Important note: Information in this article was accurate in 2004. The state of the art may have changed since the publication date.
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In the Spring of 2003, the American Thoracic Society (ATS), Infectious Diseases Society of America, and Centers for Disease Control and Prevention (CDC) issued updated guidelines for the treatment of tuberculosis (TB).1 These guidelines are substantially longer and significantly more comprehensive than the prior ATS/CDC guidelines published in 1994.2 The document is a guideline for the treatment of TB disease only and does not include management of latent TB infection (LTBI).
There are some notable differences between the revised guideline and the 1994 treatment statement. The revised guideline strongly emphasizes that 1) the responsibility of successful treatment of TB rests with the provider rather than the patient and 2) case management should be patient-centered, with direct observation of therapy as the strongly preferred method of administration of medicines.
The document has a complete discussion of the drugs currently available to treat TB, including dosing, dose adjustments needed for renal or hepatic dysfunction, toxicities, management of common adverse effects and information about interactions between antituberculars and other drugs. Because rifamycins have the potential for drug-drug interactions with numerous agents, there is special attention to this class of drugs. It also discusses treatment issues in special groups, such as children and pregnant and breast-feeding women. According to the guidelines, treatment completion is now determined by the number of doses delivered, as well as the duration of therapy. Also included is an algorithm on how to manage treatment interruption, a problem that is not uncommon.
Among patients with TB caused by drug-susceptible organisms, those with cavitary pulmonary disease on the initial chest radiograph and/or a sputum specimen that is still culture positive for Mycobacterium tuberculosis at the completion of the initial two-month phase of treatment have been shown to be at increased risk of relapse. In patients with both of these risk factors, the rate of relapse disease is further increased. Accordingly, the guidelines recommend that the continuation phase of therapy be prolonged from four to seven months in patients with both risk factors. Patients having just one of these risks do not need to be treated with an extended continuation phase, but should be monitored closely for signs of a poor response to therapy and have treatment extended if there is not a prompt response to treatment. In order to identify patients at risk for relapse, culture of sputum specimens should be obtained in all patients with pulmonary disease at the completion of the initial two-month phase of therapy.
As a result of clinical trials examining the use of the long-acting rifamycin rifapentine for the treatment of TB, recommendations for its use are now included in the guideline. Because of the drug's extremely long half-life, it can be used once-weekly, making it an attractive option for supervised regimens. Once-weekly dosing of isoniazid and rifapentine is now included as a choice for the continuation phase of treatment in patients who meet the following criteria: 1) HIV-uninfected 2) non-cavitary, pulmonary TB, 3) M. tuberculosis that is drug-susceptible, and 4) sputum specimens are smear negative for acid-fast bacilli at the end of the initial phase of treatment. Patients with advanced TB disease or HIV infection have increased risk treatment failure and relapse when treated with highly intermittent regimens. Once-weekly treatment with rifabutin should never be used in these patients.
Treatment of TB in those with HIV infection is also addressed by the guidelines. Some patients with HIV infection are at risk for emergence of TB caused by organisms with rifamycin resistance when treated with intermittent regimens. Because of reports of disease caused by rifampin-resistant organisms in persons with advanced HIV infection, persons with CD4 counts less than 100 should not be treated with twice-weekly regimens and should receive medications daily or three times weekly. As stated above, no one with HIV infection should receive once-a-week treatment.
This year CDC issued guidelines for the use of QuantiFERONŽ-TB test.3 The QuantiFERONŽ-TB (QFT) test was approved by the Food and Drug Administration in 2001. Like the tuberculin skin test (TST), this test is used to aid in the detection of LTBI. This test measures the production of interferon-gamma and is an in vitro cytokine-based assay to detect cell-mediated immune reactivity to M. tuberculosis. Unlike a TST, this assay requires phlebotomy, can be completed with only a single patient visit, can assess and distinguish between responses to both M. tuberculosis and environmental mycobacteria, and does not boost amnestic immune responses. It appears that interpretation of the whole-blood interferon gamma assay is less subjective than the TST and that it may be less affected than TST by prior BCG vaccination, reactivity to nontuberculous mycobacteria, and reader error.4
The characteristics of the test that make it appealing as a screening tool include the ability to distinguish between M. tuberculosis and other mycobacteria, need for a single patient visit and less interference from BCG vaccination. In its recommendations for QFT, CDC suggests that this test be considered for LTBI screening of persons at increased risk of having or acquiring LTBI, including residents and employees of correctional facilities, injection drug users, recent immigrants, and some health care workers.
There are, however, several significant limitations to the use of this test. For example, it should not be used in persons with symptoms of TB since TB disease is associated with suppressed interferon-gamma responses. It should also not be used in children, pregnant women, those with HIV infection or other clinical conditions that increase the risk of progressing from LTBI to TB disease, or in the context of contact investigations since the appropriate use of the test in these situations and populations has not been defined. It also should not be used within 12 months of the administration of a TST, as the injection of purified protein derivative can affect the results of QFT. These limitations will probably make the use of this tool difficult in some settings where frequent screening takes place, such as correctional facilities. Further data on appropriate use of the test is needed and will be helpful to determine the settings and populations where this test can be best used.
