New Anti-Tuberculosis Regimen Cures 2 Months Earlier


Rifapentine-moxifloxacin based anti-tuberculosis regimen shortened the conventional six-month course of treatment to four.


Four months of treatment with a rifapentine-moxifloxacin based anti-tuberculosis regimen produced the same survival rate with absence of mycobacterium tuberculosis at 12 months as the conventional half-year regimen with rifampin-based treatment, in a phase 3 trial evaluating rifapentine based regimens with and without the fluoroquinolone in over 2000 patients in 34 sites around the world.

Susan Dorman, MD, the Medical University of South Carolina, Charleston, and colleagues of the AIDS Clinical Trials Group and the Tuberculosis Trials Consortium conducted the trial comparing 2 rifapentine-based experimental regimens against conventional treatment in patients newly diagnosed with M. tuberculosis not resistant to isoniazid, rifampin, or fluoroquinolones.

The participants were randomly assigned in equal numbers to receive either a conventional regimen consisting of rifampin, isoniazid, pyrazinamide and ethambutol; or with rifampin replaced with either rifapentine or with rifapentine and moxifloxacin.

The investigators chose rifapentine, a cyclopentyl derivative of rifampin, as an alternative to rifampin following preclinical models that suggest that increasing exposure to rifamycins could shorten the time course for treating tuberculosis.

"Rifapentine has activity against M Tuberculosis, and its longer half-life makes the drug an attractive option for increasing the duration of exposure to rifamycins while maintaining the once-daily dosing schedule that facilitates the completion of treatment," Dorman and colleagues explained.

The investigators also noted evidence that moxifloxacin exerts activity against M. tuberculosis, and that its addition to anti-tuberculosis regimens has accelerated sputum-culture conversion to negative status, albeit without yet shortening the requirement for 6 months of treatment.

Rifapentine was administered at a daily dose of 1200mg and moxifloxacin 400mg daily; with other drugs administered at standard doses adjusted for body weight. The medications in each regimen were administered 7 days per week, with the study protocol specifying direct observation of medications being taken at least 5 days per week. As food affects the absorption of rifapentine and rifampin differently, rifapentine was administered within 1 hour after ingesting food, while rifampin was taken on an empty stomach.

Dorman and colleagues reported that 4 months of treatment with the rifapentine with moxifloxacin based regimen (but not without moxifloxacin) was noninferior (within margin of 6.6 percentage points) to 6 months of the conventional rifampin-based treatment.In the microbiologically eligible populations, 15.5% of those on the rifapentine with moxifloxacin based regimen had an unfavorable outcome, compared to 14.6% on the longer rifampin-based regimen. Adverse events of grade 3 or higher occurred in 18.8% of the riapentine with moxifloxacin group, and 19.3% of those receiving the rifampin-based treatment.

The results were welcomed in an accompanying editorial,"Shortening the Short Course of Tuberculosis Treatment", by Valerie Mizrahi, PhD, Institute of Infectious Diseases and Molecular Medicine and the Department of Pathology, Wellcome Center for Infectious Diseases Research in Africa, University of Cape Town, Cape Town, South Africa, and Editor in Chief of The New England Journal of Medicine Eric Rubin, MD, PhD, an infectious disease specialist.

"It was almost as though 6 months represented some strict limit—that is, until now," Mizrahi and Rubin enthused.

That this development has been long awaited is reflected in the years since Mizrahi's previous editorial in the Journal in 2014, "Shortening Treatment for Tuberculosis—Back to Basics," in which she reviewed failure of 3 separate trials to achieve this outcome, and called for a closer look at the characteristics and potential susceptibility of M. tuberculosis.

Although they welcome the prospect of a shortened course of treatment, Mizrahi and Rubin offer some concerns about this regimen, including the need to take rifapentine after meals to maximize absorption. They also suggest that the conventional rifampin-based regimen has an advantage of comprising drugs that are not generally used for other infections.In addition to necessitating rapid drug-susceptibility testing for moxifloxacin, they note, the widespread use of the antibiotic for tuberculosis could promote resistance to fluoroquinolones in other bacteria.

"This trial does, however, establish an important principle: there is no magic 6 months of therapy," Mizrahi and Rubin declare.

"This trial not only proves that we can have a shorter short-course treatment, but also suggests that an even shorter short-course treatment might one day be feasible," they conclude.

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