• Pulmonary Clinical Trials
• Lower Respiratory Infections

Patients with sputum-positive tuberculosis (TB) had similar negative culture rates after 8 weeks of treatment with rifapentine or rifampin, according to results of the TBTC Study 29 (NCT00694629). By solid media analysis, 91.4% of the rifapentine group and 89.1% of the rifampin group had negative cultures. By liquid media, the negative-culture rates were 74.6% with rifapentine and 70.1% with rifampin, as presented by Susan E. Dorman, MD, Johns Hopkins University, Baltimore, Maryland, USA.

Rifamycins, including rifampin, form the key antibacterial component of current regimens for treating pulmonary TB but require continuous use for 6 months or longer.

The rifampin analog rifapentine demonstrated bacterial eradication after 3 months of daily treatment in a mouse model of TB [Rosenthal et al. PLoS Medicine 2007]. In healthy humans, rifapentine doses of as much as 10 mg/kg proved safe when administered once daily for a week [Keung et al. Int J Tuberc Lung Dis 1999].

Dr. Dorman reported findings from a Phase 2 study that compared rifampin 10 mg/kg and rifapentine 10 mg/kg, administered without food 5 times weekly for 8 weeks as a component of combination therapy with isoniazid, pyrazinamide, and ethambutol on behalf of the Tuberculosis Trials Consortium. The primary endpoint was the proportion of patients with negative cultures at the end of intensive-phase treatment. Secondary outcomes included safety, tolerability, and time to culture conversion.

Follow-up visits occurred at 2-week intervals and included sputum culture and assessment of safety and tolerability. The final analysis comprised 381 patients who were enrolled at sites in the United States, South America, Europe, Africa, and Asia. The study population had a median age of 33 years and a median body mass index of 20 kg/m². Between 50% and 55% of patients were enrolled in Africa, and women accounted for about a third of the study population. Ten percent to 12% of patients were HIV-positive, 70% had cavitation on chest x-ray, about 60% had smear grade 3 or 4 (high bacillary load), and the median duration of prior TB treatment was 2 days.

Per-protocol analysis showed that 128 of 179 patients (71.5%) in the rifampin arm and 152 of 202 (75.3%) in the rifapentine arm had negative sputum tests by liquid media at 8 weeks of treatment (p=0.48). By solid media, 152 of 171 patients (88.9%) in the rifampin group and 182 of 198 (91.9%) in the rifapentine group had negative sputum cultures (p=0.42).

Similar results emerged from an intention-to-treat analysis, as 72.2% of rifampin-treated patients and 76.4% of patients in the rifapentine arm had negative cultures by liquid media (p=0.39). Negative-culture rates by solid media were 88.2% and 92.1% in the rifampin and rifapentine groups, respectively (p=0.25).

A post hoc per-protocol analysis by cavitation status demonstrated a significantly higher negative-culture rate by solid media for patients with noncavitary disease who were treated with rifapentine (100% vs 89.3%; p=0.03). Otherwise, the analysis showed no significant differences between the groups.

A multivariate analysis of factors that were associated with negative sputum culture by liquid media confirmed that treatment assignment did not affect outcome. The analysis did identify four independent predictors of response, as defined by negative sputum culture: female sex (OR=2.78; p<0.01), high bacillary load (OR=0.34; p<0.01), fever (OR=0.37; p=0.01), and productive cough (OR=0.12; p<0.01).

Safety and tolerability—including treatment discontinuation—were similar between treatment groups.

“The activity of the rifapentine regimen was not superior to that of the rifampin regimen, based on the endpoint of culture status at the end of intensive-phase treatment,” Dr. Dorman said in conclusion. “There was a trend toward rifapentine superiority in noncavitary pulmonary disease.”

Pharmacokinetic studies showed relatively low exposure to rifapentine. Further studies are needed to determine the optimal dose of rifapentine and to define its role in the treatment of TB.

• © 2011 MD Conference Express