Following an earlier recommendation that two months of rifampin and pyrazinamide (RZ) could be used as an option for the treatment of LTBI 5, cases of severe liver injury were noted among patients who received this regimen. CDC issued cautions to providers and recommended enhanced monitoring for patients receiving RZ. From October 2000 through June 2003, 48 patients with severe liver injury were reported in the U.S. Eleven of these patients died.6, 7, 8
In a report published in August 2003, CDC reported the results of surveillance conducted on patients who received RZ from January 2000 through June 2002 to estimate the risk of severe liver injury associated with this regimen.9 Of the 7,737 patients who received RZ, 204 discontinued treatment because of aspartate aminotransferase serum concentrations that exceeded five times the upper limit of normal, (26.4 per 1,000 treatment initiations, 95% CI 22.8-30.0). RZ use was stopped in 146 more patients due to symptoms of hepatitis (18.9 per 1,000 treatment initiations, 95% CI 17.4-20.4). There were 30 cases of severe liver injury in the cohort, defined as hospitalization or death of the patient. Seven of these patients died, giving estimated rates of hospitalization and death of 3.0 (95% CI 1.8-4.2) and 0.9 (95% CI 0.2-1.6), respectively, per 1,000 treatment initiations. These rates are significantly higher than seen in recent studies examining adverse events associated with isoniazid for the treatment of LTBI, where median hospitalization and death rates have been reported to be 0.15 and 0.04 per 1,000 treated, respectively.
Based on these high rates of adverse effects, hospitalization and death, ATS and CDC have changed the official recommendation for the use of RZ, and now state that this regimen generally should not be offered to patients, including patients with or without HIV infection. Isoniazid should be the first choice for treatment of LTBI. Rifampin alone should be used for patients suspected to be infected with M. tuberculosis resistant to isoniazid.
Protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized by the hepatic enzyme CYP3A4. Because rifamycins induce the activity of this enzyme, there are substantial decreases in serum concentrations of these antiretroviral drugs when they are co-administered with rifamycins. The rifamycins differ in the degree to which CYP34 is induced; rifampin is the most potent followed by rifapentine and then rifabutin. Since PIs and NNRTIs, depending on the agent, can inhibit or induce this same enzyme, it is difficult to predict the drug-drug interactions that will occur when these agents are co-administered. With the addition of new antiretroviral agents or new combinations of antiretroviral agents (such as those used for pharmaco-enhancement) to the therapeutic armamentarium, and limited published studies on the pharmacokinetics of these drug-drug interactions, it is a therapeutic challenge knowing how to optimally administer these medications to patients with both HIV infection and TB.
Despite periodic updates of recommended dose adjustments for concurrent use of anti-TB and antiretroviral medicines,10,11 there is a need to present updated information to providers as new data become available. The CDC now maintains a website www.cdc.gov/nchstp/tb/TB_HIV _Drugs/TOC.htm, where this information will be updated on a continuing basis. This contains text, tables with recommendations of which rifamycins can be used with PIs and NNRTIs and dose adjustments needed for drugs that can be used together.
* Nothing to disclose
1. CDC. Treatment of Tuberculosis, American Thoracic Society, CDC, and Infectious Diseases Society of America. MMWR 2003;52 (No. RR-11), (http://www.cdc.gov/mmwr/PDF/rr/rr5211.pdf).
2. Bass JB Jr, Farer LS, Hopewell PC, O'Brien R, Jacobs RF, Ruben F, Snider DE Jr, Thornton G. Treatment of tuberculosis and tuberculosis infection in adults and children. American Thoracic Society, Centers for Disease Control. Am J Respir Crit Care Med. 1994 May;149(5):1359-74.
3. Mazurek, GH, Villarino, ME. Guidelines to using the QuantiFERONŽ-TB test for diagnosing latent Mycobacterium tuberculosis infection. MMWR 2003;52 (No. RR-2), (http://www.cdc.gov/mmwr/PDF/RR/RR5202.pdf).
4. Mazurek GH, LoBue PA, Daley CL, et al. Comparison of a whole-blood interferon gamma assay with tuberculin skin testing for detecting latent Mycobacterium tuberculosis infection. JAMA 2001; 286:1740-7.
5. American Thoracic Society, CDC. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000 Apr;161(4 Pt 2):S221-47.
6. CDC. Fatal and severe hepatitis associated with rifampin and pyrazinamide for the treatment of latent tuberculosis infection-New York and Georgia, 2000. MMWR 2001;50:289-91.
7. CDC. Update: fatal and severe liver injuries associated with rifampin and pyrazinamide for latent tuberculosis infection, and revisions in American Thoracic Society/CDC recommendations-United States, 2001. MMWR 2001;50:733-5.
8. CDC. Update: fatal and severe liver injuries associated with rifampin and pyrazinamide treatment for latent tuberculosis infection. MMWR 2002;51:998-9.
9. CDC. Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection-United States, 2003.
10. CDC. Preventions and treatment of tuberculosis among patients injected with human immunodeficiency virus: principles and therapy and revised recommendations MMWR 1998;47 (No. RR-20).
11. CDC. Updated guidelines for the use of rifabutin or rifampin for the treatment and prevention of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR 2000;49:185-9.
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