A new drug combination containing rifapentine and moxifloxacin has finally broken the 6-month treatment barrier for drug-susceptible pulmonary tuberculosis, requiring only 4 months to produce a disease-free state at 1 year in most patients. The findings were published online May 6 in The New England Journal of Medicine.
“We had started to believe that there was some magic about the 6-month duration of treatment, and this trial proves that’s not the case,” said Payam Nahid, MD, MPH, pulmonologist and professor of medicine at the University of California, San Francisco, and co–first author of the study. In an interview with Medscape Medical News, he noted that results were similar across all trial subpopulations analyzed. “Every way we looked at the performance of the regimen compared to the 6-month regimen, it was efficacious and comparable in safety and tolerability,” he said.
The reduction in treatment duration is important, said Nahid, because cutting the time by a third means patients can return more quickly to their normal lives. “The ability to cure this transmissible airborne disease sooner with a 4-month regimen really brings social benefits as well,” he said. He noted that tuberculosis disproportionately affects regions where resources are limited and where there are high poverty rates.
The results also show faster time to culture conversion with the rifapentine-moxifloxacin combination, which could translate into less transmission of tuberculosis to others, said Amyn Malik, MPH, PhD, an infectious disease epidemiologist at the Yale Institute for Global Health, who was not involved in the work. The shorter duration of the regimen can mean reduced cost and easier adherence for patients, he added in an interview with Medsape Medical News, although further studies are needed to pin down the cost savings.
Rifapentine is derived from rifampin but has a longer half-life, which supports taking only one dose a day. In a previous trial, adding moxifloxacin to the tuberculosis treatment regimen did not decrease treatment duration to less than 6 months. However, animal studies suggested that the rifapentine-moxifloxacin combination might clear disease in a shorter time than either separately. Phase 2 clinical trial results with the combination showed no safety signals.
In this open-label, phase 3, multinational trial, Nahid and colleagues pitted 4-month regimens containing 1200 mg of rifapentine taken once daily with or without 400 mg of moxifloxacin taken daily against a standard 6-month regimen of rifampin, isoniazid, pyrazinamide, and ethambutol. For both 4-month treatments, rifapentine replaced rifampin, and for one of them, moxifloxacin also replaced ethambutol.
The 2516 participants were aged 12 years and older, and all had been newly diagnosed with drug-susceptible tuberculosis. The primary outcome was freedom from tuberculosis at 12 months after starting the study, which was defined as a favorable status. Ongoing positive sputum cultures, death, withdrawal from the trial, and loss to follow-up were defined as unfavorable. For the 4-month regimen to be considered equally as effective as the 6-month version, the unfavorable outcome rate had to come within 6.6 percentage points of the rate with standard care.
Regardless of whether the researchers analyzed data for a broad patient group or for selected subpopulations, the pattern of results was the same: the rate of unfavorable outcomes never differed by 6.6 percentage points or more between rifapentine-moxifloxacin and standard care.
The differences varied from 0.4 percentage points in the all-comers intention-to-treat population to 3.1 percentage points in the most constrained subpopulation, consisting only of patients who completed at least 95% of the treatment doses. Nahid noted that the 4-month regimen was even successful in patients with relatively severe disease.
The pattern did not hold up for rifapentine without moxifloxacin, however. Unfavorable outcomes with this 4-month regimen almost always reached or exceeded the difference threshold, suggesting that it does not work as well as the 6-month standard.
Safety did not differ between the two comparable regimens. In the rifapentine-moxifloxacin group, 18.8% experienced adverse events of grade 3 or higher, compared with 19.3% of those who received the 6-month standard treatment.
For the combination to gain a foothold where it would be most helpful, a formal economic analysis may be needed, said Malik. He noted that rifapentine is more expensive than rifampin, which could lead to concerns about the cost of treatment. However, some studies suggest that reducing the number of patient visits, as would occur if the treatment were curtailed by 2 months, could offset the drug cost, “because the health system cost is usually larger,” he said.
Nahid said that the World Health Organization convened its guidelines development group last week to discuss the trial findings and to consider this 4-month regimen for the treatment of drug-susceptible pulmonary tuberculosis in adolescents and adults.
While he and his colleagues await this decision, Nahid said the results bring some optimism to researchers in the field by shifting the minimum duration from 6 to 4 months. “It’s been a 15-year journey for me,” he said, “and I am delighted to have this outcome, delighted for the thousands of patients who participated and their families and just broadly for the tuberculosis therapeutic field.”
N Engl J Med. Published online May 6, 2021. Abstract