Shorter TB Regimen Misses the Mark

— But researchers still see potential for high-dose rifampicin-based treatment strategy

A computer rendering of Mycobacterium tuberculosis

Shorter high-dose rifampicin regimens proved safe for treating pulmonary tuberculosis (TB), but failed to demonstrate noninferiority compared with the standard 6-month regimen, a phase III trial found.

For the primary efficacy outcome, an absolute 6.3% more adults receiving a 4-month regimen that included the highest dose of rifampicin had an unfavorable outcome at 12 to 18 months versus the control group (90% CI 1.1-11.5, P=0.30 for noninferiority), reported Thomas Harrison, MD, of St. George's, University of London, and colleagues.

In the control group, an unfavorable outcome -- a composite that included treatment failure, relapse, or death likely due to TB -- was observed in 7%; with the 4-month regimens, an unfavorable outcome was observed in 13.4% of patients assigned to a 1,800-mg rifampicin dose and 10% of those on a 1,200-mg rifampicin dose, according to the findings in NEJM Evidence.

Current World Health Organization (WHO) guidelines for TB recommend a 6-month regimen that includes rifampicin, a cornerstone of treatment due to its ability to kill Mycobacterium tuberculosis and the mycobacteria thought to be the cause of most relapses. But adherence is often an issue, and high-dose rifampicin regimens have been associated with more rapid lung sterilization, the research team explained.

"In the absence of an effective vaccine, I believe that making TB treatment as accessible as possible and reducing its duration from the current 6 months are our best options for eradicating the disease across the world," said co-author Amina Jindani, MD, also of St. George's, University of London, in a press release.

While a 4-month rifapentine-based regimen has shown noninferiority to the WHO-recommended 6-month treatment, Harrison and colleagues argued that rifampicin may hold certain advantages, including cost, availability, and familiarity given its use across national programs.

Despite missing on the noninferiority endpoint, Jindani said the study "proves that a higher dose of widely available drugs over just 4 months is possible and safe. This is good news for people diagnosed with TB -- it simplifies their treatment meaning they are more likely to complete the full course, giving them the best chance of being cured, whilst slashing the cost which is a huge barrier in developing countries."

Safety outcomes were similar between arms, with grade 3/4 adverse events reported in 4.0% of the control group and 4.4% to 4.5% of patients on the 4-month regimens. Overall, treatment adherence was similar across groups, at 88% to 90%, with the highest rates seen among those with a favorable outcome, at 98%.

Harrison said the 4-month 1,200 mg-dose regimen could benefit those with an earlier form of TB, while individuals with more extensive TB might respond best to a high-dose, 6-month regimen.

From 2017 to 2020, the open-label RIFASHORT (Randomised Trial to Evaluate Toxicity and Efficacy of 1,200 mg and 1,800 mg Rifampicin for Pulmonary Tuberculosis) study enrolled 672 adults with rifampicin-susceptible pulmonary TB across six countries in Africa, Asia, and South America, randomizing them 1:1:1 to three rifampicin-based regimens.

After exclusions for drug resistance, the modified intention-to-treat population included 578 patients who were followed for 18 months from the time of randomization.

All patients received ethambutol and pyrazinamide for 2 months in addition to:

  • Control: standard WHO regimen of daily rifampicin (10 mg/kg) and isoniazid for 6 months
  • Rifampicin study regimen 1: daily rifampicin (1,200 mg) and isoniazid for 4 months
  • Rifampicin study regimen 2: daily rifampicin (1,800 mg) and isoniazid for 4 months

Baseline characteristics were balanced and were reflective of the global TB patient population (median age of about 29 years, roughly three-fourths men), the researchers noted. Sites in Africa contributed the bulk of enrollees, about 70%. Patients with HIV or diabetes were excluded from enrolling.

Prespecified noninferiority criteria was set as a difference of 8 percentage points for an unfavorable outcome in patients who were sputum smear positive at baseline; to control for type I errors, noninferiority was tested for the highest-dose 4-month regimen versus control first, with the 1,200-mg regimen only formally tested if that criteria were met.

Three deaths (1.6%) due to TB as a plausible cause occurred during the treatment phase in the control group, as did four (2.2%) in the rifampicin 1,200-mg group, with an additional death in this group following the treatment period.

For the secondary endpoint of culture conversion, rates were highest early on in the study groups, at 90% to 93% by week 8 versus 86% among controls. By week 12, conversion rates were similar -- 98% across all three arms.

Along with being limited by the exclusion criteria, Harrison and colleagues noted that pharmacokinetic data were not captured. They added that concerns about the higher-dose regimen may have been more likely to prompt treatment changes.

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    Ian Ingram is Managing Editor at MedPage Today and helps cover oncology for the site.


The study was funded by the MRC/Wellcome Trust/DFID Joint Global Health Trials Scheme, and the Aga Khan Foundation.

Harrison, Jindani, and colleagues reported no conflicts of interest.

Primary Source

NEJM Evidence

Source Reference: Jindani A, et al "Four-month high-dose rifampicin regimens for pulmonary tuberculosis" NEJM Evid 2023; DOI: 10.1056/EVIDoa2300054.