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Drug combo for six months successful in treating drug-resistant TB

The new anti-tuberculosis drug combination of bedaquiline, pretomanid and linezolid cures 90% of people with deadly drug-resistant TB if given for six months, researchers report. “This is extremely significant, probably one of the biggest advances in TB therapeutics since the 1970s,” said Dr Richard Chaisson, director of the Centre for Tuberculosis Research at Johns Hopkins University, in Baltimore, who was not involved in the study.

A 90% success rate is typically only seen when TB responds to conventional therapy. When TB is resistant, the success rate is well below 50%. It averages 14% in South Africa, where the new trial was done.

“These results are very compelling, better than I ever expected,” co-author Dr Francesca Conradie is quoted in the report as saying. Patients often showed improvement within a week or two.

Current therapy requires taking up to seven drugs and enduring many side effects for at least 18 months.

“The treatment for drug-resistant TB and extensively drug-resistant TB for the past 20 years has been this horrible concoction of highly-toxic and weakly-effective drugs. Half the people developed hearing loss. Everybody got nausea and vomiting,” Chaisson said. “So, to come along with a treatment that is all oral, only takes 6 months and has a 90% cure rate is nothing short of spectacular.”

The report says getting better drugs to fight drug-resistant TB has been a difficult challenge. Pretomanid is one of only three new TB drugs approved by the US Food and Drug Administration in more than 40 years.

Tuberculosis bacteria grew resistant to conventional therapy partly because not enough was done to deal with cases where the standard combination was not working, Dr Guy Thwaites of the University of Oxford and Dr Payam Nahid of the University of California – San Francisco write in an editorial. More funds need to be invested to ensure TB bacteria don’t develop resistance to this treatment as well, they write.

“We need to guard this regimen like a pearl of great price,” said Conradie, who is deputy director of the clinical HIV research unit at the University of Witwatersrand.

The new open-label trial was done on 109 volunteers at three South African sites; 51% were HIV-positive and 84% had holes in the lung visible on chest x-rays. The patients had been living with TB for as long as 11.75 years, although the median was 12 months. Only 10% had treatment failure or relapsed during the six months after treatment ended.

The most significant side effects were related to linezolid, with 81% of patients having mild to moderate nerve tingling and 48% experiencing low blood counts.

The report says the researchers characterised those problems as “manageable” and said there might be ways to change the dose to alleviate them.

No patients dropped out of the trial because of compliance,” co-author Dr Melvin Spigelman, president of the non-profit TB Alliance, which financed the study, said in the report. The new regimen is expected to cost far less than the other, longer treatments for extensively drug-resistant TB, according to the TB Alliance. “It is critically important that surveillance for the development of resistance be improved around the world and testing be more affordable and available,” Spigelman said. “It would be naive to believe we can abolish resistance, but we can certainly do a much better job than has been done historically.”

Abstract
Background: Patients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes.

Methods: In an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs — bedaquiline, pretomanid, and linezolid — that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated.
Results: A total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid.
Conclusions: The combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed.

Authors
Francesca Conradie, Andreas H Diacon, Nosipho Ngubane, Pauline Howell, Daniel Everitt, Angela M Crook, Carl M Mendel, Erica Egizi, Joanna Moreira, Juliano Timm, Timothy D McHugh, Genevieve H Wills, Anna Bateson, Robert Hunt, Christo Van Niekerk, Mengchun Li, Morounfolu Olugbosi, Melvin Spigelman

[link url="https://www.reuters.com/article/us-health-tb-regimen/new-tb-drug-regimen-controls-resistant-disease-in-9-of-10-cases-study-idUSKBN20S02Y"]Full Reuters Health report[/link]

[link url="https://www.nejm.org/doi/full/10.1056/NEJMoa1901814"]New England Journal of Medicine abstract[/link]

[link url="https://www.nejm.org/doi/full/10.1056/NEJMe2000860"]New England Journal of Medicine comment[/link]

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