Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid

Background. Rifapentine is a cyclopentyl-substituted rifamycin whose serum half-life is five times that of rifampin. The US Public Health Service Stud y 22 compared a once-weekly regimen of isoniazid and rifapentine with twice weekly isoniazid and rifampin in the continuation phase (the last 4 months ) of treatment for pulmonary tuberculosis in HIV-seropositive and HIV-seron egative patients. This report concerns only the HIV-seropositive part of th e trial, which has ended, The HIV-seronegative part will stop follow-up in 2001. Methods. Adults with culture-positive, drug-susceptible pulmonary tuberculo sis who completed 2 months of four-drug (isoniazid, rifampin, pyrazinamide, ethambutol) treatment (induction phase) were randomly assigned 900 mg ison iazid and 600 mg rifapentine once weekly, or 900 mg isoniazid and 600 mg ri fampin twice weekly. All therapy was directly observed. Statistical analysi s used univariate, Kaplan-Meier, and logistic and proportional hazards regr ession methods. Findings. 71 HIV-seropositive patients were enrolled: 61 completed therapy and were assessed for relapse, Five of 30 patients in the once-weekly isoni azid/rifapentine group relapsed, compared with three of 31 patients in the twice-weekly isoniazid/rifampin group (log rank chi(2) = 0.69, p = 0.41). H owever, four of five relapses in the once-weekly isoniazid/rifapentine grou p had monoresistance to rifamycin, compared with none of three in the rifam pin group (p = 0.05). Patients who relapsed with rifamycin monoresistance w ere younger (median age 29 vs 41 years), had lower baseline CD4 cell counts (median 16 vs 144 mu L), and were more likely to have extrapulmonary invol vement (75% vs 18%, p = 0.03) and concomitant therapy with antifungal agent s (75% vs 9%, p = 0.006). No rifamycin monoresistant relapse has occurred a mong 1004 HIV-seronegative patients enrolled to date. Interpretation. Relapse with rifamycin monoresistant tuberculosis occurred among HIV-seropositive tuberculosis patients treated with a once-weekly iso niazid/rifapentine continuation-phase regimen. Until more effective regimen s have been identified and assessed in clinical trials, HIV-seropositive pe ople with tuberculosis should not be treated with a once-weekly isoniazid/r ifapentine regimen.