Three months of rifapentine and isoniazid for latent tuberculosis infection.

BACKGROUND: Treatment of latent Mycobacterium tuberculosis infection is an essential component of tuberculosis control and elimination. The current standard regimen of isoniazid for 9 months is efficacious but is limited by toxicity and low rates of treatment completion. METHODS: We conducted an open-label, randomized noninferiority trial comparing 3 months of directly observed once-weekly therapy with rifapentine (900 mg) plus isoniazid (900 mg) (combination-therapy group) with 9 months of self-administered daily isoniazid (300 mg) (isoniazid-only group) in subjects at high risk for tuberculosis. Subjects were enrolled from the United States, Canada, Brazil, and Spain and followed for 33 months. The primary end point was confirmed tuberculosis, and the noninferiority margin was 0.75%. RESULTS: In the modified intention-to-treat analysis, tuberculosis developed in 7 of 3986 subjects in the combination-therapy group (cumulative rate, 0.19%) and in 15 of 3745 subjects in the isoniazid-only group (cumulative rate, 0.43%), for a difference of 0.24 percentage points. Rates of treatment completion were 82.1% in the combination-therapy group and 69.0% in the isoniazid-only group (P<0.001). Rates of permanent drug discontinuation owing to an adverse event were 4.9% in the combination-therapy group and 3.7% in the isoniazid-only group (P=0.009). Rates of investigator-assessed drug-related hepatotoxicity were 0.4% and 2.7%, respectively (P<0.001). CONCLUSIONS: The use of rifapentine plus isoniazid for 3 months was as effective as 9 months of isoniazid alone in preventing tuberculosis and had a higher treatment-completion rate. Long-term safety monitoring will be important. (Funded by the Centers for Disease Control and Prevention; PREVENT TB ClinicalTrials.gov number, NCT00023452.).

T-SPOT.TB responses during treatment of pulmonary tuberculosis.

BACKGROUND: Immune responses to Mycobacterium tuberculosis antigens could serve as surrogate markers of treatment response. METHODS: Using the T-SPOT.TB assay and frozen peripheral blood mononuclear cells, we enumerated ESAT-6- and CFP-10-specific IFN-gamma-producing T cells over time in pulmonary TB patients receiving directly observed treatment. T cell responses (measured as "spot forming cells" or "SFCs") were assessed prior to treatment and at 16 and 24 weeks of treatment. RESULTS: 58 patients were evaluated, of whom 57 were HIV seronegative. Mean (SD) ESAT-6, CFP-10, and summed RD1 specific SFCs declined from 42.7 (72.7), 41.2 (66.4), and 83.8 (105.7) at baseline to 23.3 (39.4, p = 0.01), 23.2 (29.4, p = 0.18), and 46.5 (59.5, p = 0.02) at completion of 24 weeks of treatment, respectively. Only 10% of individuals with a baseline reactive test reverted to negative at treatment week 24. For the group that was culture positive at completion of 8 weeks of treatment compared to the culture negative group, the incidence rate ratio (IRR) of ESAT-6, CFP-10, and summed RD1 specific SFC counts were, respectively, 2.23 (p = 0.048), 1.51 (p = 0.20), and 1.83 (p = 0.047). Patients with cavitary disease had mean ESAT-6 specific SFC counts that were higher than those without cavitary disease (IRR 2.08, p = 0.034). CONCLUSION: IFN-gamma-producing RD1-specific T cells, as measured in the T-SPOT.TB assay, may be directly related to bacterial load in patients undergoing treatment for pulmonary TB. However, high inter-subject variability in quantitative results coupled with failure of reversion to negative of qualitative results in most subjects at treatment completion may limit the utility of this assay as a surrogate marker for treatment efficacy.

Repeated administration of high-dose intermittent rifapentine reduces rifapentine and moxifloxacin plasma concentrations.

Moxifloxacin- and rifapentine-based regimens are under investigation for the treatment of tuberculosis. However, rifapentine may induce enzymes that metabolize moxifloxacin, resulting in decreased moxifloxacin concentrations. In this phase I, two-period, sequential-design study, 13 subjects received 400 mg moxifloxacin daily for 4 days followed by daily moxifloxacin coadministered with 900 mg rifapentine thrice weekly. Pharmacokinetic analyses were performed after the 4th and 19th doses of moxifloxacin and after the 1st and 7th doses of rifapentine. For moxifloxacin, the mean area under the concentration-time curve from 0 to 24 h (AUC(0-24)) decreased by 17.2% (P = 0.0006) when the drug was coadministered with rifapentine, and the mean half-life (t(1/2)) decreased from 11.1 to 8.9 h (P = 0.0033). For rifapentine, the mean AUC(0-48) after seven thrice-weekly doses decreased by 20.3% (P = 0.0035) compared to the AUC(0-48) after the first dose, and the mean t(1/2) decreased from 18.5 to 14.8 h (P = 0.0004). The AUC(0-48) for the 25-desacetyl-rifapentine metabolite diminished 21%. Two days after completing the study drugs, one subject developed a fever and hepatitis, and another developed a flu-like illness with a rash. In conclusion, rifapentine modestly reduced moxifloxacin concentrations. Changes consistent with rifapentine autoinduction of metabolism were seen. Adverse reactions in two subjects may have represented rifamycin hypersensitivity syndrome, although some features were atypical.

Decreased CD4+ lymphocytes and innate immune responses in adults with previous extrapulmonary tuberculosis.

BACKGROUND: CD4+ lymphocytes control Mycobacterium tuberculosis infection through cytokine-mediated macrophage activation. Extrapulmonary tuberculosis is presumably a marker of immunodeficiency, but cytokine responses have not been well studied in such patients. OBJECTIVE: Assess immune defects in persons with previous extrapulmonary tuberculosis. METHODS: In vitro cytokine responses of PBMCs from HIV-seronegative adults with previous extrapulmonary tuberculosis (n = 10) were compared with responses from persons with previous pulmonary tuberculosis (n = 24) and latent M tuberculosis infection (n = 30) in a case-control study. RESULTS: Patients and controls did not differ according to age, sex, race, or monocytes. The median time between tuberculosis diagnosis and study entry was 72 and 122 weeks in extrapulmonary and pulmonary patients, respectively (P = .2). Median CD4+ counts were 660, 814, and 974 lymphocytes/mm3 in extrapulmonary, pulmonary, and latently infected patients, respectively (P = .03). At 48 hours, median unstimulated cytokine levels were uniformly lower in extrapulmonary patients than both sets of controls. These differences persisted after controlling for CD4+ count by linear regression analysis. Despite lower unstimulated levels, median TNF-alpha response was higher in patients with extrapulmonary and pulmonary tuberculosis than latently infected persons after stimulation with PHA 1% (P = .006) and PHA+IL-12 (1 ng/mL; P = .02); IL-10 remained low in patients with extrapulmonary tuberculosis after the same stimuli (P = .04 and .06, respectively). There was no primary immunodeficiency in the IL-12/23-IFN-gamma axis. CONCLUSION: HIV-seronegative adults with previous extrapulmonary tuberculosis had lower CD4+ lymphocytes and unstimulated cytokine production. This suggests a subtle abnormality in innate immune function. CLINICAL IMPLICATIONS: These characteristics could identify persons at risk for severe tuberculosis manifestations.