Long-term Sirturo therapy safe, effective against MDR-TB

Issue: May 2016

Data presented at ECCMID 2016 showed that a 24-week or longer regimen of Sirturo was well-tolerated and effective against multidrug-resistant tuberculosis.

Lorenzo Guglielmetti, MD, of the Center of Immunology and Infectious Diseases, Paris, France, and colleagues evaluated 45 patients with MDR-TB who initiated Sirturo (bedaquiline, Janssen Therapeutics) treatment from January 2011 through December 2013. Seventy-six percent of the patients were previously treated for TB. Among them, 37% showed resistance to fluoroquinolones or second-line injectables, and 54% showed resistance to both drug classes. The researchers reported that TB strains were resistant to a median of nine drugs.

Lorenzo Guglielmetti

Seventy-three percent of patients received more than 6 months of bedaquiline. In addition to bedaquiline, the most commonly prescribed drugs included Zyvox (linezolid, Pfizer; 96%), PAS (89%), cycloserine (71%), amikacin (71%), imipenem-amoxicillin/clavulanate (62%), and moxifloxacin (53%).

According to study data, 36 out of 45 patients (80%) achieved favorable treatment outcomes, with no difference between the standard and prolonged bedaquiline groups. However, one patient relapsed after 449 days of treatment.

Five patients experienced QTcF interval values greater than 500 ms after receiving bedaquiline for a median duration of 3 months, which led to three patients discontinuing treatment. None of the patients experienced cardiac adverse events, and no other adverse events attributed to bedaquiline were reported. Moreover, no increased liver toxicity nor QT prolongation were recorded in patients receiving prolonged bedaquiline treatment.

“Long-term bedaquiline treatment was safe and effective in this cohort of patients with advanced resistance patterns and extensive disease,” the researchers concluded. “Prolongation of bedaquiline beyond 24 weeks should be considered in selected MDR-TB cases.”

Preliminary findings published in Clinical Infectious Diseases by the same research group demonstrated that bedaquiline, combined with other drugs, resulted in culture conversion in almost all patients with MDR-TB (97%) after 6 months of treatment.

The researchers performed a retrospective cohort study that included 35 patients with MDR-TB who received at least 1 month of bedaquiline between from January 2010 to July 2013. Nineteen of the patients had extensively drug-resistant TB. Twenty-six of the patients received bedaquiline as part of their initial MDR-TB treatment; the other nine patients had received a median of 85 days of treatment before bedaquiline initiation. All patients received a median of four additional antibiotics.

Among 29 patients who had culture-positive pulmonary TB at bedaquiline initiation, 28 achieved culture conversion after 6 months of treatment. Sputum-smear conversion occurred in 20 of the 29 patients initially smear-positive. The median time to culture conversion was 85 days, and the median time to sputum-smear conversion was 103 days.

In a multivariable analysis, the researchers found that the presence of lung cavities (HR=0.04; 95% CI, 0.01-0.2) and a hepatitis C virus infection (HR=0.21; 95% CI, 0.08-0.54) were associated with slower time to culture conversion. Treatment with any fluoroquinolone for 30 days or more, however, was associated with a faster time to culture conversion (HR=3.28; 95% CI, 1.3-8.27).

“Of interest, bedaquiline was combined with linezolid in 94% of our patients,” the researchers wrote. “The relevant role of linezolid in the treatment of MDR-TB and particularly of fluoroquinolone-resistant strains has been recently highlighted and could partially explain our satisfactory results.”

References:

Guglielmetti L, et al. Abstract 7614. Presented at: European Congress of Clinical Microbiology and Infectious Diseases; April 9-12, 2016; Amsterdam.

Guglielmetti L. Clin Infect Dis. 2014;doi:10.1093/cid/ciu786.

Disclosure: Three researchers report receiving fees, payment or research grants from AstraZeneca or Janssen Pharmaceuticals.