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Sirturo-delamanid combination safe, effective against MDR-TB
Researchers recommend expanding access to a combination regimen of Sirturo and delamanid for multidrug-resistant tuberculosis after preliminary data showed the treatment was safe and associated with high cure rates in patients who previously had “very little treatment success.”
Both Sirturo (bedaquiline, Janssen Therapeutics) — approved by the FDA and European Medicines Agency (EMA) in 2012 — and delamanid — approved by the EMA and Japan’s Pharmaceuticals Medical Devices Agency in 2014 — have shown promise against MDR-TB in randomized controlled trials and routine health care settings, but limited data and “theoretical safety concerns” regarding their effect on QT interval prolongation have prevented WHO from issuing recommendations on combining the drugs, according to Gabriella Ferlazzo, MD, of the Médecins Sans Frontiéres’ (MSF) Southern Africa Medical Unit, and colleagues.
Two clinical trials are currently underway to investigate a combination regimen of bedaquiline-delamanid, with results expected in 3 to 5 years. However, MSF, also known as Doctors Without Borders, has supported its use since 2016 in areas that are highly affected by MDR-TB.
“Waiting 3 to 5 years until the studies are complete and formal results are available could result in excess morbidity and mortality in people with [MDR-TB] while also contributing to ongoing community transmission,” Ferlazzo and colleagues wrote in The Lancet Infectious Diseases. “MSF remains committed not only to providing this therapy, but also to carefully analyzing and reporting the data.”
The researchers recently reported the outcomes of 28 patients with MDR-TB who received 400 mg of bedaquiline once daily for 2 weeks, then 200 mg of bedaquiline three times per week with 100 mg of delamanid twice daily. Their analysis included data from the first 6 months of treatment. All participants underwent an electrocardiogram at baseline, then every 2 weeks during the first 3 months of treatment, and every month thereafter. The researchers assessed for prolonged QT corrected intervals using the Fridericia formula (QtcF). They defined QTcF prolongation as any QTcF interval of 500 ms or more, or an increase of 60 ms or more from baseline.
Among the 28 patients, 11 were coinfected with HIV; 24 had TB isolates resistant to fluoroquinolones; and 14 had extensively drug-resistant TB. Of the 23 patients with confirmed positive cultures at baseline, 74% converted to a negative culture after 6 months of treatment.
Overall, bedaquiline-delamanid appeared to be safe, according to the researchers. Although no patients had more than 500 ms in their QTcF interval, four patients experienced a 60-ms increase or higher from their baseline levels. However, none of these patients permanently discontinued treatment.
Seven patients had one or more serious adverse events, mostly gastrointestinal disorders (25%), nervous system disorders (25%) or psychiatric disorders (12%). Most of these were resolved, according to the researchers. Four serious adverse events were potentially related to both bedaquiline and delamanid. One patient with advanced HIV who was not receiving ART at the time of MDR-TB treatment initiation died, most likely from immune reconstitution inflammatory syndrome.
Despite the small sample size and a lack of more long-term data, Marina Tadolini, MD, research fellow in the department of medical and surgical sciences at the University of Bologna, and colleagues said in a related editorial that the study findings will be useful in guiding patient care.
“The study results further confirm that, under specific conditions (adequate expertise and monitoring capacities, quality-controlled laboratory, support by a team of experts), combined treatment with bedaquiline and delamanid can be justified in patients with few therapeutic options,” they wrote. – by Stephanie Viguers
Disclosures: The authors report no relevant financial disclosures.