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DENVER -- Most patients with tuberculosis (TB) who received a treatment regimen that included the repurposed leprosy drug clofazimine converted to negative sputum cultures after 12 weeks, but a substantial proportion went on to have unfavorable outcomes, according to an interim analysis of the phase IIc CloFast trial.

After 12 weeks of treatment with a clofazimine/rifapentine-containing regimen, 89% of participants with severe TB tested negative on a sputum culture, which was similar to the 90% of those receiving a standard-of-care regimen (adjusted HR 1.17, 90% CI 0.79-1.73), reported John Metcalfe, MD, PhD, MPH, of the University of California San Francisco, at the Conference on Retroviruses and Opportunistic Infections.

However, at 65 weeks, 41% of patients on the clofazimine regimen developed unfavorable clinical or bacteriologic outcomes versus 29% in the standard-care group.

These findings led to the trial being terminated early, Metcalfe told attendees.

Metcalfe pointed out that 69% of participants had advanced, severe TB confirmed on chest x-ray, and 26% had a 3+ sputum acid-fast bacillus level. "This was not a low- or limited-risk population in any way," he said.

Conventional TB treatment consists of a multidrug regimen that must usually be taken for at least 6 months and has high rates of nonadherence and drug resistance. To address these issues, there has been interest in repurposing clofazimine, which showed promise of being rapidly and highly effective against TB in a , Metcalfe explained.

Metcalfe posited that the mouse model that the CloFast trial drew upon was likely not applicable to more severe TB pathology in human lungs and that the human-equivalent dose of clofazimine may also have been wrong.

During a Q&A session, Nicholas Paton, MD, of the National University of Singapore and investigator in the Truncate-TB trial, noted that "we had a very similar high-dose clofazimine regimen for 2 months and had relatively low rates of unfavorable outcomes in the order of 11-13%. The differences are that we used twice the dose that you used and the study population obviously had milder disease. Before we totally dismiss clofazimine, it would be useful to try and put that data together."

Metcalfe said that another major drawback to the clofazimine regimen was the number of serious adverse events that emerged during the trial. Among participants receiving the clofazimine-based regimen, 45% developed grade 3 or higher adverse events through week 65 versus 16% in the standard-of-care arm. This difference was driven by a change in creatinine clearance, he said, and except for one other trial, that finding had not been previously described.

"We don't know whether this is an interference with the creatinine assay or if it reflects actual transient renal injury," he said. However, relatively few participants treated with clofazimine experienced distress from skin hyperpigmentation, a known side effect of the drug, or QT prolongation.

"Given that its toxicity and efficacy are questionable, this certainly tips the scales against clofazimine and opens the question of what should the future of clofazimine treatment for TB look like," Metcalfe added.

The CloFast trial enrolled a total of 104 patients from Malawi, South Africa, Zimbabwe, India, and Haiti. Of these participants, 58 were randomized to receive rifapentine/isoniazid/pyrazinamide/ethambutol/clofazimine for 12 weeks, and 31 were randomized to conventional treatment with rifampicin/isoniazid/pyrazinamide/ethambutol for 6 months. Fifteen patients were randomized to a third arm of the study, looking at pharmacokinetics to evaluate a clofazimine loading dose, but data from that arm were not included in the interim analysis.

Participants in the study were mostly male (78%), with a median age of 32, and 28% were living with HIV.

The primary outcomes of the study were time to a stable, negative TB liquid culture conversion through week 12 and the proportion of participants who experienced an adverse event of grade 3 or higher through week 65. The hazard ratio for the primary outcome was adjusted for HIV status and severe TB. The key secondary outcome was the proportion of participants with an unfavorable clinical or bacteriologic outcome by week 65.

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