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Notice to Readers: Acquired Rifamycin Resistance in Persons with
Advanced HIV Disease Being Treated for Active Tuberculosis with
Intermittent Rifamycin-Based Regimens
Rifamycin drugs (i.e., rifampin, rifabutin, and rifapentine) are essential for short-course chemotherapy in persons
with active tuberculosis (TB). However, adverse drug-drug interactions complicate the concurrent use of rifamycins and
protease inhibitor drugs in persons with active TB who also are infected with human immunodeficiency virus (HIV-TB).
CDC has recommended use of rifabutin in place of rifampin in multidrug regimens for the treatment of active TB in HIV-TB
because rifabutin can be administered with antiretroviral treatment regimens that include protease inhibitors
(1,2). These recommendations included twice-weekly intermittent therapy. Because intermittent rifabutin-based regimens had not
been evaluated in clinical trials of HIV-TB, CDC's TB Trials Consortium (TBTC) initiated TBTC Study 23, a single-arm trial
of twice-weekly rifabutin-based therapy for treatment of HIV-TB.
On March 6, TBTC's Data and Safety Monitoring Board (DSMB) advised CDC to suspend enrollment in Study
23 because of the occurrence of five cases of acquired rifamycin resistance among patients enrolled in the study. Although
the rate of treatment failure or relapse in the study has been low (preliminary life table rate of 4.1% among the 156 patients
with some time at risk), all five patients with failure/relapse had acquired rifamycin resistance. All are responding well to
treatment with alternative regimens.
In the study, common features in patients with acquired rifamycin resistance were very low CD4 cell count (all
<60/mm3) at TB diagnosis and receipt of twice-weekly therapy (in four of five) during the intensive phase (i.e., the first 2 months
of rifamycin-based short-course therapy for TB); all five received twice-weekly therapy in the continuation phase. The
low relapse rate suggests that rifabutin has excellent activity in the treatment of HIV-TB. However, a relation appears to
exist between the frequency of dosing and the risk for acquired resistance. In an earlier study of treatment of HIV-TB using
once-weekly rifapentine plus isoniazid, acquired rifamycin resistance was common
(3). Acquired rifamycin resistance also
occurred in a previous study of HIV-TB treated with twice-weekly rifampin plus isoniazid
(4). It is not known whether the risk for acquired rifamycin resistance is greater with rifabutin than with rifampin. In all of these studies, patients with
acquired rifamycin resistance had very low CD4 cell counts at the time of TB diagnosis. The consistency of these findings suggests
that once- or twice-weekly therapy including isoniazid and a rifamycin increases the risk for acquired rifamycin resistance
among TB patients with advanced HIV disease.
Additional data are needed to clarify these issues. Until data become available, CDC recommends that persons with
HIV-TB and CD4 cell counts <100/mm3 should not be treated with highly intermittent (i.e., once- or twice-weekly)
regimens.
These patients should receive daily therapy during the intensive phase, and daily or three doses a week during
the continuation phase. In this group of patients, CDC recommends directly observed therapy for both daily and
three-doses-a-week regimens. The low relapse rate suggests that current recommendations concerning duration are sufficient (i.e., 6
months minimum, extended to 9 months in patients with delayed response to therapy).
CDC does not advise additional action at this time for patients with advanced HIV disease who have completed
TB therapy with intermittent regimens and are clinically stable. However, clinicians should treat suspected relapse in
such patients with regimens active against rifamycin-resistant TB until results of susceptibility testing are available.
For HIV-TB patients with CD4 cell counts
<100/mm3 who are being treated with twice-weekly rifamycin-based
therapy, CDC recommends more frequent therapy with the same agents (i.e., daily or three times a week).
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;353:1843--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. Clin Infect Dis 1998;26:1148--58.
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