Clinical Pearls & Morning Reports
Published May 5, 2021
Dorman et al. conducted a phase 3 trial that compared two 4-month rifapentine-based regimens with a standard 6-month regimen (control). The control regimen involved 8 weeks of once-daily rifampin, isoniazid, pyrazinamide, and ethambutol followed by 18 weeks of once-daily rifampin and isoniazid. The rifapentine regimen involved 8 weeks of once-daily rifapentine, isoniazid, pyrazinamide, and ethambutol followed by 9 weeks of once-daily rifapentine and isoniazid. The rifapentine–moxifloxacin regimen involved 8 weeks of once-daily rifapentine, isoniazid, pyrazinamide, and moxifloxacin followed by 9 weeks of once-daily rifapentine, isoniazid, and moxifloxacin. Read the NEJM Original Article here.
Q: What was the rationale for replacing rifampin with rifapentine in the trial by Dorman et al.?
A: Rifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis. Rifapentine is a cyclopentyl derivative of rifampin, the most widely used rifamycin worldwide. Rifapentine has activity against Mycobacterium tuberculosis, and its longer half-life makes the drug an attractive option for increasing the duration of exposure to rifamycin while maintaining the once-daily dosing schedule that facilitates the completion of treatment.
Q: Why was moxifloxacin assessed in combination with rifapentine in the trial by Dorman et al.?
A: Moxifloxacin is a fluoroquinolone with activity against M. tuberculosis. The addition of moxifloxacin to other first-line antibiotics against tuberculosis, including rifampin, accelerates sputum-culture conversion to negative status early in the course of treatment but is insufficient to shorten therapy to 4 months. Combination treatment that includes both rifapentine and moxifloxacin was shown to be active in the murine model of tuberculosis and provided a stable cure after 3 months of treatment.
A: In this phase 3 trial, the efficacy of the 4-month regimen containing rifapentine and moxifloxacin was noninferior to that of the standard 6-month regimen. The efficacy results for the rifapentine–moxifloxacin regimen were consistent across analysis populations in sensitivity and prespecified subgroup analyses. The efficacy of the 4-month regimen containing rifapentine without moxifloxacin did not meet the criteria for noninferiority. Note that a total of 8% of the trial participants were coinfected with HIV, a fact that limits the power to compare regimens in this trial population.
A: The incidence of grade 3 or higher adverse events during the on-treatment period was similar in the rifapentine–moxifloxacin group and the control group and was slightly lower in the rifapentine group. The percentages of participants with grade 3 or higher alanine aminotransferase or aspartate aminotransferase levels were similar across the treatment regimens. A grade 3 or higher serum total bilirubin level was reported in a higher percentage of participants in the rifapentine-based regimen groups than in the control group, although 25 adverse events that met the Hy’s law criteria for drug-induced liver injury were distributed equally across the treatment groups. Rifamycins can increase the serum bilirubin level through dose-dependent interference with bilirubin uptake that is typically subclinical and not associated with hepatocellular injury. Nevertheless, careful monitoring for hepatotoxicity should be performed during the course of the 4-month rifapentine-based regimens.