Acquired Rifamycin Resistance with Twice-Weekly Treatment of HIV-related Tuberculosis

Abstract

Rationale: Rifabutin was recommended in place of rifampin during treatment of HIV-related tuberculosis (TB) to facilitate concomitant potent antiretroviral therapy, but this approach has not been evaluated in a prospective study. Objective: To evaluate the activity of intermittent rifabutin-based therapy. Methods: Patients with culture-confirmed TB were treated under direct supervision with 2 mo of rifabutin, isoniazid, pyrazinamide, and ethambutol (given daily, thrice-weekly, or twice-weekly per the local tuberculosis control program), followed by 4 mo of twiceweekly rifabutin plus isoniazid. Measurements: Culture-positive treatment failure or relapse. Main Results: A total of 169 eligible patients were enrolled. Most had advanced HIV disease; the median CD4 cell count and HIV-RNA level were 90 cells/mm 3 (interquartile range, 35-175) and 5.3 log 10 copies/ml (interquartile range, 4.8-5.7), respectively. Nine (5.3%) patients had culture-positive treatment failure (n ϭ 3) or relapse (n ϭ 6). Eight of these nine (89%) cases had isolates with acquired rifamycin resistance. Treatment failure or relapse was associated with baseline CD4 lymphocyte count, being 12.3% (9/73; 95% confidence interval, 6.5-22.0%) among patients with CD4 Ͻ 100 cells/mm 3 versus 0% (0/65; 95% confidence interval, 0.0-4.5%) among those with higher CD4 lymphocyte counts (p Ͻ 0.01). One hundred thirty-seven (81%) patients received antiretroviral therapy during TB treatment. Adverse events were common, but only two patients (1%) permanently discontinued study drugs. Conclusions: Intermittent rifabutin-based therapy for HIV-related TB was well tolerated, but there was a high risk of treatment failure or relapse with acquired rifamycin resistance among patients with low CD4 lymphocyte counts.

Treatment Outcomes of Patients with HIV and Tuberculosis

“…Patients who received 6 months of a rifamycin-based tuberculosis regimen were four times more likely to relapse than those treated longer than 6 months, and patients who received intermittent dosing were four times more likely to relapse than those who had daily dosing (Table 4). Although the association of relapse with intermittent therapy is in line with recent publications (20,28), the importance of the duration of treatment in our study is not. A recent metaanalysis of prospective clinical trials reported no significant difference in risk of recurrence between HIV-infected patients who received 5 to 6 months of rifampin-based therapy and those who received 7 months or longer (29).…”

“…Other variables predictive of relapse in prior publications (2,(17)(18)(19), including culture status at 2 months, cavitation on chest radiography, having bilateral pulmonary involvement, and being a nonHispanic white person, did not predict relapse in our population (all p Ͼ 0.20). Intermittent rifabutin-based therapy has also been associated with increased risk of relapse (20); however, rifabutin was not prescribed in the treatment of any of our cases whose tuberculosis relapsed. The finding that HIV serostatus independently predicted relapse was particularly notable given that HIV-infected patients were treated on average for a significantly longer duration than HIV-uninfected/unknown patients (10.2 mo vs. 8.4 mo; p Ͻ 0.001) ( Table 2).…”

Causes of Death in HIV-infected Persons Who Have Tuberculosis, Thailand

“…Previous epidemiologic studies in Thailand and other countries have demonstrated marked improvement in duration of survival among HIV-infected TB patients treated with ART during TB treatment (2,7,16,(36)(37)(38). Our study confi rms this fi nding and suggests that ART use most likely would dramatically reduce both early and late deaths.…”

Community-Based Rapid Oral Human Immunodeficiency Virus Testing for Tuberculosis Patients in Lima, Peru

“…2,3 Tuberculosis is currently the leading cause of death among HIV-positive patients worldwide, 1 with excess morbidity and mortality among co-infected individuals compared with HIV-negative TB cases and HIV-positive persons without active TB. [4][5][6][7][8][9] Among co-infected persons, early HIV diagnosis is critical not only to ensure timely initiation of highly active antiretroviral therapy (HAART), but also to guide decisions about TB treatment regimens [10][11][12][13][14] and to prevent further spread of infection. If one considers that the largest proportion of TB-related mortality occurs within the first two months of treatment, delays in HAART initiation can lead to worsening of illness and death.…”