From Pages to Practice
Every year, at least 10 million people worldwide are diagnosed with tuberculosis and an estimated 1.5 million people die from the disease. Currently, the standard regimen requires at least 6 months of treatment with rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE).
Rifamycins are a backbone of antituberculosis treatment. Phase 2 clinical trials have demonstrated an association between exposure to rifamycins and reduction in bacillary burden. Rifapentine, in particular, has a longer half-life than rifampin and activity against Mycobacterium tuberculosis. Moxifloxacin is a fluoroquinolone with activity against M. tuberculosis.
In a phase 3 trial, investigators examined the efficacy of a shorter treatment regimen with once-daily rifapentine, with or without moxifloxacin, in patients with drug-susceptible pulmonary tuberculosis. In one 4-month regimen, rifampin was replaced with rifapentine, and in another, rifampin was replaced with rifapentine and ethambutol with moxifloxacin. The primary outcome was tuberculosis-free survival at 1 year. The standard 6-month regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol was the control.
Rifapentine with moxifloxacin was noninferior to the standard regimen but rifapentine without moxifloxacin was not noninferior. The authors concluded that the efficacy of a 4-month rifapentine-based regimen with moxifloxacin was noninferior to the standard 6-month regimen in treating tuberculosis.
This trial provides evidence that shorter-course therapy might be possible for patients with pulmonary tuberculosis. However, the limited availability and high cost of rifapentine in some parts of the world will hinder its use.
The following NEJM Journal Watch summary provides more details of the study.
Richard T. Ellison III, MD, reviewing Dorman SE et al. N Engl J Med 2021 May 6
Tuberculosis care has been hindered by the required minimum 6-month course of antimicrobial therapy. Now, researchers have conducted a phase 3 noninferiority trial evaluating 6 months of rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE; standard therapy) compared with either of two 4-month regimens (each with 1200-mg rifapentine daily [replacing rifampin]; one regimen with and one without 400-mg moxifloxacin daily [replacing ethambutol]) with a primary efficacy outcome of tuberculosis-free survival at 12 months. Investigators randomized 2516 patients in 13 countries with pulmonary tuberculosis; 2343 participants had microbiologic confirmation of tuberculosis (including 194 with concurrent HIV infection and 1703 with cavitation) and 2234 were fully assessable. Outcomes were defined as favorable (e.g., tuberculosis-free survival at 12 months), unfavorable (e.g., positive sputum cultures at ≥17 weeks), or not assessable.
For the microbiologically confirmed population, unfavorable outcomes were seen in 14.6% (RIPE), 15.5% (rifapentine-moxifloxacin), and 17.7% (rifapentine); for the fully assessable population, unfavorable outcomes were seen in 9.6%, 11.6%, and 14.2%. The 4-month rifapentine-moxifloxacin regimen — but not the rifapentine regimen — met predefined noninferiority criteria. Further, rifapentine-moxifloxacin met the noninferiority criteria for all predefined subgroup analyses. In addition, time to culture negativity was shorter in both rifapentine groups than the standard therapy group. Adverse events did not differ significantly among the three groups (although hyperbilirubinemia was more common in both rifapentine groups).
Comment: As the authors note, study limitations included nonblinded analysis and the concern that the number of participants was too small to assess efficacy in HIV-infected patients or risk for hepatotoxicity. In addition, the high cost and limited availability of rifapentine will likely constrain the use of this regimen in the developing world. Still, these findings offer hope for a new era of shorter-course therapy for pulmonary tuberculosis (and probably also extrapulmonary tuberculosis).