MDR-TB: Bedaquiline Has Better Cure Rate, but More Deaths

Veronica Hackethal, MD

August 21, 2014

Bedaquiline (Sirturo, TMC207, Janssen Therapeutics) has a better cure rate than placebo in multidrug-resistant tuberculosis (MDR-TB), according to a randomized controlled trial funded by Janssen Pharmaceuticals and published in the August 22 issue of the New England Journal of Medicine.

"On the basis of the [World Health Organization] definition of cure, nearly twice as many patients in the bedaquiline group as in the placebo group were cured," the authors write.

"The addition of bedaquiline to a preferred background regimen for 24 weeks resulted in faster culture conversion and significantly more culture conversions at 120 weeks," the authors continue. "There were more deaths in the bedaquiline group than in the placebo group."

In 2012, bedaquiline received accelerated approval from the US Food and Drug Administration (FDA) for treating MDR pulmonary TB in patients without other effective treatment options. Bedaquiline is the first anti-TB drug with a new mechanism of action to gain FDA approval in 40 years. As an ATP synthase inhibitor, bedaquiline depletes mycobacteria of their energy stores and can potentially remain active against TB, which often becomes resistant to older, bacteriostatic drugs.

The phase 2b double-blind randomized controlled trial took place in Brazil, India, Latvia, Peru, the Philippines, Russia, South Africa, and Thailand. Researchers enrolled adult participants who had been recently diagnosed with pulmonary MDR-TB sensitive to at least 3 of 5 drugs used in the background regimen received by both groups. They randomly assigned 79 participants to receive 400 mg bedaquiline once daily for 2 weeks, and then 200 mg 3 times weekly for 22 weeks. They also randomly assigned 81 patients to receive placebo. Researchers followed-up participants for 120 weeks and collected sputum samples for analysis at baseline, 8, 24, and 72 weeks.

Participants in the bedaquiline group converted more rapidly to a negative sputum culture compared with placebo (125 vs 83 days, respectively; hazard ratio for bedaquiline, 2.44; 95% confidence interval, 1.57 - 3.80; P < .001). Bedaquiline also increased the rate of conversion to a negative culture at 24 weeks (79% vs 58%; P= .008) and at 120 weeks (62% vs 44%; P = .04).

At 120 weeks, participants who received bedaquiline had cure rates of 58% compared with 32% with placebo (P = .003). Participants in the bedaquiline group also had lower risk of developing additionally drug-resistant TB (2 vs 16 patients, respectively).

Both groups experienced similar adverse events. However, 10 (13%) deaths occurred in the bedaquiline group compared with 2 (2%) with placebo (P = .02), "with no causal pattern evident," the authors mention.

In a linked perspective, Edward Cox, MD, MPH, and Katherine Laessig, MD, both from the Center for Drug Evaluation and Research, FDA, Silver Spring, Maryland, explained the "paradoxical" approval of bedaquiline, even though the results show a higher mortality with bedaquiline compared with placebo.

"[T]he FDA assessment is that the benefits [of bedaquiline] outweigh the risks...for patients with smear-positive, [MDR] pulmonary [TB], for whom there were insufficient treatment options," Dr. Cox and Dr. Laessig write. Moreover, they note that the drug's product label contains a boxed warning about the mortality results, and the warnings and precautions and adverse reactions sections also highlight this risk.

The risks include "the observed mortality imbalance," they add. "The risk associated with inadequate treatment of tuberculosis includes the likely progression of disease, which would be fatal in some cases, and the development of increased antimycobacterial resistance."

The risks and benefits need to be considered in the clinic. "My main concern with this drug is that more of the patients who received bedaquiline died than the patients who received placebo," commented Jessica Ridgway, MD, assistant professor of infectious diseases and global health and associate hospital epidemiologist at the University of Chicago, Illinois, when contacted by Medscape Medical News for an outside opinion. "While most of the deaths occurred after they had stopped taking bedaquiline, and the deaths didn't seem to be caused by the bedaquiline, the increased mortality in the bedaquiline group is still concerning."

When used, bedaquiline should be combined with at least 3 other active anti-TB drugs, Dr. Ridgway explained. Physicians should also keep in mind that bedaquiline was not tested in patients excluded from this study, so results for such patients are unknown. These include patients with previous treatment for MDR-TB, advanced HIV with a CD4 count less than 300 cells/mm3, extrapulmonary TB, certain cardiac abnormalities, alcohol or drug abuse, and pregnant or breast-feeding women. In addition, patients with prolonged QTc intervals should not receive the drug because of the risk for cardiac arrhythmias, Dr. Ridgway continued.

"Based on this study, clinicians should certainly consider adding this drug to the treatment regimen for patients with MDR-TB. Not only would it improve cure rate for patients, but it may decrease the spread of MDR-TB. Since it decreases the time to conversion to negative culture, patients taking bedaquiline may not be contagious for as long as other patients," Dr. Ridgway emphasized, "As we continue to see increases in the proportion of TB that is MDR or [extensively drug-resistant] worldwide, we desperately new medications to treat TB. So having new drugs like bedaquiline is incredibly important."

Several authors report being employees, consulting, personal fees, and/or other support from Johnson & Johnson, Quintiles, and/or Janssen. Dr. Cox, Dr. Laessig, and Dr. Ridgway have disclosed no relevant financial relationships.

N Engl J Med. 2014;371:689-691, 723-732. Abstract


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