4-month rifapentine-moxifloxacin regimen on par with 6-month standard care for TB

A shorter treatment course of 4 months with a rifapentine-based regimen containing moxifloxacin proves to be noninferior to a standard 6-month regimen in patients with drug-susceptible tuberculosis (TB), a phase III randomized trial has shown.

“Shortening a regimen by 2 months would make treatment somewhat less cumbersome and probably make it more cost-effective,” stated Drs Eric Rubin and Valerie Mizrahi from Brigham and Women's Hospital in Boston, Massachusetts, US and University of Cape Town, Cape Town, South Africa, respectively, in a linked editorial. [N Engl J Med 2021;384:1764-1765]

In the open-label, multicentre, phase III trial, 2,343 patients with drug-susceptible TB (median age 31 years, 71 percent male) were randomized 1:1:1 to a 4-month regimen containing once-daily rifapentine 1,200 mg, with or without moxifloxacin (400 mg once daily), or a standard 6-month regimen comprising rifampin, isoniazid, pyrazinamide, and ethambutol. [N Engl J Med 2021;384:1705-1718]

The 4-month rifapentine-moxifloxacin regimen was noninferior to the standard 6-month regimen, with similar rates of unfavourable outcome* in the two treatment groups at 12 months (15.5 percent vs 14.6 percent, 95 percent confidence interval [CI], -2.6 to 4.5) in the microbiologically eligible population**.  

Similar finding was seen in the assessable population, which comprised a subset of the microbiologically eligible population who had assessable outcome status (11.6 percent vs 9.6 percent, 95 percent CI, −1.1 to 5.1).

In contrast, rifapentine without moxifloxacin failed to meet the criteria for noninferiority vs the standard regimen in either population (17.7 vs 14.6 percent in the microbiologically eligible population; and 14.2 percent vs 9.6 percent in the assessable population.

Practical considerations

“Both rifapentine and moxifloxacin are widely available and could probably be packaged appropriately for use by national TB programmes,” pointed out Rubin and Mizrahi.

Nonetheless, the researchers raised several issues worth considering in assessing the feasibility of this shorter regimen for national TB programmes.

“First, rapid drug-susceptibility testing to fluoroquinolones and isoniazid should be performed in addition to … susceptibility testing for rifampin,” according to the researchers. “Second, absorption of rifapentine in the gut is improved in the presence of high-fat foods.”

“[While the shorter rifapentine-moxifloxacin regimen may make treatment less cumbersome,] the infrastructure required to ensure adherence would be largely unchanged. The need to take rifapentine after meals to maximize absorption could introduce new issues with adherence,” noted Rubin and Mizrahi.

“Moreover, one of the advantages of the currently used TB drugs is that they are not widely used in other infections,” they added. “In addition to necessitating rapid drug-susceptibility testing for moxifloxacin, widespread use of this antibiotic for the treatment of TB could promote resistance to fluoroquinolones in other bacteria.”

Additional considerations

Grade ≥3 adverse events occurred at similar rates during treatment period in the rifapentine-moxifloxacin and the standard regimen groups (18.8 percent vs 19.3 percent), whereas the rate was slightly lower in the rifapentine group (14.3 percent). Also, there was no evidence of a heightened risk of cardiotoxicity.

While there was a higher incidence of hyperbilirubinaemia among patients treated with rifapentine-containing regimen, the researchers observed no notable difference in the incidence of elevated serum aminotransferase levels among the three treatment groups.

“Nevertheless, careful monitoring for hepatotoxicity should be performed during the course of the 4-month rifapentine-based regimens, given the theoretical increase in the risk of hepatotoxicity with increased exposure to a rifamycin,” they suggested.

*if a participant had Mycobacterium (M.) tuberculosis-positive cultures from two sputum specimens obtained at or after week 17 without an intervening negative culture, died or was withdrawn from the trial or lost to follow-up during the treatment period, had an M. tuberculosis–positive culture when last seen, died from tuberculosis during the post-treatment follow-up, or received additional treatment for TB

**a culture positive for that was not resistant to isoniazid, rifampin, or fluoroquinolones