High-dose rifapentine with moxifloxacin for pulmonary tuberculosis

Abstract

Background: Tuberculosis regimens that are shorter and simpler than the current 6-month daily regimen are needed.

Methods: We randomly assigned patients with newly diagnosed, smear-positive, drug-sensitive tuberculosis to one of three regimens: a control regimen that included 2 months of ethambutol, isoniazid, rifampicin, and pyrazinamide administered daily followed by 4 months of daily isoniazid and rifampicin; a 4-month regimen in which the isoniazid in the control regimen was replaced by moxifloxacin administered daily for 2 months followed by moxifloxacin and 900 mg of rifapentine administered twice weekly for 2 months; or a 6-month regimen in which isoniazid was replaced by daily moxifloxacin for 2 months followed by one weekly dose of both moxifloxacin and 1200 mg of rifapentine for 4 months. Sputum specimens were examined on microscopy and after culture at regular intervals. The primary end point was a composite treatment failure and relapse, with noninferiority based on a margin of 6 percentage points and 90% confidence intervals.

Results: We enrolled a total of 827 patients from South Africa, Zimbabwe, Botswana, and Zambia; 28% of patients were coinfected with the human immunodefiency virus. In the per-protocol analysis, the proportion of patients with an unfavorable response was 4.9% in the control group, 3.2% in the 6-month group (adjusted difference from control, -1.8 percentage points; 90% confidence interval [CI], -6.1 to 2.4), and 18.2% in the 4-month group (adjusted difference from control, 13.6 percentage points; 90% CI, 8.1 to 19.1). In the modified intention-to-treat analysis these proportions were 14.4% in the control group, 13.7% in the 6-month group (adjusted difference from control, 0.4 percentage points; 90% CI, -4.7 to 5.6), and 26.9% in the 4-month group (adjusted difference from control, 13.1 percentage points; 90% CI, 6.8 to 19.4).

Conclusions: The 6-month regimen that included weekly administration of high-dose rifapentine and moxifloxacin was as effective as the control regimen. The 4-month regimen was not noninferior to the control regimen. (Funded by the European and Developing Countries Clinical Trials Partnership and the Wellcome Trust; RIFAQUIN Current Controlled Trials number, ISRCTN44153044.).

Figure 1. Screening, Randomization, and Analysis of the Study Populations

Among the patients who did not undergo randomization, there were 17 patients who did not do so for other reasons: 4 patients had a history of seizures, 4 did not return in order to undergo randomization, 3 weighed less than 35 kg, 1 had extra-pulmonary tuberculosis, 1 had no firm address, 1 was younger than 18 years of age, 1 was receiving antiretroviral therapy, and 1 had tachycardia. In addition, there was 1 patient in whom attempts to draw blood were unsuccessful. MIRU–VNTRS denotes mycobacterial interspersed repetitive unit–variable-number tandem repeats, and TB tuberculosis.

Figure 2. Differences from the Control Regimen in Unfavorable Outcome Rates (90% Confidence Intervals)

The dashed line represents the 6 percentage-point margin of noninferiority for the modified intention-to-treat population and the per-protocol population as compared with the control.

Figure 3. Kaplan–Meier Failure Estimates of the Time to a Favorable Outcome in the Per-Protocol Population

The inset shows the same data on an enlarged y axis.