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).

References

1. CDC. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. MMWR 1998;47(No. RR-20).
2. 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 1999;49:185-9.
3. 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.
4. El-Sadr W., Perlman D. C., Matts J. P., 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.