lists the first- and second-line drugs available for the treatment of TB. Table 2 lists the recommended doses and adverse effects for first-line drugs.

First-Line Drugs

Second-Line Drugs

*Not approved by the Food and Drug Administration for use in the treatment of tuberculosis (TB).

There are 2 phases of treatment for patients with TB—the initiation phase (bactericidal or intensive phase), which consists of 2 months of therapy, and the continuation phase (subsequent sterilizing phase), which lasts 4 to 7 months for patients with drug-susceptible disease. Therapy for TB should be initiated with a 4-drug regimen consisting of isoniazid, rifampin, pyrazinamide, and ethambutol because of concerns about the prevalence of drug resistance (Table 1). Appropriate clinical specimens should be obtained to make a definitive diagnosis and recover M tuberculosis from a culture so that susceptibility testing may be performed.

For patients with drug-susceptible disease, pyrazinamide should be discontinued after 2 months of therapy, which is the end of the initiation phase. Ethambutol can also be discontinued after 2 months of therapy or as soon as drug susceptibility is confirmed. Isoniazid and rifampin are continued for an additional 4 months during the continuation phase to complete a minimum of 6 months of therapy for drug-susceptible disease. Patients at high risk for relapse after 6 months of therapy are those with cavitary pulmonary TB who continue to have positive TB cultures after 2 months of therapy.¹⁷ Such patients should have therapy extended for an additional 3 months during the continuation phase for a total of 9 months of therapy. A treatment algorithm for drug-susceptible pulmonary TB is shown in Figure 2.

All patients diagnosed with TB should be strongly encouraged to undergo human immunodeficiency virus (HIV) testing.⁵ Tuberculosis may be the first disease that brings an HIV-infected person into the health care system. Treatment of TB among HIV-infected persons is similar to that in those not infected with HIV with 2 exceptions. One exception is that HIV-infected patients should not be treated with a once-weekly isoniazid and rifapentine regimen during the continuation phase because of an unacceptably high increased risk of relapse with this regimen, which occurs frequently with organisms that have acquired rifamycin resistance.¹⁸ Second, HIV-infected patients with CD4 cell counts lower than 100/μL should not receive twice-weekly intermittent regimens (eg, isoniazid and rifampin or isoniazid and rifabutin during the continuation phase) because acquired rifamycin resistance has also been reported in this setting.¹⁹ It has been recommended that HIV-infected patients with low CD4 cell counts should receive therapy daily or 3 times weekly.^{5 ,19} Patients infected with HIV who have drug-susceptible TB can generally be treated for 6 months (Table 1). For those HIV-infected patients with TB who are slow to respond to therapy or who have a suboptimal response (eg, cultures are still positive after 2 months of therapy), prolongation of the continuation phase to 7 months for a total of 9 months of treatment is suggested.

The use of antiretroviral therapy among HIV-infected patients with TB is complicated by overlapping toxicity profiles of some anti-TB and antiretroviral drugs, complex drug interactions, and the occurrence of immune reconstitution reactions.²⁰ The use of antiretroviral therapy during TB treatment is complex for both the patient and the physician.²¹ Thus, there needs to be close coordination of care between HIV and TB clinicians. A long list of clinically significant drug interactions involving rifamycins has been published.^{5 ,20} Rifamycins induce the hepatic cytochrome P450 3A system. Rifampin is the most potent inducer and cannot be given with most protease inhibitors and some nonnucleoside reverse transcriptase inhibitors because it results in low serum levels of these drugs. Rifabutin has less of an effect and therefore can be used with certain protease inhibitors. Updated recommendations on the use of antiretroviral regimens among patients undergoing treatment for TB have been published²² and are available from the CDC at http://www.cdc.gov/nchstp/tb/TB_HIV_Drugs/TOC.htm.

Persons infected with HIV who begin taking antiretroviral agents early in the course of their anti-TB therapy are more likely to experience the immune reconstitution syndrome, which is characterized by exacerbation of symptoms and signs or by radiographic manifestations of TB.²³ There are no data to indicate the optimal timing of initiation of antiretroviral therapy among HIV-infected patients with TB. However, to try to reduce the risk of immune reconstitution reactions from occurring, it has been recommended to delay initiation of antiretrovirals until after 2 months of anti-TB therapy if possible.⁵

The basic principles that underlie the treatment of pulmonary TB also apply to extrapulmonary forms of the disease. A 6-month course of therapy is recommended for treating drug-susceptible TB involving any site with the exception of the meninges for which a 9- to 12-month regimen is recommended.⁵ Prolongation of therapy also should be considered for patients with extrapulmonary TB that is slow to respond to treatment. The addition of corticosteroids is strongly recommended for patients with TB pericarditis and meningitis to improve outcomes and decrease mortality.^{5 ,24}

