Bedaquiline-pretomanid-linezolid combo tackles highly drug-resistant TB

The combined regimen of bedaquiline, pretomanid, and linezolid (BPaL) may help treat highly drug-resistant tuberculosis (TB), even with lower doses or shorter treatment duration of linezolid, according to results of the phase III ZeNix trial presented at IAS 2021.

“The results of the ZeNix trial support the observed high efficacy of the BPaL regimen as seen in the Nix trial. There appears to be a lower [number] of adverse events of note with the preservation of a high rate of efficacy of around 90 percent,” said principal investigator Dr Francesca Conradie from the University of Witwatersrand, Johannesburg, South Africa, during a press briefing. [https://www.youtube.com/watch?v=RQNec5dY6os, accessed 6 August 2021]

The trial, led by the non-profit TB drug developer TB Alliance, was conducted in 11 sites in Georgia, Moldova, Russia, and South Africa. Study participants were 181 patients with highly drug-resistant TB, 20 percent (n=36) of whom were also HIV positive. They received bedaquiline (200 mg/day for 8 weeks followed by 100 mg/day for 18 weeks) plus pretomanid (200 mg/day) for 6 months and were randomized to different doses of linezolid (1200 mg/day for 6 months [1200L6M], 1200 mg/day for 2 months [1200L2M], 600 mg/day for 6 months [600L6M], or 600 mg/day for 2 months [600L2M]).

Six months after treatment end, treatment success was high in all four groups, specifically 93 percent with linezolid 1200L6M, 89 percent with 1200L2M, 91 percent with 600L6M, and 84 percent with 600L2M. [IAS 2021, abstract OALB01LB02]

Peripheral neuropathy rates were higher among patients who received linezolid 1200L6M (38 percent) compared with those who received linezolid 1200L2M (24 percent), 600L6M (24 percent), or 600L2M (13 percent).

Similarly, myelosuppression rates were also higher with linezolid 1200L6M (29 percent), compared with the 1200L2M, 600L6M, and 600L2M doses (15, 13, and 16 percent, respectively). Anaemia, the most common manifestation of myelosuppression, occurred in 22, 17, 2, and 7 percent, respectively. Four patients in the linezolid 1200L6M group experienced reversible optic neuropathy. 

Linezolid dose modifications (reductions, interruptions, or discontinuations) were more common in the 1200L6M group compared with the 1200L2M, 600L6M, and 600L2M groups (51, 28, 13, and 13 percent, respectively).

“The ZeNix trial confirms the high relapse-free cure rate for the BPaL regimen in highly resistant TB,” said Conradie and co-authors. “The results … are very reassuring. With a reduction in the dose and/or duration of linezolid, we can still offer patients a high chance of cure in only 6 months,” said Conradie.

“My personal opinion is that 600L6M is most likely to be the best strategy for the treatment of this highly-resistant TB population,” she said.

The outcomes did not vary in patients with HIV. Patients who are successfully treated with antiretroviral therapy (ART) are likely to succeed on the ZeNix regimen, though contraindications should be considered, she added.

“Our most commonly used ART regimen of dolutegravir, tenofovir, and lamivudine or emtricitabine can be co-prescribed and with this there are no potential interactions,” she said.

“Until recently, patients with highly drug-resistant TB – among the most difficult infections to identify and treat – had to suffer through a combination of as many as eight antibiotics, some involving daily injections, for 18 months or longer,” said Dr Mel Spigelman, President and CEO of TB Alliance. [https://www.tballiance.org.za/news/zenix-press-release-english, accessed 6 August 2021]

“We now have evidence that the BPaL regimen can be optimized to make it even easier to use,” he said.

“This month, we will mark 100 years since the BCG vaccine for TB was first administered. This vaccine has saved many lives, but unfortunately, it has very limited effectiveness and it is still the only TB vaccine we have,” commented Professor Hendrik Streeck, director of the Institute of Virology and Institute for HIV Research, Bonn, Germany, and IAS 2021 local co-chair.

“This anniversary is a reminder of the urgent need for improved prevention and treatment options, including for highly drug-resistant TB,” he said.