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Acquired Rifamycin Resistance in Persons with Advanced HIV Disease

by Janice Boutotte, MS, RN, CS

Medication regimens that are used to treat persons with active tuberculosis (TB) disease contain multiple drugs. These medications must be taken as directed to minimize the risk of drug resistance and must continue for a sufficient length of time to ensure cure. The inclusion of a rifamycin drug (eg, rifampin, rifabutin, or rifapentine) is essential for short-course (6 to 9 months) chemotherapy.1

The rifamycins interact with several drugs used to treat HIV disease, including protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTI). These drug interactions primarily result from changes in the metabolism of the antiretroviral agents, markedly decreasing their blood concentrations. Conversely, some of the PIs increase the blood concentration of the rifamycins, leading to rifamycin toxicity. To address these problems, the Centers for Disease Control and Prevention (CDC) recommends that rifabutin be used in place of rifampin to treat HIV-infected persons receiving PIs or NNRTIs, using a reduced dose of rifabutin. Rifabutin has less interaction with the PIs and NNRTIs and is less affected by them than is rifampin.2,3 In addition, only a few PIs (ie, indinavir) and NNRTIs are recommended.2 Because new PIs and NNRTIs are frequently appearing on the market, consult the CDC website for the most up-to-date recommendations regarding interactions with PIs and NNRTIs.4

The treatment regimen for TB disease usually lasts 6 months and includes 2 months of four drugs-isoniazid, rifampin, pyrazinamide, and ethambutol (the initiation phase)-followed by four months of isoniazid and rifampin (the continuation phase).1 The CDC recommends 2 to 4 weeks of daily therapy; the remainder of therapy may be taken on either a daily basis, or intermittently, two to three times a week. All persons on intermittent therapy should have their treatment directly observed by a healthcare worker.

Several recent clinical trials to evaluate the efficacy of intermittent rifamycin-based regimens for treatment of TB patients co-infected with HIV have resulted in the occurrence of acquired rifamycin resistance of Mycobacterium tuberculosis among study patients.5,6,7 The trials included regimens of twice-weekly rifabutin5; once-weekly rifapentine plus isoniazid6; and twice-weekly rifampin plus isoniazid.7 These arms of the studies were discontinued when several cases of rifamycin resistance developed.

In the studies, a relationship appeared to exist between the frequency of dosing in patients with severe immunosuppression and the risk for acquired drug resistance. It is not known whether the risk for acquired rifamycin resistance is greater with rifabutin than with rifampin. In all these studies, patients with acquired rifamycin resistance had very low CD4 cell counts at the time of their TB diagnosis. The consistency of these findings suggests that once- or twice-weekly therapy including isoniazid and a rifamycin increases the risk for acquiring rifamycin resistance among TB patients with advanced HIV disease.5

Because of these adverse events, the CDC recommends that persons with HIV-TB co-infection whose CD4 cell counts are <100/mm3 or unknown should not be treated with once- or twice-weekly intermittent regimens until more data become available.5 These patients should receive daily therapy during the initiation phase and daily doses or three doses a week during the continuation phase. The CDC also recommends directly observed therapy for both daily and thrice-weekly treatment in TB/HIV patients.5

Janice Boutotte, MS, RN, CS is Director of Patient Management Services, Department of Public Health, Division of Tuberculosis Prevention and Control. She is also currently a doctoral candidate at the University of Massachusetts, Lowell, in the Nursing Health Promotion Program. 

References

     1.   American Thoracic Society. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care. 1994;149:.

     2.   Centers for Disease Control. 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(9):.

     3.   Centers for Disease Control. Prevention and treatment of tuberculosis among patients with human immunodeficiency virus: principles of therapy and revised recommendations. MMWR. 1998;47(No. RR-20).

     4.   Centers for Disease Control, NCHSTP, Division of TB Elimination website: <http://www.cdc.gov/nchstp/tb/>

     5.   Centers for Disease Control. Notice to Readers: Acquired rifamycin resistance in persons with advanced HIV disease being treated for active tuberculosis with intermittent rifamycin-based regimens. MMWR. 2002;51(10):.

     6.   Vernon A, Burman W, Benator D, Khan A, Bozeman L. Tuberculosis Trials Consortium. Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid. Lancet. 1999;353:.

     7.   El-Sadr W, Perlman DC, Matts JP, et al. Evaluation of an intensive intermittent-induction regimen and duration of short-course treatment for human immunodeficiency virus-related pulmonary tuberculosis. Clinical Infectious Diseases. 1998;26:.  

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