Treatment of drug-resistant TB, especially multidrug-resistant TB, which is defined by resistance to at least isoniazid and rifampin, is quite challenging and should only be performed by or in close consultation with an expert in the management of drug-resistant disease. Treatment guidelines for multidrug-resistant TB have been published.⁵

For patients undergoing treatment for pulmonary TB, it is recommended that a sputum specimen for an AFB smear and culture should be obtained at least monthly until 2 consecutive specimens are culture-negative.⁵ It is crucial to obtain a sputum specimen for an AFB smear and culture after 2 months of therapy because this result is an important risk predictor of relapse. Drug-susceptibility tests should always be performed on the initial positive culture and should be repeated on M tuberculosis isolates from patients who have positive cultures after 3 months of treatment. All patients undergoing treatment for TB should be seen on a monthly basis and have a clinical evaluation to identify possible adverse effects of the anti-TB medications and to assess adherence.

Following decades of neglect, there is now renewed hope and interest in the development of drugs to treat TB.²⁵ The effort for drug development is in large part being coordinated by the Global Alliance for TB Drug Development,²⁶ a recently established organization that has been building public-private partnerships with the objective of creating a portfolio of new TB drugs and bringing a new TB drug to the market in the next decade. There has been considerable excitement about the potential of a newly discovered novel diarylquinoline that considerably reduces the time necessary to treat TB in mice.²⁷ Further studies are needed to determine if this potential will be met in the treatment of humans with TB.

As cases of TB have decreased in the United States,³ there has been renewed interest and focus on the treatment of latent TB infection as an important TB-control strategy.^{28 - 29} Two broad categories of candidates for latent TB infection testing are persons who are likely to have been recently infected (such as contacts to infectious TB cases) and persons who are at increased risk of progression to TB disease following infection with M tuberculosis because of certain clinical conditions (eg, HIV infection and selected medical conditions; recent immigrants to the United States from high TB-burden countries).⁶ Prior to beginning treatment for latent TB infection, it is essential that active TB be excluded by a chest radiograph and symptom review in all persons suspected of having latent TB infection.

For more than 100 years, the only test to identify latent TB infection was the tuberculin skin test. Diagnostic criteria for what constitutes a positive tuberculin skin test appear in Article ⁶ Limitations of the tuberculin skin test include (1) reader variability; (2) false-positive test results due to cross-reactivity with environmental mycobacteria and with previous BCG vaccination; and (3) false-negative test results due to anergy in immunosuppressed individuals, emphasizing the need for new and better diagnostic tests for latent TB infection.²⁹ In recent years, peripheral blood T-cell–based interferon γ (IFN-γ) assays have been developed and investigated. There are 2 commercially available tests: a whole-blood IFN-γ release assay (QuantiFERON-TB Gold, Cellestis Ltd, Victoria, Australia), which has been recently approved by the Food and Drug Administration; and an enzyme-linked immunospot assay (T SPOT-TB, Oxford Immunotec, Oxford, England), which is approved for use in Europe. The CDC has published guidelines on the use of the first generation QuantiFERON-TB assay, which is no longer available,³⁰ and will be publishing guidelines for use of second generation QuantiFERON-TB Gold, which uses TB-specific antigens, in selected patient populations. These T-cell–based assays offer hope for improved sensitivity and specificity for the diagnosis of infection with M tuberculosis.^{31 - 35} However, prospective studies are needed to determine (1) whether IFN-γ responses are predictive of those who have a high risk of progression to active TB, (2) the utility of such tests in specialized subgroups of patients (including children and HIV-infected persons), and (3) whether treating latent TB infection based on IFN-γ results will reduce the TB burden in low-incidence countries such as the United States.

Response With ≥5-mm Induration

Response With ≥10-mm Induration

Response With ≥15-mm Induration

Source: American Thoracic Society.⁶

*Risk of TB in patients treated with corticosteroids increases with higher dose and longer duration.

†For persons who are otherwise at low risk and are tested at the start of employment, a 15-mm induration response or higher is considered positive.

Isoniazid remains the drug of choice for treatment of latent TB infection (Table 3).^{6 - 7} The effectiveness of isoniazid for treatment of latent TB infection has been reported to range from 25% to 92%.⁶ However, when the analysis was restricted to persons who were compliant with the medication, the protective efficacy was approximately 90%. The preferred duration of treatment with isoniazid for latent TB infection in all patient populations is 9 months because clinical trial data suggest that the maximal benefit is achieved by this period (Table 3).^{6 ,36} Treatment with isoniazid for 6 months is an alternative for HIV-seronegative adults.

The most important adverse effect of isoniazid is hepatitis. The rate of symptomatic isoniazid-related hepatitis has been estimated to be 1 to 3 per 1000 persons.^{37 - 38} However, asymptomatic liver enzyme abnormalities are relatively common.^{39 - 40} The most important cofactor for the development of isoniazid-induced hepatitis is alcohol consumption. All persons taking isoniazid should be educated about the symptoms of hepatitis so that they can be evaluated before hepatitis becomes severe. In an effort to prevent the development of neuropathy, 25 to 50 mg/d of pyridoxine should be given concurrently with isoniazid to persons predisposed to neuropathy (such as patients with diabetes, uremia, malnutrition, and HIV infection), pregnant women, and persons with seizure disorders.

Treatment with rifampin alone for 4 months is an alternative choice for treatment of latent TB infection (Table 3). However, rifampin for treatment of latent TB infection has not been extensively studied. In the only large randomized trial evaluating its use, 10% of the patients taking rifampin alone for 3 months developed TB within 5 years of completing therapy.⁴¹ Rifampin is best used in patients who are presumed to have infection with isoniazid-resistant strains of M tuberculosis. Data regarding toxicity in patients taking rifampin alone for latent TB infection are limited. However, rifampin alone appeared to be well-tolerated and had a very low rate of hepatotoxicity in 3 published studies.^{41 - 43}

For patients being treated for latent TB infection, baseline and monthly laboratory testing of liver enzymes are not routinely recommended by the guidelines from the American Thoracic Society and the CDC.⁶ Baseline and monthly laboratory testing of liver enzymes is recommended for HIV-infected persons; pregnant women and those women who are within 3 months postpartum; persons with a chronic liver disease; and persons who consume alcohol regularly.⁶ Baseline and monthly monitoring of liver enzymes should also be performed for patients with comorbid illnesses who are also taking other medications that can be hepatotoxic. Isoniazid or rifampin should not be given if a symptomatic patient’s serum transaminase level is higher than 3 times the upper limit of normal or if an asymptomatic patient’s serum transaminase level is higher than 5 times the upper limit of normal.^{6 - 7} Recommendations on doses and length of therapy for latent TB infection are summarized in Table 3.

In 2000, guidelines from the American Thoracic Society and the CDC recommended a third option for the treatment of latent TB infection in adults: a 2-month regimen of rifampin and pyrazinamide.⁶ This recommendation was based on studies performed in HIV-infected persons that suggested this regimen was as effective and safe as isoniazid.^{44 - 46} Unfortunately, following the initial recommendation for the wider use of rifampin and pyrazinamide for latent TB infection among all adults,⁶ 48 cases of severe liver injury and/or death were reported to the CDC among patients treated with the regimen of rifampin and pyrazinamide.⁷ The CDC estimated the rate of hospitalization from liver injury related to the regimen of rifampin and pyrazinamide to be 3 per 1000 persons treated for latent TB infection and the rate of death from liver injury to be 0.9 per 1000 persons treated, which is substantially higher than the risk of death reported in the literature for isoniazid (0-0.3 per 1000 persons; median, 0.04 per 1000 persons).⁷ As a result, revised guidelines that rifampin plus pyrazinamide should not be used to treat latent TB infection in either HIV-infected or uninfected persons were published by the American Thoracic Society and the CDC in 2003 and were endorsed by the Infectious Diseases Society of America.⁷

Several additional studies have examined the risk of hepatic toxicity of treatment with rifampin and pyrazinamide for latent TB infection.^{46 - 56} These studies demonstrate an increased rate of hepatotoxicity for patients not infected with HIV and treated with rifampin and pyrazinamide for latent TB infection. Combining results from all of these studies results in a rate of moderate-to-severe liver injury of 7.3%. The reason for the increased rate of hepatotoxicity among those taking this regimen for latent TB infection is not known.

A major limitation of the treatment of latent TB infection is poor completion rates for self-administered therapy.^{57 - 58} Nearly 40 years after isoniazid was introduced into clinical practice for the treatment of latent TB infection, little progress has been made in the identification of new, shorter, and safer regimens for the treatment of latent TB infection.^{58 - 59} Currently, the CDC-funded TB Trials Consortium is performing a randomized, multicenter study to compare a 3-month regimen of isoniazid and rifapentine given once weekly with a 9-month regimen of isoniazid given daily. Results from that study will not be available for several years.

Updated recommendations on the treatment of TB and latent TB infection exist. Prescribing an appropriate treatment regimen for TB and ensuring completion of therapy is best achieved with directly observed therapy, which is essential for curing patients with the disease, minimizing the risk of emergence of drug-resistant disease, and for enhancing TB control. Thus, treatment of TB often requires close collaboration between the public and private sectors. New drugs are needed for the treatment of multidrug-resistant TB and to shorten treatment regimens to less than 6 months for those with drug-susceptible TB. Better diagnostic tests for latent TB infection and shorter, safe, and efficacious treatment regimens are needed to enhance the use of detection and treatment of latent TB infection as a TB-control strategy.